A Study To Evaluate The Abuse Potential Of Single Oral Doses Of Dimebon (Latrepirdine) In Healthy Recreational Polydrug Users

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00975481
• Collaborator: Medivation, Inc. (Industry)
• Enrollment: 36
• Arms: 6
• Duration (Months): 4

Study Details

Study Description

Brief Summary

Dimebon will not exhibit abuse potential when compared to placebo or a positive control (alprazolam).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease; Huntington's Disease	Drug: dimebon; Drug: dimebon; Drug: dimebon; Drug: placebo; Drug: alprazolam; Drug: alprazolam	Phase 1

Detailed Description

The main purpose for this study is to determine whether dimebon exhibits abuse potential.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Official Title: A Randomized, Double-Blind, Placebo- And Active-Controlled Single-Dose, Crossover Study To Evaluate The Abuse Potential Of Single Doses Of Dimebon (Latrepirdine) In Healthy Recreational Polydrug Users
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: dimebon 20 mg	Drug: dimebon; Oral tablet; 20 mg dimebon, single dose
Experimental: dimebon 40 mg	Drug: dimebon; Oral tablet; 40 mg dimebon, single dose
Experimental: dimebon 60 mg	Drug: dimebon; Oral tablet; 60 mg dimebon, single dose
Placebo Comparator: placebo	Drug: placebo; Oral tablet or capsule; placebo, single dose
Active Comparator: alprazolam 1 mg	Drug: alprazolam; Oral capsule; 1 mg alprazolam, single dose
Active Comparator: alprazolam 3 mg	Drug: alprazolam; Oral capsule; 3 mg alprazolam, single dose

Outcome Measures

Primary Outcome Measures

1. Balance of Effects- Drug Liking VAS: Peak Effect (Maximum Effect [Emax]) and Minimum Effect (Emin) [0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

   Drug liking VAS is one of the measures of balance of effects that assesses the degree that a participant likes a drug effect at the time the question is being asked (that is, at the moment). It is scored using a 100 millimeter (mm) bipolar visual analogue scale (VAS) anchored in the center with a neutral anchor of "neither like nor dislike" (score of 50 mm), on the left with "strong disliking" (score of 0 mm) and on the right with "strong liking" (score of 100 mm). Emax is largest effect score between 0.5 to 24 hours post-dose. Emin is smallest effect score between 0.5 to 24 hours post-dose.

2. Balance of Effects- Overall Drug Liking VAS: Peak Effect (Maximum Effect [Emax]) and Minimum Effect (Emin) [6, 12, 24 hours post-dose]

   Overall drug liking VAS is one of the measures of balance of effects that assesses the participant's global perception of drug liking (that is, effects over the whole course of the drug experience including any carryover effects). A 100 mm bipolar VAS is used to assess response based on a score ranging from 0 mm to 100 mm (0 mm = "strong disliking", 50 mm= "neither like nor dislike", and 100 mm= "strong liking"). Emax is the largest effect score between 6 to 24 hours post-dose. Emin is the smallest effect score between 6 to 24 hours post-dose.

3. Balance of Effects- Take Drug Again VAS: Peak Effect (Maximum Effect [Emax]) [6, 12, 24 hours post-dose]

   Take drug again VAS is one of the measures of balance of effects. It is a subjective assessment of the degree to which a participant would desire to take the drug again if given the opportunity. It is presented on a 100 mm bipolar VAS with score ranging from 0 mm to 100 mm (score of 0 mm = "definitely not", 50 mm = "do not care", and 100 mm = "definitely so"). Emax is largest effect score between 6 hours to 24 hours.

4. Balance of Effects- Good and Bad Effects VAS: Peak Effect (Maximum Effect [Emax]) and Minimum Effect (Emin) [0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

   Good and Bad effects VAS is one of the measures of balance of effects that assesses the effect experienced by the participant on a 100 mm bipolar VAS, anchored in the center with a neutral anchor of neither good nor bad effects (score of 50 mm), on the left with bad effects(score of 0 mm) and on the right with good effects (score of 100 mm). Emax is largest effect score between 0.5 to 24 hours post-dose. Emin is smallest effect score between 0.5 to 24 hours post-dose.

5. Balance of Effects- Subjective Drug Value (SDV): Maximum Effect (Emax) [6, 12, 24 hrs post-dose]

   SDV is one of measures of balance of effects. It is a proxy measure of reinforcing efficacy that involves a series of independent, theoretical forced choices between drug administered and different monetary values. Participants were asked to choose between receiving another dose of same drug or an envelope containing specified amount of money, but they did not receive drug or money as described. Possible score range from 0.25 to 50. Higher score range indicates higher SDV. Emax: largest effect score between 6-24 hours post-dose.

6. Positive Effects- Addiction Research Center Inventory (ARCI) Morphine Benzedrine Group (MBG): Maximum Effect (Emax) [0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 12, 24 hours post-dose]

   ARCI (MBG) is one of the measures of positive effects. It is a set of 16 questions in which each question contributes to total score. Participants indicate their responses by selecting 'False' or 'True'. One point is given for each response that agrees with the scoring direction on scale i.e, true items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when the answer is opposite to the scoring direction. Score range: 0 to 16, higher score indicated positive effects. Emax: largest effect score between 0 to 24 hours post-dose.

7. Positive Effects- Good Drug Effects: Peak Effect (Maximum Effect [Emax]) [0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

   Good drug effects VAS is one of the measures of positive effects that assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is the largest effect score between 0.5 to 24 hours post-dose.

8. Positive Effects- High VAS: Peak Effect (Maximum Effect [Emax]) [0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

   High VAS is one of the measures of positive effects that assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is largest effect score between 0 to 24 hours.

9. Negative Effects- Bad Drug Effects: Peak Effect (Maximum Effect [Emax]) [0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

   Bad effects VAS is one of the measures of negative effects that assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is largest effect score between 0.5 to 24 hrs.

10. Negative Effects- Addiction Research Center Inventory (ARCI) Lysergic Acid Diethylamide (LSD): Maximum Effect (Emax) [0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

    ARCI (LSD) is one of the measures of negative effects. It is a set of 14 questions in which each question contributes to total score. Participants indicate their responses by selecting 'False' or 'True'. One point is given for each response that agrees with scoring direction on scale i.e, true items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when the answer is opposite to scoring direction. Score range: 0 to 14, higher score indicated higher negative effects. Emax: largest effect score between 0 to 24 hours post-dose.

11. Sedative Effects- Addiction Research Center Inventory (ARCI) Pentobarbital Chlorpromazine Group (PCAG): Maximum Effect (Emax) [0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

    ARCI (PCAG) is one of the measures of sedative effects. It is a set of 15 questions in which each question contributes to total score. Participants indicate their responses by selecting 'False' or 'True'. One point is given for each response that agrees with the scoring direction on scale i.e, true items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when answer is opposite to scoring direction. Score range: 0 to 15, higher score indicated higher sedative effects. Emax: largest effect score between 0 to 24 hours post-dose.

12. Sedative Effects- Alertness/Drowsiness: Minimum Effect (Emin) [0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

    Alertness/Drowsiness VAS is one of the measures of sedative effects. It is scored using a 100 mm bipolar VAS anchored in the center with a neutral anchor of "neither drowsy nor alert" (score of 50 mm), on the left with "very drowsy" (score of 0 mm) and on the right with "very alert" (score of 100 mm). Emin is the smallest effect score between 0 to 24 hours post-dose.

13. Other Subjective Effects- Any Drug Effects: Peak Effect (Maximum Effect [Emax]) [0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

    Any drug effects VAS is one of the measures of other subjective effects. It assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is the largest effect score between 0.5 to 24 hours post-dose.

14. Other Subjective Effects- Drug Similarity [12 hours post-dose]

    Drug similarity VAS is one of the measures of other subjective effects. It assesses the similarity of the drug recently received by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= not at all similar) to 'extremely' (score of 100 mm= very similar). Recently received drugs were compared with placebo, benzodiazepines, codeine/morphine, Tetrahydrocannabinol (THC), pseudoephedrine.

15. Other Subjective Effects- Addiction Research Center Inventory (ARCI) Benzedrine Group (BG): Maximum Effect (Emax) and Minimum Effect (Emin) [0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose]

    ARCI (BG) is measure of other subjective effects. It is a set of 13 questions in which each question contributes to total score. Participants select 'False' / 'True' for response. One point given for each response that agrees with scoring direction, true items receive score of 1 if answer 'True', false items receive score of 1 if answer 'False'. No points if answer is opposite to scoring direction. Score range: 0 to 13, higher score indicated higher other subjective effects. Emax: largest effect score between 0 - 24 hours post-dose. Emin: smallest effect score between 0 - 24 hours post-dose.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Healthy male and/or female subjects between the ages of 18 and 55 years.

• Recreational polydrug user with a history of CNS depressant use.

Exclusion Criteria:

• History of clinically significant neurologic condition(s), such as seizures, convulsions, epilepsy, or significant head injury, as judged by the investigator or designee.

• A known history of hypersensitivity or previous intolerance to dimebon or other antihistamines.

• Self-reported history of drug or alcohol dependence (except nicotine or caffeine) in the 2 years prior to screening, or drug or alcohol dependence as defined by the (DSM-IV-TR) in 12 months prior to screening, including subjects who have ever been in a substance rehabilitation program (other than treatment for smoking cessation).

• History of clinically significant psychiatric disorder(s), as judged by the investigator or qualified designee.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Pfizer
• Medivation, Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00975481
• Other Study ID Numbers: B1451037
• First Posted: Sep 11, 2009
• Last Update Posted: Apr 2, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by Pfizer: oral single-dose 6-way crossover recreational drug users abuse potential pharmacodynamics safety
• Additional relevant MeSH terms: Alzheimer Disease; Huntington Disease; Alprazolam

Study Results

Participant Flow

Arm/Group Title	PBO, ALP 1mg, DIM 60 mg, ALP 3 mg, DIM 40 mg, DIM 20 mg	ALP 1 mg, ALP 3 mg, PBO, DIM 20 mg, DIM 60 mg, DIM 40 mg	ALP 3 mg, DIM 20 mg, ALP 1 mg, DIM 40 mg, PBO, DIM 60 mg	DIM 20 mg, DIM 40 mg, ALP 3 mg, DIM 60 mg, ALP 1 mg, PBO	DIM 40 mg, DIM 60 mg, DIM 20 mg, PBO, ALP 3 mg, ALP 1 mg	DIM 60 mg, PBO, DIM 40 mg, ALP 1mg, DIM 20 mg, ALP 3 mg
Arm/Group Description	Placebo (PBO) matched to 3 alprazolam (ALP) capsules and placebo matched to 3 dimebon (DIM) tablets on Day 1 in the first intervention period; followed by alprazolam 1 milligram (mg) capsule, placebo matched to 2 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the second intervention period; then dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 in the third intervention period; then alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 in fourth intervention period; then dimebon 40 mg tablets and placebo matched to dimebon tablet and placebo matched to 3 alprazolam capsules on Day 1 in the fifth intervention period; and dimebon 20 mg tablet, placebo matched to 2 dimebon tablets and placebo matched to 3 alprazolam capsules on Day 1 in the sixth intervention period. A washout period of at least 7 days was maintained between each dose.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the first intervention period; followed by alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 in the second intervention period; then placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the third intervention period; then dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 in the fourth intervention period; then dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 in the fifth intervention period; and dimebon 40 mg tablets, placebo matched to dimebon tablet and placebo matched to 3 alprazolam capsules on Day 1 in the sixth intervention period. A washout period of at least 7 days was maintained between each dose.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 in the first intervention period; followed by dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 in the second intervention period; then alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the third intervention period; then dimebon 40 mg tablets, placebo matched to dimebon tablet and placebo matched to 3 alprazolam capsules on Day 1 in the fourth interventional period; then placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the fifth intervention period; and dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 in the sixth intervention period. A washout period of 7 days was maintained between each dose.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets and placebo matched to 3 alprazolam capsules on Day 1 in the first intervention period; followed by dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 in the second intervention period; then alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 in the third intervention period; then dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 in the fourth intervention period; then alprazolam 1mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 in the fifth intervention period; and placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the sixth intervention period. A washout period of at least 7 days was maintained between each dose.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 in the first intervention period; followed by dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 in the second intervention period; then dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 in the third intervention period; then placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the fourth intervention period; then alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 in the fifth intervention period; and alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 in the sixth intervention period. A washout period of at least 7 days was maintained between each dose.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 in the first intervention period; followed by placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 in the second intervention period; then dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 in the third intervention period; then alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 in the fourth intervention group; then dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 in the fifth intervention period; and alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 in the sixth intervention period. A washout period of at least 7 days was maintained between each dose.
Period Title: First Intervention Period
STARTED	6	6	6	6	6	6
COMPLETED	6	6	6	6	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	6	6	6	6	6	6
COMPLETED	6	6	6	6	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	6	6	6	6	6	6
COMPLETED	4	5	5	6	6	6
NOT COMPLETED	2	1	1	0	0	0
Period Title: First Intervention Period
STARTED	4	5	5	6	6	6
COMPLETED	4	5	5	6	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	4	5	5	6	6	6
COMPLETED	4	5	5	6	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	4	5	5	6	6	6
COMPLETED	4	5	5	6	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	4	5	5	6	6	6
COMPLETED	4	5	4	5	6	6
NOT COMPLETED	0	0	1	1	0	0
Period Title: First Intervention Period
STARTED	4	5	4	5	6	6
COMPLETED	4	5	4	5	6	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	4	5	4	5	6	6
COMPLETED	4	5	4	5	5	6
NOT COMPLETED	0	0	0	0	1	0
Period Title: First Intervention Period
STARTED	4	5	4	5	5	6
COMPLETED	4	5	4	5	5	6
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention Period
STARTED	4	5	4	5	5	6
COMPLETED	4	5	4	5	5	6
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes participants randomized to receive placebo first, alprazolam 1 mg first, alprazolam 3 mg first, dimebon 20 mg first, dimebon 40 mg first and dimebon 60 mg first.
Overall Participants	36
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.4 (9.7)
Sex: Female, Male (Count of Participants)
Female	8 22.2%
Male	28 77.8%
Body Mass Index (kilogram/square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram/square meter (kg/m^2)]	24.6 (3.4)

Outcome Measures

1. Primary Outcome

Title	Balance of Effects- Drug Liking VAS: Peak Effect (Maximum Effect [Emax]) and Minimum Effect (Emin)
Description	Drug liking VAS is one of the measures of balance of effects that assesses the degree that a participant likes a drug effect at the time the question is being asked (that is, at the moment). It is scored using a 100 millimeter (mm) bipolar visual analogue scale (VAS) anchored in the center with a neutral anchor of "neither like nor dislike" (score of 50 mm), on the left with "strong disliking" (score of 0 mm) and on the right with "strong liking" (score of 100 mm). Emax is largest effect score between 0.5 to 24 hours post-dose. Emin is smallest effect score between 0.5 to 24 hours post-dose.
Time Frame	0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis population included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Emax	57.8 (10.03)	78.6 (17.53)	82.2 (14.55)	57.2 (11.76)	55.8 (9.41)	58.5 (12.54)
Emin	47.0 (9.38)	45.4 (11.21)	37.4 (17.32)	48.4 (8.89)	49.0 (3.59)	46.5 (10.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95 percent (%) Confidence Interval (CI) were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with Restricted Maximum Likelihood (REML) estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.8096
	Confidence Interval	(2-Sided) 95%; 15.0866 to 26.5327
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	24.4625
	Confidence Interval	(2-Sided) 95%; 18.7321 to 30.1929
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8428
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5792
	Confidence Interval	(2-Sided) 95%; -6.3385 to 5.1800
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4957
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.9993
	Confidence Interval	(2-Sided) 95%; -7.7832 to 3.7845
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7431
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9683
	Confidence Interval	(2-Sided) 95%; -4.8567 to 6.7932
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.3889
	Confidence Interval	(2-Sided) 95%; -27.1044 to -15.6734
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-22.8090
	Confidence Interval	(2-Sided) 95%; -28.5584 to -17.0596
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-19.8414
	Confidence Interval	(2-Sided) 95%; -25.6435 to -14.0393
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-25.0418
	Confidence Interval	(2-Sided) 95%; -30.6705 to -19.4130
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-26.4618
	Confidence Interval	(2-Sided) 95%; -32.1455 to -20.7782
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-23.4943
	Confidence Interval	(2-Sided) 95%; -29.2440 to -17.7445
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5720
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4538
	Confidence Interval	(2-Sided) 95%; -6.5274 to 3.6198
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.9938
	Confidence Interval	(2-Sided) 95%; -14.0695 to -3.9180
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4704
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8686
	Confidence Interval	(2-Sided) 95%; -3.2342 to 6.9713
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4255
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.0725
	Confidence Interval	(2-Sided) 95%; -3.0533 to 7.1984
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8959
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3425
	Confidence Interval	(2-Sided) 95%; -5.5053 to 4.8204
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1967
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.3224
	Confidence Interval	(2-Sided) 95%; -1.7402 to 8.3850
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1733
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5264
	Confidence Interval	(2-Sided) 95%; -1.5676 to 8.6203
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6697
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1113
	Confidence Interval	(2-Sided) 95%; -4.0285 to 6.2512
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.8623
	Confidence Interval	(2-Sided) 95%; 5.8712 to 15.8535
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.0663
	Confidence Interval	(2-Sided) 95%; 6.0281 to 16.1045
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.6513
	Confidence Interval	(2-Sided) 95%; 3.5552 to 13.7474
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Balance of Effects- Overall Drug Liking VAS: Peak Effect (Maximum Effect [Emax]) and Minimum Effect (Emin)
Description	Overall drug liking VAS is one of the measures of balance of effects that assesses the participant's global perception of drug liking (that is, effects over the whole course of the drug experience including any carryover effects). A 100 mm bipolar VAS is used to assess response based on a score ranging from 0 mm to 100 mm (0 mm = "strong disliking", 50 mm= "neither like nor dislike", and 100 mm= "strong liking"). Emax is the largest effect score between 6 to 24 hours post-dose. Emin is the smallest effect score between 6 to 24 hours post-dose.
Time Frame	6, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to 1 dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.
Measure Participants	32	33	34	33	32	31
Emax	57.8 (14.31)	74.6 (18.99)	78.0 (15.50)	56.5 (11.44)	55.4 (11.29)	58.1 (12.52)
Emin	52.5 (9.13)	64.5 (20.17)	62.6 (18.13)	48.2 (15.96)	52.0 (8.75)	51.1 (8.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.6388
	Confidence Interval	(2-Sided) 95%; 10.5727 to 22.7049
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	19.8432
	Confidence Interval	(2-Sided) 95%; 13.7627 to 25.9238
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6029
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.6121
	Confidence Interval	(2-Sided) 95%; -7.7209 to 4.4967
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3477
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.9241
	Confidence Interval	(2-Sided) 95%; -9.0571 to 3.2089
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9769
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0908
	Confidence Interval	(2-Sided) 95%; -6.0850 to 6.2667
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.2509
	Confidence Interval	(2-Sided) 95%; -24.3155 to -12.1864
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.5629
	Confidence Interval	(2-Sided) 95%; -25.6616 to -13.4642
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.5480
	Confidence Interval	(2-Sided) 95%; -22.7036 to -10.3923
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.4554
	Confidence Interval	(2-Sided) 95%; -27.4199 to -15.4908
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-22.7673
	Confidence Interval	(2-Sided) 95%; -28.7925 to -16.7422
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.7524
	Confidence Interval	(2-Sided) 95%; -25.8485 to -13.6563
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	12.0888
	Confidence Interval	(2-Sided) 95%; 5.3225 to 18.8551
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0038
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.0768
	Confidence Interval	(2-Sided) 95%; 3.3132 to 16.8403
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2257
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.1875
	Confidence Interval	(2-Sided) 95%; -10.9890 to 2.6139
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8042
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8589
	Confidence Interval	(2-Sided) 95%; -7.6927 to 5.9750
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6399
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.6335
	Confidence Interval	(2-Sided) 95%; -8.5177 to 5.2506
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.2763
	Confidence Interval	(2-Sided) 95%; -23.0228 to -9.5229
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.9477
	Confidence Interval	(2-Sided) 95%; -19.7374 to -6.1580
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.7223
	Confidence Interval	(2-Sided) 95%; -20.5720 to -6.8727
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.2643
	Confidence Interval	(2-Sided) 95%; -20.9226 to -7.6060
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.9356
	Confidence Interval	(2-Sided) 95%; -17.6548 to -4.2165
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.7103
	Confidence Interval	(2-Sided) 95%; -18.5055 to -4.9151
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Balance of Effects- Take Drug Again VAS: Peak Effect (Maximum Effect [Emax])
Description	Take drug again VAS is one of the measures of balance of effects. It is a subjective assessment of the degree to which a participant would desire to take the drug again if given the opportunity. It is presented on a 100 mm bipolar VAS with score ranging from 0 mm to 100 mm (score of 0 mm = "definitely not", 50 mm = "do not care", and 100 mm = "definitely so"). Emax is largest effect score between 6 hours to 24 hours.
Time Frame	6, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam tablets, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [mm]	53.9 (22.30)	77.5 (22.26)	83.2 (15.99)	47.6 (28.66)	50.4 (26.23)	52.5 (25.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	24.0090
	Confidence Interval	(2-Sided) 95%; 13.7265 to 34.2916
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	29.4156
	Confidence Interval	(2-Sided) 95%; 19.1160 to 39.7151
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2239
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.3979
	Confidence Interval	(2-Sided) 95%; -16.7479 to 3.9521
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4326
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.1396
	Confidence Interval	(2-Sided) 95%; -14.5328 to 6.2526
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7447
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7283
	Confidence Interval	(2-Sided) 95%; -12.1950 to 8.7383
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-30.4069
	Confidence Interval	(2-Sided) 95%; -40.6795 to -20.1343
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-28.1487
	Confidence Interval	(2-Sided) 95%; -38.4812 to -17.8161
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-25.7374
	Confidence Interval	(2-Sided) 95%; -36.1651 to -15.3096
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-35.8134
	Confidence Interval	(2-Sided) 95%; -45.9257 to -25.7012
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-33.5552
	Confidence Interval	(2-Sided) 95%; -43.7675 to -23.3429
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-31.1439
	Confidence Interval	(2-Sided) 95%; -41.4754 to -20.8124
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Balance of Effects- Good and Bad Effects VAS: Peak Effect (Maximum Effect [Emax]) and Minimum Effect (Emin)
Description	Good and Bad effects VAS is one of the measures of balance of effects that assesses the effect experienced by the participant on a 100 mm bipolar VAS, anchored in the center with a neutral anchor of neither good nor bad effects (score of 50 mm), on the left with bad effects(score of 0 mm) and on the right with good effects (score of 100 mm). Emax is largest effect score between 0.5 to 24 hours post-dose. Emin is smallest effect score between 0.5 to 24 hours post-dose.
Time Frame	0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsule, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.
Measure Participants	32	33	34	33	32	31
Emax	56.2 (7.15)	80.9 (15.93)	81.9 (14.40)	57.9 (13.53)	56.6 (11.21)	57.6 (8.92)
Emin	48.0 (8.83)	46.7 (10.70)	38.6 (15.76)	49.3 (2.79)	48.3 (8.82)	48.9 (3.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	24.8779
	Confidence Interval	(2-Sided) 95%; 19.5658 to 30.1899
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	25.9857
	Confidence Interval	(2-Sided) 95%; 20.6670 to 31.3043
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4489
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.0544
	Confidence Interval	(2-Sided) 95%; -3.2911 to 7.3998
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8329
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5743
	Confidence Interval	(2-Sided) 95%; -4.7941 to 5.9427
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5387
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.6863
	Confidence Interval	(2-Sided) 95%; -3.7203 to 7.0929
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-22.8235
	Confidence Interval	(2-Sided) 95%; -28.1283 to -17.5187
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-24.3036
	Confidence Interval	(2-Sided) 95%; -29.6400 to -18.9672
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-23.1916
	Confidence Interval	(2-Sided) 95%; -28.5768 to -17.8064
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-23.9313
	Confidence Interval	(2-Sided) 95%; -29.1559 to -18.7066
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-25.4114
	Confidence Interval	(2-Sided) 95%; -30.6869 to -20.1358
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-24.2994
	Confidence Interval	(2-Sided) 95%; -29.6361 to -18.9626
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5349
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4301
	Confidence Interval	(2-Sided) 95%; -5.9725 to 3.1123
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.1367
	Confidence Interval	(2-Sided) 95%; -13.6684 to -4.6050
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5637
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.3357
	Confidence Interval	(2-Sided) 95%; -3.2244 to 5.8958
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8612
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4065
	Confidence Interval	(2-Sided) 95%; -4.1779 to 4.9909
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6954
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9175
	Confidence Interval	(2-Sided) 95%; -3.7022 to 5.5373
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2287
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.7658
	Confidence Interval	(2-Sided) 95%; -1.7552 to 7.2868
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4267
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8366
	Confidence Interval	(2-Sided) 95%; -2.7158 to 6.3890
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3140
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.3476
	Confidence Interval	(2-Sided) 95%; -2.2429 to 6.9381
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.4724
	Confidence Interval	(2-Sided) 95%; 5.9992 to 14.9456
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.5432
	Confidence Interval	(2-Sided) 95%; 5.0320 to 14.0544
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.0542
	Confidence Interval	(2-Sided) 95%; 5.4940 to 14.6144
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Balance of Effects- Subjective Drug Value (SDV): Maximum Effect (Emax)
Description	SDV is one of measures of balance of effects. It is a proxy measure of reinforcing efficacy that involves a series of independent, theoretical forced choices between drug administered and different monetary values. Participants were asked to choose between receiving another dose of same drug or an envelope containing specified amount of money, but they did not receive drug or money as described. Possible score range from 0.25 to 50. Higher score range indicates higher SDV. Emax: largest effect score between 6-24 hours post-dose.
Time Frame	6, 12, 24 hrs post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsule, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [Dollar]	4.805 (9.7833)	19.621 (16.2519)	25.551 (17.0192)	6.098 (12.3269)	3.836 (6.5345)	4.573 (9.8211)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	14.4728
	Confidence Interval	(2-Sided) 95%; 9.4718 to 19.4737
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	19.7284
	Confidence Interval	(2-Sided) 95%; 14.7131 to 24.7437
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9348
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2088
	Confidence Interval	(2-Sided) 95%; -4.8289 to 5.2466
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5009
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7271
	Confidence Interval	(2-Sided) 95%; -6.7841 to 3.3299
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8975
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3325
	Confidence Interval	(2-Sided) 95%; -5.4245 to 4.7595
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.2640
	Confidence Interval	(2-Sided) 95%; -19.2660 to -9.2619
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.1999
	Confidence Interval	(2-Sided) 95%; -21.2294 to -11.1704
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.8053
	Confidence Interval	(2-Sided) 95%; -19.8822 to -9.7283
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.5195
	Confidence Interval	(2-Sided) 95%; -24.4361 to -14.6030
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.4555
	Confidence Interval	(2-Sided) 95%; -26.4230 to -16.4880
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.0609
	Confidence Interval	(2-Sided) 95%; -25.0872 to -15.0345
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Positive Effects- Addiction Research Center Inventory (ARCI) Morphine Benzedrine Group (MBG): Maximum Effect (Emax)
Description	ARCI (MBG) is one of the measures of positive effects. It is a set of 16 questions in which each question contributes to total score. Participants indicate their responses by selecting 'False' or 'True'. One point is given for each response that agrees with the scoring direction on scale i.e, true items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when the answer is opposite to the scoring direction. Score range: 0 to 16, higher score indicated positive effects. Emax: largest effect score between 0 to 24 hours post-dose.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [Units on scale]	3.2 (2.51)	6.2 (4.16)	8.1 (4.37)	3.5 (3.10)	3.6 (3.22)	3.5 (2.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1634
	Confidence Interval	(2-Sided) 95%; 1.9014 to 4.4254
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.6706
	Confidence Interval	(2-Sided) 95%; 3.4066 to 5.9346
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8184
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1478
	Confidence Interval	(2-Sided) 95%; -1.1217 to 1.4173
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7324
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2211
	Confidence Interval	(2-Sided) 95%; -1.0540 to 1.4963
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8844
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0946
	Confidence Interval	(2-Sided) 95%; -1.1898 to 1.3791
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0156
	Confidence Interval	(2-Sided) 95%; -4.2754 to -1.7558
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.9423
	Confidence Interval	(2-Sided) 95%; -4.2101 to -1.6745
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0688
	Confidence Interval	(2-Sided) 95%; -4.3484 to -1.7891
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.5228
	Confidence Interval	(2-Sided) 95%; -5.7651 to -3.2805
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.4495
	Confidence Interval	(2-Sided) 95%; -5.7031 to -3.1959
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.5760
	Confidence Interval	(2-Sided) 95%; -5.8438 to -3.3081
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	Positive Effects- Good Drug Effects: Peak Effect (Maximum Effect [Emax])
Description	Good drug effects VAS is one of the measures of positive effects that assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is the largest effect score between 0.5 to 24 hours post-dose.
Time Frame	0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [mm]	35.2 (31.94)	81.2 (18.16)	84.7 (14.32)	34.4 (32.87)	32.0 (32.33)	39.7 (31.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	46.0798
	Confidence Interval	(2-Sided) 95%; 34.0453 to 58.1142
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	49.8771
	Confidence Interval	(2-Sided) 95%; 37.8247 to 61.9295
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9248
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5797
	Confidence Interval	(2-Sided) 95%; -12.6918 to 11.5325
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5857
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.3632
	Confidence Interval	(2-Sided) 95%; -15.5264 to 8.8000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4768
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.4225
	Confidence Interval	(2-Sided) 95%; -7.8270 to 16.6719
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-46.6594
	Confidence Interval	(2-Sided) 95%; -58.6804 to -34.6385
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-49.4430
	Confidence Interval	(2-Sided) 95%; -61.5346 to -37.3514
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-41.6573
	Confidence Interval	(2-Sided) 95%; -53.8600 to -29.4546
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-50.4567
	Confidence Interval	(2-Sided) 95%; -62.2925 to -38.6210
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-53.2403
	Confidence Interval	(2-Sided) 95%; -65.1923 to -41.2882
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-45.4546
	Confidence Interval	(2-Sided) 95%; -57.5459 to -33.3633
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Positive Effects- High VAS: Peak Effect (Maximum Effect [Emax])
Description	High VAS is one of the measures of positive effects that assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is largest effect score between 0 to 24 hours.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [mm]	30.4 (30.22)	77.1 (24.93)	88.0 (13.13)	25.9 (28.39)	29.9 (33.07)	35.8 (32.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	46.8450
	Confidence Interval	(2-Sided) 95%; 34.6464 to 59.0436
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	57.5013
	Confidence Interval	(2-Sided) 95%; 45.3036 to 69.6991
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4129
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.0913
	Confidence Interval	(2-Sided) 95%; -17.3421 to 7.1595
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8488
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.1893
	Confidence Interval	(2-Sided) 95%; -13.4954 to 11.1168
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4086
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.1995
	Confidence Interval	(2-Sided) 95%; -7.1963 to 17.5954
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.9363
	Confidence Interval	(2-Sided) 95%; -64.1108 to -39.7618
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-48.0343
	Confidence Interval	(2-Sided) 95%; -60.2801 to -35.7885
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-41.6455
	Confidence Interval	(2-Sided) 95%; -53.9964 to -29.2946
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-62.5926
	Confidence Interval	(2-Sided) 95%; -74.5881 to -50.5971
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-58.6906
	Confidence Interval	(2-Sided) 95%; -70.7965 to -46.5847
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-52.3018
	Confidence Interval	(2-Sided) 95%; -64.5427 to -40.0609
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	Negative Effects- Bad Drug Effects: Peak Effect (Maximum Effect [Emax])
Description	Bad effects VAS is one of the measures of negative effects that assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is largest effect score between 0.5 to 24 hrs.
Time Frame	0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [mm]	17.2 (24.38)	33.9 (29.88)	44.6 (23.58)	15.9 (25.38)	16.8 (24.27)	19.7 (25.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.4604
	Confidence Interval	(2-Sided) 95%; 6.3210 to 26.5998
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	27.9971
	Confidence Interval	(2-Sided) 95%; 17.8247 to 38.1696
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8254
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.1425
	Confidence Interval	(2-Sided) 95%; -11.3591 to 9.0742
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8858
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7470
	Confidence Interval	(2-Sided) 95%; -9.5075 to 11.0015
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5128
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.4279
	Confidence Interval	(2-Sided) 95%; -6.8972 to 13.7529
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.6028
	Confidence Interval	(2-Sided) 95%; -27.7485 to -7.4572
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.7134
	Confidence Interval	(2-Sided) 95%; -25.9136 to -5.5132
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0135
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.0325
	Confidence Interval	(2-Sided) 95%; -23.3295 to -2.7355
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-29.1396
	Confidence Interval	(2-Sided) 95%; -39.1071 to -19.1721
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-27.2502
	Confidence Interval	(2-Sided) 95%; -37.3224 to -17.1780
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-24.5693
	Confidence Interval	(2-Sided) 95%; -34.7614 to -14.3772
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	Negative Effects- Addiction Research Center Inventory (ARCI) Lysergic Acid Diethylamide (LSD): Maximum Effect (Emax)
Description	ARCI (LSD) is one of the measures of negative effects. It is a set of 14 questions in which each question contributes to total score. Participants indicate their responses by selecting 'False' or 'True'. One point is given for each response that agrees with scoring direction on scale i.e, true items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when the answer is opposite to scoring direction. Score range: 0 to 14, higher score indicated higher negative effects. Emax: largest effect score between 0 to 24 hours post-dose.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [Units on Scale]	3.8 (1.83)	4.9 (1.76)	7.0 (2.57)	3.8 (1.42)	3.8 (1.50)	3.6 (1.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2535
	Confidence Interval	(2-Sided) 95%; 0.5623 to 1.9446
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5010
	Confidence Interval	(2-Sided) 95%; 2.8073 to 4.1948
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3347
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3418
	Confidence Interval	(2-Sided) 95%; -0.3559 to 1.0396
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3678
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3208
	Confidence Interval	(2-Sided) 95%; -0.3808 to 1.0225
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9197
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0360
	Confidence Interval	(2-Sided) 95%; -0.6686 to 0.7406
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0099
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9117
	Confidence Interval	(2-Sided) 95%; -1.6013 to -0.2220
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0088
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9326
	Confidence Interval	(2-Sided) 95%; -1.6269 to -0.2384
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2175
	Confidence Interval	(2-Sided) 95%; -1.9171 to -0.5178
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.1592
	Confidence Interval	(2-Sided) 95%; -3.8380 to -2.4804
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.1802
	Confidence Interval	(2-Sided) 95%; -3.8656 to -2.4947
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.4650
	Confidence Interval	(2-Sided) 95%; -4.1583 to -2.7717
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Sedative Effects- Addiction Research Center Inventory (ARCI) Pentobarbital Chlorpromazine Group (PCAG): Maximum Effect (Emax)
Description	ARCI (PCAG) is one of the measures of sedative effects. It is a set of 15 questions in which each question contributes to total score. Participants indicate their responses by selecting 'False' or 'True'. One point is given for each response that agrees with the scoring direction on scale i.e, true items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when answer is opposite to scoring direction. Score range: 0 to 15, higher score indicated higher sedative effects. Emax: largest effect score between 0 to 24 hours post-dose.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [Units on Scale]	4.7 (2.57)	9.9 (3.51)	11.5 (2.48)	5.3 (3.26)	5.5 (2.75)	5.5 (2.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.2943
	Confidence Interval	(2-Sided) 95%; 4.0783 to 6.5102
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.8983
	Confidence Interval	(2-Sided) 95%; 5.6799 to 8.1167
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2917
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.6545
	Confidence Interval	(2-Sided) 95%; -0.5676 to 1.8767
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1738
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8489
	Confidence Interval	(2-Sided) 95%; -0.3784 to 2.0763
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1373
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9372
	Confidence Interval	(2-Sided) 95%; -0.3024 to 2.1767
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.6397
	Confidence Interval	(2-Sided) 95%; -5.8537 to -3.4257
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.4453
	Confidence Interval	(2-Sided) 95%; -5.6662 to -3.2244
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.3571
	Confidence Interval	(2-Sided) 95%; -5.5887 to -3.1255
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.2437
	Confidence Interval	(2-Sided) 95%; -7.4397 to -5.0477
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.0493
	Confidence Interval	(2-Sided) 95%; -7.2568 to -4.8419
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.9611
	Confidence Interval	(2-Sided) 95%; -7.1812 to -4.7410
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Sedative Effects- Alertness/Drowsiness: Minimum Effect (Emin)
Description	Alertness/Drowsiness VAS is one of the measures of sedative effects. It is scored using a 100 mm bipolar VAS anchored in the center with a neutral anchor of "neither drowsy nor alert" (score of 50 mm), on the left with "very drowsy" (score of 0 mm) and on the right with "very alert" (score of 100 mm). Emin is the smallest effect score between 0 to 24 hours post-dose.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [mm]	42.1 (18.77)	14.4 (17.83)	8.6 (9.36)	42.9 (21.32)	37.7 (21.32)	38.5 (16.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-26.6205
	Confidence Interval	(2-Sided) 95%; -33.1192 to -20.1219
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-32.5724
	Confidence Interval	(2-Sided) 95%; -39.1073 to -26.0375
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5685
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8966
	Confidence Interval	(2-Sided) 95%; -4.6607 to 8.4540
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2848
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.5761
	Confidence Interval	(2-Sided) 95%; -10.1590 to 3.0068
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3440
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.1754
	Confidence Interval	(2-Sided) 95%; -9.7855 to 3.4347
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.5172
	Confidence Interval	(2-Sided) 95%; 22.0454 to 34.9890
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.0445
	Confidence Interval	(2-Sided) 95%; 16.5383 to 29.5506
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.4452
	Confidence Interval	(2-Sided) 95%; 16.8772 to 30.0131
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	34.4690
	Confidence Interval	(2-Sided) 95%; 28.1136 to 40.8244
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.9963
	Confidence Interval	(2-Sided) 95%; 22.5734 to 35.4192
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	29.3970
	Confidence Interval	(2-Sided) 95%; 22.8946 to 35.8994
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Primary Outcome

Title	Other Subjective Effects- Any Drug Effects: Peak Effect (Maximum Effect [Emax])
Description	Any drug effects VAS is one of the measures of other subjective effects. It assesses the effect experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= definitely not) to 'extremely' (score of 100 mm= definitely so). Emax is the largest effect score between 0.5 to 24 hours post-dose.
Time Frame	0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Mean (Standard Deviation) [mm]	37.2 (35.30)	84.0 (23.27)	88.7 (11.12)	37.5 (35.91)	33.4 (34.54)	44.4 (34.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	46.6044
	Confidence Interval	(2-Sided) 95%; 33.4091 to 59.7996
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	50.7222
	Confidence Interval	(2-Sided) 95%; 37.5038 to 63.9407
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9174
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6987
	Confidence Interval	(2-Sided) 95%; -13.9815 to 12.5840
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.5629
	Confidence Interval	(2-Sided) 95%; -17.9006 to 8.7749
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3482
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.3982
	Confidence Interval	(2-Sided) 95%; -7.0337 to 19.8301
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-47.3031
	Confidence Interval	(2-Sided) 95%; -60.4869 to -34.1193
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.1672
	Confidence Interval	(2-Sided) 95%; -64.4276 to -37.9069
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-40.2062
	Confidence Interval	(2-Sided) 95%; -53.5890 to -26.8234
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.4210
	Confidence Interval	(2-Sided) 95%; -64.3974 to -38.4445
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-55.2851
	Confidence Interval	(2-Sided) 95%; -68.3904 to -42.1798
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	Mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-44.3241
	Confidence Interval	(2-Sided) 95%; -57.5825 to -31.0656
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Primary Outcome

Title	Other Subjective Effects- Drug Similarity
Description	Drug similarity VAS is one of the measures of other subjective effects. It assesses the similarity of the drug recently received by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (score of 0 mm= not at all similar) to 'extremely' (score of 100 mm= very similar). Recently received drugs were compared with placebo, benzodiazepines, codeine/morphine, Tetrahydrocannabinol (THC), pseudoephedrine.
Time Frame	12 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period. 'n' is signifying those participants who were evaluated for this measure for various drugs for similarity in each treatment group.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Placebo (n=32, 33, 34, 33, 32, 31)	56.3 (42.65)	10.2 (22.20)	4.0 (12.27)	61.4 (36.34)	57.8 (43.15)	55.7 (42.15)
Benzodiazepines (n=23, 23, 25, 24, 22, 22)	51.0 (38.99)	88.6 (21.87)	92.7 (20.66)	33.0 (40.56)	42.6 (40.81)	53.0 (40.45)
Codeine/Morphine (n=20, 20, 23, 22, 20, 20)	18.5 (28.02)	42.7 (38.43)	46.3 (33.82)	14.7 (28.49)	24.5 (29.55)	28.2 (29.66)
THC (n=32, 33, 34, 33, 32, 31)	21.2 (27.97)	45.6 (37.08)	48.9 (32.96)	21.9 (30.44)	16.2 (25.88)	25.3 (31.56)
Pseudoephedrine (n=6, 6, 6, 6, 7, 5)	21.8 (33.42)	21.5 (27.70)	66.5 (12.14)	31.7 (35.35)	30.7 (28.89)	33.4 (26.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI was obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-46.3823
	Confidence Interval	(2-Sided) 95%; -62.1244 to -30.6401
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.5199
	Confidence Interval	(2-Sided) 95%; -67.2633 to -35.7765
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4524
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.0366
	Confidence Interval	(2-Sided) 95%; -9.7924 to 21.8657
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7620
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.4423
	Confidence Interval	(2-Sided) 95%; -13.4599 to 18.3446
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9846
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1573
	Confidence Interval	(2-Sided) 95%; -15.8609 to 16.1754
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	52.4189
	Confidence Interval	(2-Sided) 95%; 36.7157 to 68.1221
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	48.8246
	Confidence Interval	(2-Sided) 95%; 33.0228 to 64.6264
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	46.5395
	Confidence Interval	(2-Sided) 95%; 30.5968 to 62.4823
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	57.5565
	Confidence Interval	(2-Sided) 95%; 42.0679 to 73.0451
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	53.9622
	Confidence Interval	(2-Sided) 95%; 38.3293 to 69.5952
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For placebo, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	51.6772
	Confidence Interval	(2-Sided) 95%; 35.8660 to 67.4884
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	37.4454
	Confidence Interval	(2-Sided) 95%; 17.7051 to 57.1857
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	41.6714
	Confidence Interval	(2-Sided) 95%; 22.2888 to 61.0540
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0744
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.7583
	Confidence Interval	(2-Sided) 95%; -37.2956 to 1.7789
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3458
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.5551
	Confidence Interval	(2-Sided) 95%; -29.5573 to 10.4471
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9375
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7920
	Confidence Interval	(2-Sided) 95%; -19.1777 to 20.7616
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-55.2037
	Confidence Interval	(2-Sided) 95%; -74.8113 to -35.5961
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-47.0005
	Confidence Interval	(2-Sided) 95%; -67.0020 to -26.9989
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-36.6534
	Confidence Interval	(2-Sided) 95%; -56.7246 to -16.5822
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-59.4297
	Confidence Interval	(2-Sided) 95%; -78.5162 to -40.3433
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-51.2265
	Confidence Interval	(2-Sided) 95%; -70.8131 to -31.6399
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For benzodiazepines, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-40.8794
	Confidence Interval	(2-Sided) 95%; -60.4726 to -21.2862
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0102
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.5197
	Confidence Interval	(2-Sided) 95%; 5.7096 to 41.3298
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	27.7321
	Confidence Interval	(2-Sided) 95%; 10.3632 to 45.1011
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5935
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.7334
	Confidence Interval	(2-Sided) 95%; -22.2807 to 12.8140
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6945
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5486
	Confidence Interval	(2-Sided) 95%; -14.3397 to 21.4370
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4177
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.2936
	Confidence Interval	(2-Sided) 95%; -10.4975 to 25.0847
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-28.2531
	Confidence Interval	(2-Sided) 95%; -45.8020 to -10.7042
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0299
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.9711
	Confidence Interval	(2-Sided) 95%; -37.9541 to -1.9880
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0759
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.2261
	Confidence Interval	(2-Sided) 95%; -34.1785 to 1.7264
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-32.4655
	Confidence Interval	(2-Sided) 95%; -49.2278 to -15.7032
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0069
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-24.1835
	Confidence Interval	(2-Sided) 95%; -41.5832 to -6.7838
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For codeine/morphine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0222
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.4385
	Confidence Interval	(2-Sided) 95%; -37.8861 to -2.9910
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	24.5890
	Confidence Interval	(2-Sided) 95%; 12.0126 to 37.1654
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	29.1100
	Confidence Interval	(2-Sided) 95%; 16.4903 to 41.7298
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6809
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.6428
	Confidence Interval	(2-Sided) 95%; -10.0309 to 15.3165
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6067
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.3215
	Confidence Interval	(2-Sided) 95%; -16.0415 to 9.3985
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3999
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.4722
	Confidence Interval	(2-Sided) 95%; -7.3350 to 18.2795
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.9461
	Confidence Interval	(2-Sided) 95%; -34.5327 to -9.3596
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-27.9105
	Confidence Interval	(2-Sided) 95%; -40.5640 to -15.2570
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0036
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.1168
	Confidence Interval	(2-Sided) 95%; -31.8907 to -6.3428
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-26.4672
	Confidence Interval	(2-Sided) 95%; -38.8298 to -14.1046
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-32.4315
	Confidence Interval	(2-Sided) 95%; -44.9250 to -19.9380
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For THC, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-23.6378
	Confidence Interval	(2-Sided) 95%; -36.2802 to -10.9954
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9728
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.6675
	Confidence Interval	(2-Sided) 95%; -39.7080 to 41.0430
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0246
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	42.7977
	Confidence Interval	(2-Sided) 95%; 6.1059 to 79.4894
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7068
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.5411
	Confidence Interval	(2-Sided) 95%; -33.7850 to 48.8672
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5492
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.7069
	Confidence Interval	(2-Sided) 95%; -26.0358 to 47.4496
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5899
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.1248
	Confidence Interval	(2-Sided) 95%; -31.3098 to 53.5595
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6998
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.8736
	Confidence Interval	(2-Sided) 95%; -29.8691 to 43.6163
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6187
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.0394
	Confidence Interval	(2-Sided) 95%; -31.4818 to 51.5606
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5863
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.4573
	Confidence Interval	(2-Sided) 95%; -29.0355 to 49.9502
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0832
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-35.2566
	Confidence Interval	(2-Sided) 95%; -75.6080 to 5.0948
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0827
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-32.0907
	Confidence Interval	(2-Sided) 95%; -68.7519 to 4.5704
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For pseudoephedrine, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1386
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-31.6728
	Confidence Interval	(2-Sided) 95%; -74.5352 to 11.1895
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Primary Outcome

Title	Other Subjective Effects- Addiction Research Center Inventory (ARCI) Benzedrine Group (BG): Maximum Effect (Emax) and Minimum Effect (Emin)
Description	ARCI (BG) is measure of other subjective effects. It is a set of 13 questions in which each question contributes to total score. Participants select 'False' / 'True' for response. One point given for each response that agrees with scoring direction, true items receive score of 1 if answer 'True', false items receive score of 1 if answer 'False'. No points if answer is opposite to scoring direction. Score range: 0 to 13, higher score indicated higher other subjective effects. Emax: largest effect score between 0 - 24 hours post-dose. Emin: smallest effect score between 0 - 24 hours post-dose.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacodynamic analysis included all randomized participants in the treatment phase who received at least 1 dose of study medication and had at least 1 pharmacodynamic parameter in at least 1 treatment period.

Arm/Group Title	Placebo	Alprazolam 1 mg	Alprazolam 3 mg	Dimebon 20 mg	Dimebon 40 mg	Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.	Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.	Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
Measure Participants	32	33	34	33	32	31
Emax	6.3 (1.14)	6.6 (1.34)	7.2 (2.01)	6.5 (1.72)	6.3 (1.66)	6.4 (1.38)
Emin	4.8 (1.90)	2.5 (2.05)	1.7 (1.31)	4.4 (2.08)	4.7 (1.72)	4.3 (1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1691
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3637
	Confidence Interval	(2-Sided) 95%; -0.1566 to 0.8840
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8444
	Confidence Interval	(2-Sided) 95%; 0.3238 to 1.3650
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4305
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2093
	Confidence Interval	(2-Sided) 95%; -0.3141 to 0.7327
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6517
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1206
	Confidence Interval	(2-Sided) 95%; -0.4064 to 0.6476
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8892
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0374
	Confidence Interval	(2-Sided) 95%; -0.5666 to 0.4919
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5576
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1544
	Confidence Interval	(2-Sided) 95%; -0.6737 to 0.3649
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3594
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2431
	Confidence Interval	(2-Sided) 95%; -0.7658 to 0.2796
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1355
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4011
	Confidence Interval	(2-Sided) 95%; -0.9291 to 0.1270
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0153
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6351
	Confidence Interval	(2-Sided) 95%; -1.1466 to -0.1236
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0065
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7238
	Confidence Interval	(2-Sided) 95%; -1.2418 to -0.2059
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emax, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8818
	Confidence Interval	(2-Sided) 95%; -1.4042 to -0.3594
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.1614
	Confidence Interval	(2-Sided) 95%; -2.9373 to -1.3856
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 3 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0336
	Confidence Interval	(2-Sided) 95%; -3.8085 to -2.2587
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4804
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2791
	Confidence Interval	(2-Sided) 95%; -1.0586 to 0.5004
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9519
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0240
	Confidence Interval	(2-Sided) 95%; -0.7608 to 0.8087
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2152
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4970
	Confidence Interval	(2-Sided) 95%; -1.2860 to 0.2921
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8824
	Confidence Interval	(2-Sided) 95%; 1.1094 to 2.6553
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1854
	Confidence Interval	(2-Sided) 95%; 1.4070 to 2.9638
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 1 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.6645
	Confidence Interval	(2-Sided) 95%; 0.8786 to 2.4503
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 20 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.7545
	Confidence Interval	(2-Sided) 95%; 1.9912 to 3.5179
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 40 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.0576
	Confidence Interval	(2-Sided) 95%; 2.2858 to 3.8294
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Alprazolam 3 mg, Dimebon 60 mg
	Comments	For Emin, mixed-effect model was used which included treatment, period and sequence as fixed effects, baseline measurement as covariate where applicable, and participant nested within sequence as random effect. The estimates of adjusted mean differences and corresponding 95% CI were obtained from the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-effect model was implemented with REML estimation method and Kenward-Roger degrees of freedom algorithm.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.5366
	Confidence Interval	(2-Sided) 95%; 1.7578 to 3.3155
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Placebo		Alprazolam 1 mg		Alprazolam 3 mg		Dimebon 20 mg		Dimebon 40 mg		Dimebon 60 mg
Arm/Group Description	Placebo matched to 3 alprazolam capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.		Alprazolam 1 mg capsule, placebo matched to 2 alprazolam capsules, and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.		Alprazolam 3 mg capsules and placebo matched to 3 dimebon tablets on Day 1 of any of the six intervention periods.		Dimebon 20 mg tablet, placebo matched to 2 dimebon tablets, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.		Dimebon 40 mg tablets, placebo matched to dimebon tablet, and placebo matched to 3 alprazolam capsules on Day 1 of any of the six intervention periods.		Dimebon 60 mg tablets and placebo matched to 3 alprazolam capsules on Day 1 of any of the six interventional periods.
All Cause Mortality
	Placebo		Alprazolam 1 mg		Alprazolam 3 mg		Dimebon 20 mg		Dimebon 40 mg		Dimebon 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Alprazolam 1 mg		Alprazolam 3 mg		Dimebon 20 mg		Dimebon 40 mg		Dimebon 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Alprazolam 1 mg		Alprazolam 3 mg		Dimebon 20 mg		Dimebon 40 mg		Dimebon 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/32 (34.4%)		30/33 (90.9%)		34/34 (100%)		18/33 (54.5%)		20/32 (62.5%)		17/31 (54.8%)
Eye disorders
Dry eye	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Diarrhoea	0/32 (0%)		1/33 (3%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Nausea	1/32 (3.1%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Vomiting	0/32 (0%)		1/33 (3%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		1/31 (3.2%)
General disorders
Chills	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		1/31 (3.2%)
Fatigue	2/32 (6.3%)		4/33 (12.1%)		1/34 (2.9%)		5/33 (15.2%)		2/32 (6.3%)		3/31 (9.7%)
Feeling of relaxation	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		1/31 (3.2%)
Influenza like illness	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Pyrexia	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		1/31 (3.2%)
Infections and infestations
Gastroenteritis	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Hordeolum	0/32 (0%)		0/33 (0%)		0/34 (0%)		1/33 (3%)		1/32 (3.1%)		0/31 (0%)
Nasopharyngitis	0/32 (0%)		1/33 (3%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Upper respiratory tract infection	1/32 (3.1%)		1/33 (3%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Injury, poisoning and procedural complications
Excoriation	0/32 (0%)		0/33 (0%)		0/34 (0%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Fall	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Mouth injury	0/32 (0%)		1/33 (3%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Soft tissue injury	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Investigations
Blood creatinine phosphokinase increased	1/32 (3.1%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/32 (0%)		1/33 (3%)		0/34 (0%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Musculoskeletal stiffness	0/32 (0%)		0/33 (0%)		0/34 (0%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Myalgia	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		1/32 (3.1%)		0/31 (0%)
Neck pain	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		2/32 (6.3%)		0/31 (0%)
Nervous system disorders
Disturbance in attention	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Dizziness	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		1/32 (3.1%)		1/31 (3.2%)
Dysarthria	0/32 (0%)		0/33 (0%)		2/34 (5.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Head discomfort	0/32 (0%)		0/33 (0%)		0/34 (0%)		2/33 (6.1%)		0/32 (0%)		0/31 (0%)
Headache	2/32 (6.3%)		0/33 (0%)		0/34 (0%)		3/33 (9.1%)		2/32 (6.3%)		2/31 (6.5%)
Hypoaesthesia	1/32 (3.1%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Somnolence	9/32 (28.1%)		26/33 (78.8%)		34/34 (100%)		7/33 (21.2%)		12/32 (37.5%)		13/31 (41.9%)
Speech disorder	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Syncope	0/32 (0%)		0/33 (0%)		1/34 (2.9%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Psychiatric disorders
Anxiety	0/32 (0%)		1/33 (3%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Euphoric mood	1/32 (3.1%)		2/33 (6.1%)		3/34 (8.8%)		1/33 (3%)		1/32 (3.1%)		0/31 (0%)
Hypervigilance	0/32 (0%)		0/33 (0%)		0/34 (0%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Tension	1/32 (3.1%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		1/32 (3.1%)		1/31 (3.2%)
Rhinorrhoea	0/32 (0%)		1/33 (3%)		0/34 (0%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		1/32 (3.1%)		0/31 (0%)
Erythema	0/32 (0%)		0/33 (0%)		0/34 (0%)		1/33 (3%)		0/32 (0%)		0/31 (0%)
Pruritus	0/32 (0%)		0/33 (0%)		0/34 (0%)		0/33 (0%)		1/32 (3.1%)		0/31 (0%)
Rash	0/32 (0%)		1/33 (3%)		1/34 (2.9%)		1/33 (3%)		1/32 (3.1%)		0/31 (0%)
Vascular disorders
Hypotension	0/32 (0%)		1/33 (3%)		0/34 (0%)		0/33 (0%)		0/32 (0%)		0/31 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.