Stephen R. Wachtel

Comparison of the subjective effects of Δ9-tetrahydrocannabinol and marijuana in humans

Rationale. There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Δ9-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form.Objective. Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.Methods. In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC.Results. In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences.Conclusion. These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.

The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers

Despite extensive evidence that selective dopamine antagonists attenuate the reinforcing effects of stimulants in laboratory animals, there is little evidence that dopamine antagonists block the positive subjective effects of stimulants in humans. However, recent evidence suggests that the subjective effects of stimulants in humans may depend in part on serotonin. The goal of this study was to examine the effects of haloperidol, a drug that primarily blocks dopamine receptors, and risperidone, a drug that blocks both dopamine and serotonin receptors, on the physiological and subjective effects of methamphetamine in healthy volunteers. Two groups of subjects participated in a placebo-controlled, within-subject, 2 x 2 repeated measures design. One group was tested with haloperidol (3 mg; N = 18), the other with risperidone (0.75 mg; N = 18). Each subject participated in four sessions receiving all combinations of antagonist or placebo and methamphetamine (20 mg) or placebo. Dependent measures included vital signs and standardized questionnaires of subjective effects. At these doses, both haloperidol and risperidone produced mild sedative-like effects compared to placebo. However, neither drug consistently reduced the stimulant-like effects of methamphetamine. These results add to the growing body of literature suggesting that D(2) dopamine receptor antagonists do not block the euphorigenic subjective effects of stimulant drugs in humans, and also do not support the idea that serotonin contributes significantly to these effects.

Role of Aromatic l-Amino Acid Decarboxylase for Dopamine Replacement by Genetically Modified Fibroblasts in a Rat Model of Parkinson's Disease

Abstract: Investigations of gene therapy for Parkinsons disease have focused primarily on strategies that replace tyrosine hydroxylase. In the present study, the role of aromatic l‐amino acid decarboxylase in gene therapy with tyrosine hydroxylase was examined by adding the gene for aromatic l‐amino acid decarboxylase to our paradigm using primary fibroblasts transduced with both tyrosine hydroxylase and GTP cyclohydrolase I. We compared catecholamine synthesis in vitro in cultures of cells with tyrosine hydroxylase and aromatic l‐amino acid decarboxylase together versus cocultures of cells containing these enzymes separately. l‐DOPA and dopamine levels were higher in the cocultures that separated the enzymes. To determine the role of aromatic l‐amino acid decarboxylase in vivo, cells containing tyrosine hydroxylase and GTP cyclohydrolase I were grafted alone or in combination with cells containing aromatic l‐amino acid decarboxylase into the 6‐hydroxydopamine‐denervated rat striatum. Grafts containing aromatic l‐amino acid decarboxylase produced less l‐DOPA and dopamine as monitored by microdialysis. These findings indicate that not only is there sufficient aromatic l‐amino acid decarboxylase near striatal grafts producing l‐DOPA, but also the close proximity of the enzyme to tyrosine hydroxylase is detrimental for optimal dopamine production. This is most likely due to feedback inhibition of tyrosine hydroxylase by dopamine.

Naltrexone does not block the subjective effects of oral Δ9-tetrahydrocannabinol in humans

Abstract Δ 9 -tetrahydrocannabinol (THC) and opioids have many common effects. In addition, some THC effects in laboratory animals can be blocked or attenuated by opioid antagonists. This suggests that opioid systems mediate or modulate some THC effects. To determine whether opioid systems mediate THC effects in humans, the effects of the opioid antagonist naltrexone on subjective responses to THC were examined in 14 marijuana users. Subjects participated in a double-blinded, cross-over design in which each subject received all combinations of naltrexone (0 or 50 mg) and THC (0, 7.5, or 15 mg). THC increased heart rate and self-reported drug effects, such as euphoria and marijuana-like effects, and decreased psychomotor performance. Naltrexone increased heart rate and decreased self-reported measures of vigor and hunger but did not alter any of the effects of THC. These results suggest that the subjective, physiological, and behavioral effects of THC in humans are not mediated through opioid systems.

An fMRI Study of the Effect of Amphetamine on Brain Activity

Functional magnetic resonance imaging was used to evaluate the effects of oral d-amphetamine on brain activation elicited by auditory and simple motor tasks in ten normal right-handed subjects. We measured the percent signal change and number of voxels activated by a tone discrimination task and a right hand finger-tapping task after 20 mg of d-amphetamine and after placebo. Compared to placebo, amphetamine significantly increased the number of activated voxels in the left and right primary auditory cortices during the tone discrimination task and increased the number of activated voxels in the ipsilateral primary sensorimotor cortex and right middle frontal area during the motor task. Although highly specific vascular effects of drug cannot be ruled out as an explanation, these results could also mean that amphetamine increases the neuronal activity associated with each of these two tasks.

The dopamine D1 receptor antagonist SCH 23390 can exert D1 agonist-like effects on rat nucleus accumbens neurons.

Interactions between the selective dopamine D1-class receptor antagonist SCH 23390 and the dopamine D2-class receptor agonist quinpirole on nucleus accumbens neurons were investigated with extracellular single cell recording and microiontophoresis. Because dopamine D1 receptor stimulation enables many dopamine D2 receptor-mediated effects, SCH 23390 was expected to antagonize quinpirole-induced inhibition of activity. Although concurrent iontophoretic administration of SCH 23390 attenuated the inhibitory effects of quinpirole on most neurons, the antagonist further suppressed the firing of most neurons during attempts to reverse quinpirole-induced inhibition. SCH 23390 also reinstated (enabled) quinpirole-induced inhibition in rats acutely depleted of dopamine. These findings suggest that under certain conditions, SCH 23390 may exert dopamine D1 agonist-like effects.

Lack of effect of intravenous hydrocortisone on mood in humans: a preliminary study.

Patients receiving therapy with hydrocortisone often report that this drug produces stimulant‐like effects or feelings of well‐being. However, little is known about the mood‐elevating effects of hydrocortisone after acute administration. Four healthy volunteers (two men and two women) received intravenous doses of hydrocortisone (0, 25, 50, 100 or 200 mg) on five separate sessions. Plasma levels of cortisol and adrenocorticotropic hormone (ACTH) were obtained, vital signs were monitored, and subjects completed a series of standardized subjective effects questionnaires. Despite large increases in circulating levels of cortisol, hydrocortisone did not produce any detectable stimulant‐like effect on mood or vital signs. To the contrary, hydrocortisone had a mild sedative‐like effect, decreasing ‘arousal’. These preliminary data indicate that acute increases in cortisol do not have either subjective stimulant‐like or mood‐elevating effects.