Naltrexone does not attenuate the effects of intravenous Δ9-tetrahydrocannabinol in healthy humans.

Although a wealth of preclinical evidence indicates an interplay between the µ-opioid (MOR) and cannabinoid 1 receptor (CB1R) systems, the precise nature of the cross modulation in humans is unclear. The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist, naltrexone, on the subjective, behavioural and cognitive effects of the CB1R agonist, Δ9-tetrahydrocannabinol (THC), in healthy human subjects. Healthy human subjects, screened carefully for any medical or psychiatric illness, were administered either placebo or active naltrexone (25 mg) orally on each test day, followed 45 min later by placebo and 165 min later by active i.v. THC (0.025 mg/kg) in a randomized, fixed-order, double-blind manner. Subjective, behavioural and cognitive effects were assessed before and at several points after each drug administration. THC produced expected effects, including euphoria, anxiety, transient perceptual alterations, transient psychotomimetic effects and cognitive impairments. However, naltrexone did not produce any effects alone, nor did it attenuate any of THC's effects. Thus, in healthy human subjects who use cannabis intermittently, MOR antagonism does not modulate the common acute subjective, behavioural and cognitive effects of THC.

Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information.

INTRODUCTION: Cannabis and agonists of the brain cannabinoid receptor (CB1R) produce acute memory impairments in humans. However, the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans. The objective of this analysis was to determine whether the administration of Δ9-Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, impairs encoding and/or retrieval of verbal information. MATERIALS AND METHODS: Healthy subjects were recruited from the community. Subjects were administered the Rey-Auditory Verbal Learning Test (RAVLT) either before administration of THC (experiment #1) (n=38) or while under the influence of THC (experiment #2) (n=57). Immediate and delayed recall on the RAVLT was compared. Subjects received intravenous THC, in a placebo-controlled, double-blind, randomized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication. RESULTS: Total immediate recall, short delayed recall, and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC (experiment #2) and not when the RAVLT was administered prior. CONCLUSIONS: THC acutely interferes with encoding of verbal memory without interfering with retrieval. These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information. Future studies will be necessary to determine whether THC impairs encoding of non-verbal information, to what extent THC impairs memory consolidation, and the role of other cannabinoids in the memory-impairing effects of cannabis. CLINICAL TRIAL INFORMATION: Cannabinoids, Neural Synchrony, and Information Processing (THC-Gamma) http://clinicaltrials.gov/ct2/show/study/NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http://clinicaltrials.gov/ct2/show/NCT00678730 NCT00678730.

Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism.

BACKGROUND AND AIMS: A family history (FH) of alcoholism accounts for approximately 50% of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB1R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB1R function decreases alcohol-related behaviors and enhanced CB1R function increases them. In this first human study, we probed CB1R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). DESIGN, SETTING, AND PARTICIPANTS: Healthy volunteers (n = 30) participated in a three test day study during which they received 0.018 and 0.036 mg/kg of Δ(9)-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions. MEASUREMENTS: Primary outcome measures were subjective "high," perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ(9)-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable. FINDINGS: Greater FH was correlated with greater "high" and perceptual alterations induced by Δ(9)-THC. This enhanced sensitivity with increasing FH was specific to Δ(9)-THC's rewarding effects and persisted even when FH was calculated using an alternate method. CONCLUSIONS: Enhanced sensitivity to the rewarding effects of Δ(9)-THC in high-FH volunteers suggests that alterations in CB1R function might contribute to alcohol misuse vulnerability.

Lower ß2*-nicotinic acetylcholine receptor availability in smokers with schizophrenia.

OBJECTIVE: There is a strong association between cigarette smoking and schizophrenia. Nicotine's actions in the brain are mediated through nicotinic acetylcholine receptors. Those containing α(4) and ß(2) subunits are the most abundant ones in the brain, have the highest affinity for nicotine, and are critical in mediating nicotine's reinforcing properties. Healthy tobacco smokers have significantly higher levels of ß(2)*-nicotinic acetylcholine receptors than do nonsmokers. However, in postmortem studies, smokers with schizophrenia do not show these higher levels. The purpose of this study was to measure ß(2)*-nicotinic acetylcholine receptors in vivo and to relate levels to concurrent behavioral measures of smoking and schizophrenia. METHOD: By using single-photon emission computed tomography with the ß(2)*-nicotinic acetylcholine receptor agonist radiotracer [(123)I]5-IA-85380, the availability of receptors was measured in smokers with schizophrenia (11 men) and matched comparison smokers after 1 week of confirmed smoking abstinence. RESULTS: Smokers with schizophrenia showed significantly lower (21%-26%) ß(2)*-nicotinic acetylcholine receptor availability relative to comparison smokers in the frontal cortex, parietal cortex, and thalamus (in descending order). There was a specific and robust negative correlation between regional ß(2)*-nicotinic acetylcholine receptor availability and negative symptoms. CONCLUSIONS: These are the first in vivo findings of lower ß(2)*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. The relationship between ß(2)*-nicotinic acetylcholine receptor availability and negative symptoms may explain the high rates of smoking in schizophrenia and the relationship between smoking and negative symptoms. Findings support the development of medications targeting the ß(2)*-nicotinic acetylcholine receptor system for the treatment of negative symptoms.

The safety of studies with intravenous Δ9-tetrahydrocannabinol in humans, with case histories.

RATIONALE: Delta-9-tetrahydrocannabinol (THC) is one of the few cannabinoid receptor ligands that can be used to probe the cannabinoid system in humans. Despite increasing interest in the cannabinoid receptor system, use of intravenous THC as a research tool has been limited by concerns about its abuse liability and psychoactive effects. OBJECTIVES: This study aims to evaluate the safety of all intravenous THC studies conducted at this center for the past 13 years. METHODS: Included were 11 studies with 266 subjects (14 schizophrenia patients and 252 healthy subjects, of whom 76 were frequent cannabis users), 351 active THC infusions, and 226 placebo infusions. Subjects were monitored for subjective and physical adverse events and followed up to 12 months beyond study participation. RESULTS: There was one serious and 70 minor adverse events in 9.7% of subjects and 7.4% of infusions, with 8.5% occurring after the end of the test day. Nausea and dizziness were the most frequent side effects. Adverse events were more likely to be associated with faster infusion rates (2-5 min) and higher doses (>2.1 mg/70 kg). Of 149 subjects on whom long-term follow-up data were gathered, 94% reported either no change or a reduction in their desire to use cannabis in the post-study period, 18% stated that their cannabis use decreased, and 3% stated that it increased in the post-study period. CONCLUSIONS: With careful subject selection and screening, risk to subjects is relatively low. Safeguards are generally sufficient and effective, reducing both the duration and severity of adverse events.

Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence.

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.

Dose-related modulation of event-related potentials to novel and target stimuli by intravenous Δ9-THC in humans.

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory 'oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective 'high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ(9)-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing.