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

D’Souza, Deepak Cyril; Cortes-Briones, Jose; Creatura, Gina; Bluez, Grai; Thurnauer, Halle; Deaso, Emma; Bielen, Kim; Surti, Toral; Radhakrishnan, Rajiv; Gupta, Aarti; Gupta, Swapnil; Cahill, John D.; Sherif, Mohamed; Makriyannis, Alexandros; Morgan, Peter T.; Ranganathan, Mohini; Skosnik, Patrick D.

doi:10.1016/s2215-0366(18)30427-9

Cited by 144 publications

(129 citation statements)

References 38 publications

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“…As a result, A carriers can be used as a human genetic model of elevations in anandamide, which may be able to inform whether FAAH inhibitors would have an effect on these intermediate endophenotypes . Indeed, FAAH inhibitors have been shown to be effective for treating CUD . However, research has also shown that those with the C allele have an increased risk of CUD and related endophenotypes .…”

Section: Discussionsupporting

confidence: 88%

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Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme

et al. 2019

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Understanding genetic factors that contribute to cannabis use disorder (CUD) is important, but to date, findings have been equivocal. Single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 gene (CNR1; rs1049353 and rs806378) and fatty acid amide hydrolase (FAAH) gene (rs324420) have been implicated in CUD. Their relationship to addiction endophenotypes such as cannabis-related state satiety, the salience of appetitive cues, and craving after acute cannabinoid administration has not been investigated. Forty-eight cannabis users participated in a double-blind, placebo-controlled, four-way crossover experiment where they were administered treatments in a randomized order via vaporization: placebo, Δ 9 -tetrahydrocannabinol (THC) (8 mg), THC + cannabidiol (THC + CBD) (8 + 16 mg), and CBD (16 mg). Cannabis-related state satiety, appetitive cue salience (cannabis and food), and cannabis craving were assessed each day. Participants were genotyped for rs1049353, rs806378, and rs324420. Results indicated that CNR1 rs1049353 GG carriers showed increased state satiety after THC/THC + CBD administration in comparison with placebo and reduced the salience of appetitive cues after THC in comparison with CBD administration; A carriers did not vary on either of these measures indicative of a vulnerability to CUD. CNR1 rs806378 CC carriers showed greater salience to appetitive cues in comparison with T carriers, but there was no evidence for changes in state satiety. FAAH rs324420 A carriers showed greater bias to appetitive cues after THC, in comparison with CC carriers. FAAH CC carriers showed reduced bias after THC in comparison with CBD. No SNPs modulated craving. These findings identify candidate neurocognitive mechanisms through which endocannabinoid system genetics may influence vulnerability to CUD.

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Section: Discussionsupporting

confidence: 88%

“…Endocannabinoid signaling is terminated by enzymes such as FAAH. FAAH inhibition is a mechanism that is currently being investigated as a treatment of CUD in humans . The rs324420 single‐nucleotide polymorphism (SNP) of the FAAH enzyme is a C‐to‐A polymorphism, which results in a proline to a threonine substitution at codon 129.…”

Section: Introductionmentioning

confidence: 99%

Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme

et al. 2019

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“…Qualifying participants were originally randomized 1:1 to receive the FAAHi PF-04457845 (4 mg/day) or PBO orally for 10 days. The PF-04457845 dose chosen produces a near complete and long-lasting inhibition of FAAH (23,24,26). On days 9 and 10, participants completed a laboratory paradigm to assess fear learning, affect, and stress reactivity, as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

“…In particular, pharmacological manipulation of FAAH is essential to address whether the phenotype seen in the behavioral genetic studies is directly caused by elevated AEA or results from neurodevelopmental effects reported in AA homozygotes (16). Here, we used an orally available, brain-penetrant FAAH inhibitor (FAAHi) originally developed for analgesia, PF-04457845 (22)(23)(24)(25)(26). PF-04457845 is safe and well tolerated but was discontinued owing to lack of analgesic efficacy (24).…”

mentioning

confidence: 99%

Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial

Mayo

Asratian

Lindé

et al. 2020

Biological Psychiatry

162

105

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BACKGROUND: Posttraumatic stress disorder, an area of large unmet medical needs, is characterized by persistence of fear memories and maladaptive stress responses. In rodents, elevation of the endocannabinoid anandamide due to inhibition of fatty acid amide hydrolase (FAAH) facilitates fear extinction and protects against the anxiogenic effects of stress. We recently reported that elevated anandamide levels in people homozygous for a loss-of-function FAAH mutation are associated with a similar phenotype, suggesting a translational validity of the preclinical findings. METHODS: In this double-blind, placebo-controlled experimental medicine study, healthy adults were randomized to an FAAH inhibitor (PF-04457845, 4 mg orally, once daily; n = 16) or placebo (n = 29) for 10 days. On days 9 and 10, participants completed a task battery assessing psychophysiological indices of fear learning, stress reactivity, and stress-induced affective responses. RESULTS: FAAH inhibition produced a 10-fold increase in baseline anandamide. This was associated with potentiated recall of fear extinction memory when tested 24 hours after extinction training. FAAH inhibition also attenuated autonomic stress reactivity, assessed via electrodermal activity, and protected against stress-induced negative affect, measured via facial electromyography. CONCLUSIONS: Our data provide preliminary human evidence that FAAH inhibition can improve the recall of fear extinction memories and attenuate the anxiogenic effects of stress, in a direct translation of rodent findings. The beneficial effects of FAAH inhibition on fear extinction, as well as stress-and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for posttraumatic stress disorder.

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“…Another systematic review found mixed effects of THC preparations for the reduction of cannabis withdrawal symptoms and treatment retention. A recent randomized controlled trial (RCT) tested the efficacy and safety of the FAAH‐inhibitor PF‐04457845 in male daily cannabis users and found that those who received the drug, compared to placebo, had fewer withdrawal symptoms and used less cannabis 4 weeks later. More clinical studies are needed to examine the benefits and safety of drugs for the treatment of CUDs.…”

Section: Clinical Representationmentioning

confidence: 99%

Heavy cannabis use, dependence and the brain: a clinical perspective

et al. 2019

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Aims To summarize and evaluate our knowledge of the relationship between heavy cannabis use, cannabis use disorder (CUD) and the brain. Methods Narrative review of relevant literature identified through existing systematic reviews, meta‐analyses and a PubMed search. Epidemiology, clinical representations, potential causal mechanisms, assessments, treatment and prognosis are discussed. Results Although causality is unclear, heavy and dependent cannabis use is consistently associated with a high prevalence of comorbid psychiatric disorders and learning and memory impairments that seem to recover after a period of abstinence. Evidence regarding other cognitive domains and neurological consequences, including cerebrovascular events, is limited and inconsistent. Abstinence after treatment is only achieved in a minority of cases; treatment targeted at reduction in use appears have some success. Potential moderators of the impact of CUD on the brain include age of onset, heaviness of use, CUD severity, the ratio of ∆9‐tetrahydrocannabinol to cannabidiol and severity of comorbid disorders. Conclusions Current evidence of long‐term effects of daily cannabis use and cannabis use disorder on brain‐related outcomes is suggestive rather than conclusive, but use is associated with psychiatric morbidity and with cognitive impairments that recover after a period of abstinence.

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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

Cited by 144 publications

References 38 publications

Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme

Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme

Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial

Heavy cannabis use, dependence and the brain: a clinical perspective

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