Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study.

The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.

Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial.

BACKGROUND: Cannabis is one of the most widely used drugs worldwide. Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment. There are no approved pharmacological treatments for cannabis use disorder. One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. We aimed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users. METHODS: We did a double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18-55 years with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5). After baseline assessments, participants were randomly assigned (2:1) to receive PF-04457845 (4 mg per day) or placebo using a fixed block size of six participants, stratified by severity of cannabis use and desire to quit. Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients. The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission, and week 4 (end of treatment) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT01618656. FINDINGS: Between Sept 12, 2012, and Jan 18, 2016, 46 men were randomly assigned to PF-04457845 and 24 to placebo. Adherence to study medication was 88%, as confirmed by video-calling and pill count, and corroborated by corresponding drug and anandamide concentrations in blood. Relative to placebo, treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal (first day of treatment mean symptom score 11·00 [95% CI 7·78-15·57] vs 6·04 [4·43-8·24]; difference 4·96 [0·71-9·21]; padj=0·048; second day of treatment 11·74 [8·28-16·66] vs 6·02 [4·28-8·47]; difference 5·73 [1·13-10·32]; padj=0·035) and related mood symptoms during the inpatient phase. Additionally, treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks (mean 1·27 joints per day [95% CI 0·82-1·97] vs 0·40 [0·25-0·62]; difference 0·88 [0·29-1·46]; p=0·0003) and lower urinary THC-COOH concentrations (mean 657·92 ng/mL [95% CI 381·60-1134·30] vs 265·55 [175·60-401·57]; difference 392·37 [17·55-767·18)]; p=0·009). Eight (17%) patients in the PF-04457845 group and four (17%) in the placebo group discontinued during the treatment period. During the 4-week treatment phase, 20 (43%) of 46 participants in the PF-04457845 group and 11 (46%) of 24 participants in the placebo group had an adverse event. There were no serious adverse events. INTERPRETATION: PF-04457845, a novel FAAH inhibitor, reduced cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder. FUNDING: United States National Institute of Drug Abuse (NIDA).

Δ9-THC Disrupts Gamma (γ)-Band Neural Oscillations in Humans.

Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ(9)-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ(9)-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ(9)-THC. Δ(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders.

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.

Evoked gamma band response in male adolescent subjects at high risk for alcoholism during a visual oddball task.

This study investigates early evoked gamma band activity in male adolescent subjects at high risk for alcoholism (HR; n=68) and normal controls (LR; n=27) during a visual oddball task. A time-frequency representation method was applied to EEG data in order to obtain stimulus related early evoked (phase-locked) gamma band activity (29-45 Hz) and was analyzed within a 0-150 ms time window range. Significant reduction of the early evoked gamma band response in the frontal and parietal regions during target stimulus processing was observed in HR subjects compared to LR subjects. Additionally, the HR group showed less differentiation between target and non-target stimuli in both frontal and parietal regions compared to the LR group, indicating difficulty in early stimulus processing, probably due to a dysfunctional frontoparietal attentional network. The results indicate that the deficient early evoked gamma band response may precede the development of alcoholism and could be a potential endophenotypic marker of alcoholism risk.