Louis Lemberger

11-Hydroxy-Δ9-tetrahydrocannabinol: Pharmacology, Disposition, and Metabolism of a Major Metabolite of Marihuana in Man

11-Hydroxy-Δ9-tetrahydrocannabinol, administered intravenously to man, produces psychologic and pharmacologic effects that persist for several hours. The drug and its metabolites are excreted in urine and feces for more than 1 week. The pharmacology, disposition, and metabolism of 11-hydroxy-Δ9-tetra-hydrocannabinol mimic that of Δ9-tetrahydrocannabinol, thus providing evidence that Δ9-tetrahydrocannabinol (the major active component of marihuana) is converted to the 11-hydroxy compound in man, the latter compound being responsible for the effects.

Fluoxetine, a selective serotonin uptake inhibitor.

Fluoxetine is a selective serotonin uptake inhibitor in man. Platelets harvested from subjects to whom fluoxetine was administered (30 mg daily for 1 wk) had a diminished ability to accumulate 3H‐serotonin. The inhibition of uptake was positively correlated with the plasma concentrations of fluoxetine. Plasma from fluoxetine‐treated subjects also inhibited the uptake of 3H‐serotonin by platelets obtained from nontreated subjects. Fluoxetine was without effect on the noradrenergic nerve endings; pressor effects induced after the administration of norepinephrine or tyramine were similar whether subjects were receiving fluoxetine or placebo. Fluoxetine administration for 30 days produced similar pharmacologic effects as after the 7‐day study and included: (1) no change in sensitivity to the pressor effects of tyramine and norepinephrine and (2) marked inhibition in the uptake of 3H‐serotonin by platelets harvested from subjects on this regimen. In addition, fluoxetine caused a diminution of the concentration of endogenous serotonin in platelets, resulting in serotonin levels of only 20% of control. Fluoxetine was well absorbed and achieved peak plasma concentration at 6 hr after administration. Fluoxetine and the major metabolite, norfluoxetine, appeared to reach a steady state within 12 to 14 days. Fluoxetine, administered in single doses of 1 to 90 mg produced no behavioral or adverse effects. Similarly, after 1 wk of fluoxetine administration, no behavioral or adverse effects were observed.

Fluoxetine kinetics and protein binding in normal and impaired renal function.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40‐mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

Cardiovascular effects of delta-9-tetrahydrocannabinol in man.

The effects of a pharmacologic dose of delta‐9‐tetrahydrocannabinol (Δ‐9‐THC) on the human circulatory system were investigated. Their relation to plasma drug levels, urinary catecholamine excretion, and psychic effects was observed. Δ‐9‐THC (0.3 mg. per kilogram) was administered orally to 8 male volunteers. Four subjects also received tracer amounts of C14‐Δ‐9‐THC. Recumbent and upright heart rate, recumbent mean arterial blood pressure, forearm blood flow, and calculated forearm conductance all increased significantly following drug administration. Significant shortening of ventricular pre‐ejection period and attenuation or abolition of reflex venoconstriction in response to a deep breath were also seen. Mean arterial pressure decreased transiently with head‐up tilt and was associated with presyncope in 7 subjects, although cardioacceleratory response and forearm arteriolar constriction remained intact. Plasma levels of C14Δ‐9‐THC and its metabolites were maximal at 3 hours. Gastrointestinal absorption was 95 per cent complete. Urinary excretion of free epinephrine was significantly higher during the 6 hour period following Δ‐9‐THC administration than during a similar control period. Free norepinephrine excretion was unchanged. Several of the cardiovascular effects seen appear to be consistent with increased sympathoadrenal activity. This suggests the possibility that augmented epinephrine secretion is in part responsible for these Circulatory changes.

Influence of cannabidiol on delta‐9‐tetrahydrocannabinol effects

Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double‐blind manner. In one study, 15 male volunteers were given placebo or 25 µg/kg of THC together with either placebo or 150 µg/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin‐square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC‐like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 µg/kg) by smoke inhalation 30 min before THC (0 or 25 µg/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.

Clinical pharmacology of nabilone, a cannabinol derivative

Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose‐related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5‐mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5‐mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7‐day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.

Pergolide, a potent long‐acting dopamine‐receptor agonist

After single doses (100 to 400 µg orally), pergolide, a synthetic ergot, reduced basal plasma prolactin levels in normal subjects in a dose‐related manner. This effect persisted for more than 24 hr. Multiple doses of pergolide (150 to 250 µg daily for 7 days) resulted in a plasma prolactin decrease of more than 80%. A single dose of pergolide (150 µg orally) suppressed plasma prolactin and abolished the plasma prolactin diurnal rhythm, i.e., suppression of sleep‐induced elevation in plasma prolactin during a 40‐hr period. Perphenazine (5 mg intramuscularly)–induced plasma prolactin elevation was inhibited by pergolide; the effect was dose dependent. After single or multiple doses, pergolide had no effect on plasma follicle‐stimulating hormone, luteinizing hormone, Cortisol, growth hormone, and thyroid‐stimulating hormone. Pergolide appears to have specificity at the pituitary level for the dopamine receptors that mediate prolactin secretion.

Physiologic disposition of nabilone, a cannabinol derivative, in man.

Nabilone is a cannabinoid that is being evaluated in man as a potentially useful psychoactive drug. We found that nabilone was readily absorbed from the human gastrointestinal tract when administered orally as a coprecipitate with polyvinyl‐pyrrolidone. The absorbed drug disappearedfrom plasma rather rapidly (half‐life, approximately 2 hr), evidently due to extensive tissue distribution and rapid metabolism. The metabolites of nabilone persist in plasma for extended periods (half‐life of total radioactivity exceeds 20 hr). Circulating metabolites include isomeric carbinols formed by reduction of the ketone in the 9‐position of nabilone. Nabilone is eliminated in feces (about 65% of dose) and urine (20%). The excretory products in urine have not been identified, but metabolites that are labile to hydrolysis by β‐glucuronidase or sulfatase do not appear to be formed in signijicant amounts. A metabolite of nabilone in fixes has been identified as a diol formed by reduction of the 9‐keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. The long duration of action of nabilone in the face of rapid and extensive metabolic elimination suggests that the pharmacologic effects, at least in part, may be exerted by one or more active metabolites.

Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol.

The effects of fluoxetine, a specific serotonin reuptake inhibitor, on the psychomotor performance, physiologic response, and kinetic disposition of ethanol were examined. Fluoxetine (30 or 60 mg) with ethanol (45 ml absolute alcohol per 70 kg body weight) did not alter the plasma or blood concentrations of fluoxetine or ethanol, respectively, when compared with levels after either drug alone. There was no significant effect on standing or recumbent blood pressure or heart rate after single or multiple doses of fluoxetine alone or in the combination. Single or multiple doses of fluoxetine had no effect on the psychomotor activity (stability of stance, motor performance, or manual coordination) or subjective effects of alcohol. Data indicate that fluoxetine does not inhibit ethanol metabolism nor does it have any effects on its psychomotor activity.

Impairment of performance with low doses of marihuana.

Eight volunteers smoked marihuana cigarettes under controlled laboratory conditions on 4 separate occasions. The cigarettes were calibrated to deliver doses of 0, 3, 6, and 9 µg per kilogram of delta‐9‐tetrahydrocannabinol (THC). The experimental design was a double‐blind random block with a 1 week interval between sessions. Analysis of variance revealed a significant linear decrease in stability with increase in dose of THC. The tracking scores with Pursuit Meter (PM) demonstrated a significant increase above control for all three doses of THC. Mental performance, as evaluated by Delayed Auditory Feedback (DAF), and subjective evaluation revealed no consistent change with dose.