Background: A family history of alcoholism is a risk factor for the development of alcohol problems. Factors that modulate the positive and negative reward valence of alcohol effects may influence the likelihood of repeated and or problematic use, and are therefore of interest. Alcohol has multiple targets in the brain that independently contribute to its behavioral effects. Studies with various pharmacological probes including alcohol, ketamine and benzodiazepines suggest differences between healthy FHP and FHN individuals. There is growing preclinical evidence suggesting involvement of brain cannabinoid receptor (CB-1R) function in the pharmacological actions of alcohol and in alcohol-drinking behaviors. Cannabinoids and alcohol activate the same reward pathways. CB-1R agonists stimulate while CB-1R antagonists suppress, alcohol self-administration and the motivational properties of alcohol. Comparison to wild type mice, CB-1R knockout mice show 1) significantly lower levels of alcohol preference and consumption, 2) slower rate of acquisition of alcohol drinking behavior, 3) lower alcohol sensitivity, and 4) blunted alcohol-induced dopamine release in the nucleus accumbens. Finally, alcohol-preferring mice have a significantly lower level of CB-1R binding sites and higher affinity for CB-1R agonist than alcohol-avoiding mice. Despite these preclinical data, there is a paucity of clinical research in this area.

Hypotheses: Individuals with a family history of alcoholism (FHP) will exhibit blunted 1) euphoric, 2) perceptual and 3) amnestic effects in response to d-9-tetrahydrocannabinol (d-9-THC) administration compared to individuals without a family history of alcoholism (FHN).

This study attempts to characterize the effects of tetrahydrocannabinol (THC). Tetrahydrocannabinol is the active ingredient of marijuana, cannabis, "ganja", or "pot". This study will involve healthy volunteers who 1) have no history of alcoholism in their family or 2) have a family history of alcoholism. This study looks at individuals with or without a family history of alcoholism to determine if there is a difference between the two groups in the response to THC (euphoric effects, perception, memory changes). The study involves a screening day to determine eligibility and three test days over a period of roughly three weeks. On each of the study days, participants will have one of four doses of THC administered intravenously. During each of the three test days, subjects will receive in random order either:

• High dose: 0.036 mg/kg (2.5 mg in a 70 kg individual) dissolved in ethanol. Equivalent to smoking a full joint
• Low dose: 0.018 mg/kg (1.25 mg in a 70kg individual) dissolved in ethanol. Equivalent to smoking ½ of a joint
• Very low dose: 0.0036 mg/kg (0.25 mg in a 70 kg individual) dissolved in ethanol. Equivalent to smoking 1/10 of a joint
• Placebo: Small amount of ethanol, (quarter teaspoon).

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.

• Drug: THC
• Drug: Placebo

• Active Comparator:
  • High dose: 0.036 mg/kg (2.5 mg in a 70 kg individual) IV (in the vein) dissolved in ethanol.Equivalent to smoking a full joint
  • Low dose: 0.018 mg/kg (1.25 mg in a 70kg individual)IV (in the vein) dissolved in ethanol.Equivalent to smoking ½ of a joint
  • Very low dose: 0.0036 mg/kg (0.25 mg in a 70 kg individual)IV (in the vein) dissolved in ethanol.Equivalent to smoking 1/10 of a joint
• Placebo Comparator: Placebo: Small amount of ethanol IV (in the vein), (quarter teaspoon).

Inclusion Criteria:

• Male and female
• Greater than 18 years
• Exposure to cannabis at least once
• Absence of any evidence of substance abuse (with the exception of alcohol abuse)or intoxication on the basis of history
• Drug and ethanol-free at the time of testing based on urine toxicology and breath alcohol levels at screening and on each test day
• Medically and neurologically healthy on the basis screening

Exclusion Criteria:

• DSM-IV Axis I or II disorder other than alcohol abuse
• Cannabis naïve: to exclude the theoretical possibility that exposure to THC in the laboratory facilitates future cannabis use/abuse
• Cannabis use in the past 3 weeks: to minimize residual effects
• We will exclude subjects who have had a serious negative reaction to cannabis (i.e. acute panic or paranoid reaction).
• Current treatment with medications that may confound the effects of THC
• IQ less than 85
• Less than a high school diploma or its educational equivalent
• Pregnancy or lactation
• Unwillingness to refrain from alcohol use for three days prior to each test day
• Major current or recent (<6 weeks) psychosocial stressors. We find that some subjects who have experienced a recent stressor may while intoxicated become unnecessarily distressed