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.

The effect of chronic cannabinoids on broadband EEG neural oscillations in humans.

Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10-50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis naïve controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis.

Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations.

Central cannabinoid receptors mediate neural oscillations and are localized to networks implicated in auditory P50 sensory gating, including the hippocampus and neocortex. The current study examined whether neural oscillations evoked by the paired clicks (S1, S2) are associated with abnormal P50 gating reported in cannabis users. Seventeen heavy cannabis users and 16 cannabis naïve controls participated. Analyses included P50 amplitudes, and time-frequency analyses (event-related spectral perturbations, ERSPs; intertrial coherence, ITC). Consistent with prior studies, cannabis users exhibited reduced P50 gating. The ERSP analysis yielded attenuated high frequency activity in the beta range (13-29 Hz) post-S1 and in the gamma range (30-50 Hz) post-S2 in the cannabis group, compared with the control group. Greater levels of cannabis use were positively associated with high P50 ratios and negatively with post-S2 ERSP gamma power. Findings suggest that heavy cannabis use is associated with aberrant beta and gamma activity in the dual-click procedure, which corroborates recent work demonstrating disruption of beta/gamma by cannabinoid receptor (CB1) agonists in a rat analogue of this task and highlights the translational potential of the dual-click procedure [corrected]

Assessment of forebrain-dependent trace eyeblink conditioning in chronic cannabis users.

While CB1 knockout mice exhibit striking impairments on a cerebellar-dependent task called delay eyeblink conditioning (dEBC), these animals demonstrate intact forebrain-dependent trace EBC (tEBC). Although heavy human cannabis users also show impaired delay EBC, their performance on tEBC is currently unknown. Therefore, 13 heavy cannabis users and 13 cannabis naive controls completed a tEBC procedure. The cannabis group exhibited similar rates of conditioned responding compared to controls in the acquisition and extinction phase. Consistent with reports of overt attentional abnormalities, the cannabis group exhibited decreased N100 ERP amplitudes to the tone CS that were unrelated to mean levels of conditioning across blocks during the acquisition phase. The lack of a significant effect of heavy cannabis use on tEBC reported here, combined with the previous report of impaired dEBC in such users, mirrors the findings observed in CB1 knockout mice, and suggests that the cannabinoid system differentially mediates forebrain- and cerebellar-dependent learning processes in both humans and animals.

The effect of selective attention on the gamma-band auditory steady-state response.

Studies have demonstrated that selective attention can modulate the steady-state evoked potential to repetitive visual and tactile stimulation. However, examinations of the effect of attention on the auditory steady-state response (ASSR) have proven equivocal. The current experiment therefore utilized EEG to examine the effect of attention on the ASSR in healthy humans (n=15). Auditory click trains in the beta (20 Hz) and gamma (40 Hz) ranges were randomly presented binaurally in an oddball discrimination paradigm (each frequency served as the oddball (target) in each of two blocks). A Fast Fourier Transform was used to assess the effect of attention on the ASSR (signal power), and phase consistency across trials was assessed using the phase-locking factor (PLF). As expected, both 20 and 40 Hz targets elicited a robust P300 response, with maximal amplitudes over parietal regions. For the ASSR, it was found that EEG signal power was larger to 40 Hz targets compared to 40 Hz frequent stimuli across all frontocentral electrodes. No differences in signal power were observed during 20 Hz stimulation. Finally, increased PLF values were observed for 40 Hz targets compared to frequent trials. These results provide evidence that selective attention can enhance signal power and phase-locking of the ASSR, particularly to auditory stimulation in the gamma range.

Psychophysiological evidence of altered neural synchronization in cannabis use: relationship to schizotypy.

OBJECTIVE: Cannabis use may produce neurophysiological disturbances similar to those observed in schizophrenia, particularly in relation to altered neural synchronization. Therefore, the current experiment examined the effect of cannabis use on EEG neural synchronization using the auditory steady-state evoked potential. METHOD: Auditory steady-state evoked potentials were assessed using varying rates of stimulation (auditory click-trains of 20, 30, 40 Hz) in current cannabis users (N=17) and drug-naive comparison subjects (N=16). EEG spectral power and signal-to-noise ratio at each stimulation frequency were compared between groups. RESULTS: Cannabis users showed decreased EEG power and signal-to-noise ratio at the stimulation frequency of 20 Hz. In addition, current cannabis users demonstrated increased schizotypal personality characteristics as assessed with the Schizotypal Personality Questionnaire, which positively correlated with total years of cannabis use. Finally, within the cannabis group, 20-Hz power values were negatively correlated with Schizotypal Personality Questionnaire scores. CONCLUSIONS: These data provide evidence for neural synchronization and early-stage sensory processing deficits in cannabis use. This finding, along with the observed increased rates of schizotypy in cannabis users, adds support for a cannabinoid link to schizophrenia spectrum disorders.