Pharmacogenetics of Cannabinoid Response

Condition(s) targeted: COMT Gene Polymorphism

Intervention: delta 9 tetrahydrocannabinol (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Yale University

Official(s) and/or principal investigator(s):
Deepak D'Souza, M.D., Principal Investigator, Affiliation: Yale University

Overall contact:
Jacqueline P Elander, B.A., Phone: 2039325711, Ext: 4523, Email: jacqueline.elander@yale.edu

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.

Official title: Pharmacogenetics of Cannabinoid Response

Study design: Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment

Primary outcome: 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.

Secondary outcome: 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.

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.

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

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.

Jacqueline P Elander, B.A., Phone: 2039325711, Ext: 4523, Email: jacqueline.elander@yale.edu

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

Starting date: July 2007
Ending date: July 2012
Last updated: September 4, 2009