Preliminary study of the interactive effects of THC and ethanol on self-reported ability and simulated driving, subjective effects, and cardiovascular responses.

RATIONALE: Drug- and alcohol-related motor vehicle accidents are a leading cause of morbidity and mortality worldwide. Compared to alcohol, less is known about the effects of cannabis on driving and even less about their combined effects. OBJECTIVE: To characterize the combined and separate effects of ethanol and tetrahydrocannabinol (THC) on perceived ability to drive, subjective effects, and simulated driving. METHODS: In a within-subject (crossover), randomized, placebo-controlled, double-blind, 2 × 2 design, the effects of oral THC (10 mg [dronabinol] or placebo) and low-dose intravenous ethanol (clamped at BAC 0.04% or placebo) on perceived ability to drive, simulated driving (standard deviation of lateral position [SDLP]), subjective effects (e.g., "high"), and physiological effects (e.g., heart rate) were studied in healthy humans (n = 18). RESULTS: Subjects reported reductions in perceived ability to drive (THC < ethanol < combination) which persisted for ~ 6 h (placebo = ethanol, THC < combination). Ethanol and THC produced synergistic effects on heart rate, significant differences compared to either drug alone on perceived ability to drive and feeling states of intoxication (e.g., high), as well increases in SDLP compared to placebo. CONCLUSIONS: Perceived ability to drive is reduced under the influence of THC against the backdrop of blood alcohol levels that are below the legal limit. People should be aware that the effects of oral THC on driving may persist for up to six hours from administration. Findings are relevant to the increasingly common practice of combining alcohol and cannabinoids and the effects on driving.

Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache. BACKGROUND: Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. METHODS: Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. RESULTS: In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] -2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and -3.2 (95% CI -8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events. CONCLUSIONS: Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

Sex differences in the acute effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC).

BACKGROUND: Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated the sex differences in the acute subjective, psychotomimetic, cognitive, and physiological effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. METHODS: Healthy male and female individuals, with limited exposure to cannabis, participated in a double blind, placebo-controlled study of intravenous (IV) placebo or THC at two doses (0.015 mg/kg and 0.03 mg/kg). Visual analog scale (VAS) was used to measure subjective effects, Psychotomimetic States Inventory (PSI) and the Clinician-Administered Dissociative Symptoms Scale (CADSS) were used to assess the psychotomimetic effects and perceptual alterations, respectively, and Rey Auditory Verbal Learning Task (RAVLT) was used to evaluate cognitive effects. Outcome variables were represented as the peak change from baseline for each variable, except RAVLT which was used only once per the test day after the subjective effects. RESULTS: A total of 42 individuals participated in this study. There were no significant differences between male and female participants in background characteristics. There was a significant main effect of sex on the VAS scores for THC-induced "High" (F1,38 = 4.27, p < 0.05) and a significant dose × sex interaction (F2,77 = 3.38, p < 0.05) with female participants having greater "High" scores than male participants at the lower THC dose (0.015 mg/kg). No other sex differences were observed in acute subjective, psychotomimetic, cognitive, or physiological effects of THC. CONCLUSION: There were significant sex differences in subjective effects of feeling "High" at a lower dose of THC. However, there were no other sex-related differences in the subjective, physiological, or cognitive effects of THC.

Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin.

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, - 1.65 (95% CI: - 2.53 to - 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans.

BACKGROUND: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans. AIMS: Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg). METHODS: Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention. RESULTS/OUTCOMES: Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions. CONCLUSIONS/INTERPRETATION: These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.