Pharmacogenetics of Cannabinoid Response - Full Text View

Sponsor:	Yale University
Collaborator:	National Institute on Drug Abuse (NIDA)
Information provided by:	Yale University
ClinicalTrials.gov Identifier:	NCT00678730

Purpose

Background: Cannabis is one of the most commonly used and abused illicit substances, and may produce harmful effects in some individuals. Epidemiological data suggest that cannabis use is associated with a modest risk for the emergence of psychosis and psychotic disorders. In laboratory studies, we have shown that Delta-9-tetrahydrocannabinol (Δ-9-THC) induced transient but clinically significant psychotomimetic and amnestic effects in some but not all carefully screened healthy individuals. Further, a recent report suggests that polymorphisms of the gene for the enzyme catechol-O-methyltransferase (COMT) might moderate the risk of psychosis following cannabis exposure. COMT Val108/158Met polymorphism moderates executive function and the physiology of the prefrontal cortex in humans and is indirectly associated with increased mesolimbic dopamine transmission. Cannabinoids have been shown to increase dopaminergic transmission both in the prefrontal cortex and striatum, and these effects might contribute to the psychotomimetic and amnestic effects of cannabinoids. Similarly, hippocampal GABAergic systems may contribute to the psychotomimetic and amnestic effects of cannabinoids. Pilot data (n=15) show that otherwise healthy individuals homozygous for 1) the COMT Val108/158Met allele (Val-Val) and 2) the "tt" genotype of a SNP marker (rs279858) of the GABRA2 gene, are more vulnerable to experience psychotomimetic and amnestic effects of Δ-9-THC.

Hypotheses: 1) Subjects homozygous for COMT Val108/158Met allele (Val-Val) will exhibit enhanced psychotomimetic and amnestic effects of Δ-9-THC. 2) Polymorphisms of the GABRA2 gene and other genes relevant to the known preclinical effects of cannabinoids and also to psychotic disorders e.g., neuregulin 1(Nrg1), dysbindin (DTNBP1) will moderate the psychotomimetic and amnestic response to Δ-9-THC.

Condition	Intervention	Phase
COMT Gene Polymorphism	Drug: delta 9 tetrahydrocannabinol	Phase I

Study Type:	Interventional
Study Design:	Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment
Official Title:	Pharmacogenetics of Cannabinoid Response

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Memory Psychotic Disorders

Drug Information available for: GW-1000 Tetrahydrocannabinol Cannabis

U.S. FDA Resources

Further study details as provided by Yale University:

Primary Outcome Measures:

PANSS: Psychotic symptoms will be measured using the Positive and Negative Syndrome Scale (PANSS). Rey Auditory Verbal Learning Test (AVLT): a 15 word list learning task of verbal memory and hippocampal function that has 6 alternate versions. [ Time Frame: Baseline, +15, +25(RAVLT only), +60, +300 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

CADSS:scale that measures perceptual alterations.Visual Analog Scale: a 16-item feeling state scale associated with cannabis.CANTAB: a computerized cognitive test battery is used to measure attention and memory. [ Time Frame: Baseline, +15, +35 (CANTAB only), +60, +300 ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	162
Study Start Date:	July 2007
Estimated Study Completion Date:	July 2012
Estimated Primary Completion Date:	May 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator Very low dose (0.005 mg/kg = 0.35 mg in a 70kg individual) THC, dissolved in ethanol. This dose is roughly equivalent to smoking 1/10th of a marijuana cigarette, or "joint". Low dose (0.025 mg/kg = 1.75 mg in a 70kg individual) THC, dissolved in ethanol. This dose is roughly equivalent to smoking 1/2 of a marijuana cigarette, or "joint". Medium dose (0.05 mg/kg = 3.5 mg in a 70 kg individual) THC, dissolved in ethanol. This dose is roughly equivalent to smoking 1 marijuana cigarette, or "joint".	Drug: delta 9 tetrahydrocannabinol 0.05 mg/kg of THC dissolved in ethanol intravenously over 20 minutes
2: Placebo Comparator small amount of ethanol, (quarter teaspoon), with no THC	Drug: delta 9 tetrahydrocannabinol 0.05 mg/kg of THC dissolved in ethanol intravenously over 20 minutes

Arms

Assigned Interventions

1: Active Comparator

Very low dose (0.005 mg/kg = 0.35 mg in a 70kg individual) THC, dissolved in ethanol. This dose is roughly equivalent to smoking 1/10th of a marijuana cigarette, or "joint".
Low dose (0.025 mg/kg = 1.75 mg in a 70kg individual) THC, dissolved in ethanol. This dose is roughly equivalent to smoking 1/2 of a marijuana cigarette, or "joint".
Medium dose (0.05 mg/kg = 3.5 mg in a 70 kg individual) THC, dissolved in ethanol. This dose is roughly equivalent to smoking 1 marijuana cigarette, or "joint".

Drug: delta 9 tetrahydrocannabinol

0.05 mg/kg of THC dissolved in ethanol intravenously over 20 minutes

2: Placebo Comparator

small amount of ethanol, (quarter teaspoon), with no THC

Drug: delta 9 tetrahydrocannabinol

0.05 mg/kg of THC dissolved in ethanol intravenously over 20 minutes

Detailed Description:

This study attempts to examine genetic influences on the magnitude and quality of the psychotomimetic and amnestic effects of tetrahydrocannabinol (Δ9-THC). While we will examine the influence of polymorphisms for the COMT gene, other candidate genes e.g., GABRA2, NRG1 will be also examined.

Tetrahydrocannabinol is the active ingredient of marijuana, cannabis, "ganja", or "pot". This study will involve healthy volunteers who 1) are medically healthy, 2) do not suffer from mental illness or drug abuse and 3) have used marijuana in the past. This study looks at individuals with different COMT gene polymorphism and their response to THC (euphoric effects, perception, memory changes). The study involves a screening day to determine eligibility and two test days over a period of roughly two weeks. On each of the study days, participants will have either THC or placebo administered intravenously.

THC will be infused over about 20 minutes. Throughout the day subjects will be asked questions about their thinking and mood, and asked to perform some memory tests and puzzles. In addition, heart rate, blood pressure and temperature will be checked by a research nurse and blood samples will be collected several times throughout the day. These evaluations will continue periodically throughout the test day. There will also be three follow up questionnaires at 1, 3, and 6 months after completion of the test days.

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

18 and 55 years (extremes included) on the day of the first dosing.
Able to provide informed consent.
Good physical and mental health as determined by history taking, the Structured Clinical Interview for DSM-IV TR (SCID-NP) and collateral information, physical and laboratory examinations, ECG and vital signs recordings as judged by the investigator.

Exclusion Criteria:

DSM-IV diagnosis of alcohol or substance dependence in the past year (except nicotine dependence).
Current and lifetime DSM-IV Axis I diagnoses and Axis II diagnoses. Some allowance may be made for adjustment disorders and reactive major depression at the discretion of the investigator. Also, this study may recruit individuals who frequently use cannabis, and who may meet DSM criteria for a cannabis use disorder. Such individuals too may be included at the discretion of the investigator.
Cannabis naïve individuals.
Unstable medical conditions that necessitate frequent changes in treatment: for example, recent myocardial infarction and uncontrollable hypertension. At the discretion of the investigator, subjects with unstable medical conditions that may necessitate changes in medical treatment and hence influence study outcomes will be excluded.
Positive pregnancy test.
Major current or recent (<6 weeks) stressors.
History of counseling, except if counseling was for a life circumstance disorder (e.g., bereavement, divorce).
Lifetime history of treatment with any psychotropic medications for > 1 month duration: for example, antipsychotics, antidepressants, mood stabilizers and anxiolytics used to treat a psychiatric condition except medications used for sleep.
Major Axis I diagnosis in first degree relatives.
Individuals with LFTs above the upper limit of normal.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00678730

Contacts

Contact: Jacqueline P Elander, B.A.

2039325711 ext 4523

jacqueline.elander@yale.edu

Locations

United States, Connecticut
VA Connecticut Healthcare System	Recruiting
West Haven, Connecticut, United States, 06516

Sponsors and Collaborators

Yale University

National Institute on Drug Abuse (NIDA)

Investigators

Principal Investigator:

Deepak D'Souza, M.D.

Yale University

More Information

No publications provided

Responsible Party:	Yale University School of Medicine, Dept of Psychiatry ( Deepak Cyril D'Souza, M.D. )
Study ID Numbers:	0706002754, R01 DA 012382-05
Study First Received:	May 13, 2008
Last Updated:	September 4, 2009
ClinicalTrials.gov Identifier:	NCT00678730 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Yale University:

THC
COMT gene polymorphism
schizophrenia
cannabis use

Additional relevant MeSH terms:

Tetrahydrocannabinol
Sensory System Agents
Analgesics, Non-Narcotic
Therapeutic Uses
Physiological Effects of Drugs
Psychotropic Drugs

Hallucinogens
Peripheral Nervous System Agents
Analgesics
Central Nervous System Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 09, 2010