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 .
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
AIMS To summarize and evaluate our knowledge of the relationship between heavy cannabis use , Cannabis Use Disorder ( CUD ) , and the brain .
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 de grade s the endocannabinoid an and amide . We aim ed 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 assessment s , participants were r and omly 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 out patients . 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 Clinical Trials.gov , number NCT01618656 . FINDINGS Between Sept 12 , 2012 , and Jan 18 , 2016 , 46 men were r and omly 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 an and amide 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 )
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 .
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
AIMS To summarize and evaluate our knowledge of the relationship between heavy cannabis use , Cannabis Use Disorder ( CUD ) , and the brain .