Cannabinoids in the management of difficult to treat pain Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis Medical Marijuana: Is the Cart Before the Horse? Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up Safety, tolerability, and efficacy of orally administered cannabinoids in MS Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. 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Psychomotor performance in relation to acute oral administration of Δ9-tetrahydrocannabinol and standardized cannabis extract in healthy human subjects Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia: A Randomized, Double-Blind, Pilot Study The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis Efficacy and Safety of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic HCV Genotype 1 Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ION Trials. Open-Label, Add-on Study of Tetrahydrocannabinol for Chronic Nonmalignant Pain A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. Human Abuse Potential and Cognitive Effects of Taranabant, a Cannabinoid 1 Receptor Inverse Agonist: A Randomized, Double-Blind, Placebo- and Active-Controlled, Crossover Study in Recreational Polydrug Users Cannabis in painful HIV-associated sensory neuropathy The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS) MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial Vaporization as a Smokeless Cannabis Delivery System: A Pilot Study Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). Acute psychotropic effects of oral cannabis extract with a defined content of Delta9-tetrahydrocannabinol (THC) in healthy volunteers. Cannabinoid–Opioid Interaction in Chronic Pain Adverse event assessment, analysis, and reporting in recent published analgesic clinical trials: ACTTION systematic review and recommendations Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection Acute effects of THC on time perception in frequent and infrequent cannabis users The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Blunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis Are oral cannabinoids safe and effective in refractory neuropathic pain? Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. Randomised clinical trial of levonantradol and chlorpromazine in the prevention of radiotherapy-induced vomiting. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. Cannabis for dyskinesia in Parkinson disease Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review Dose-dependent Effects of Smoked Cannabis on Capsaicin-induced Pain and Hyperalgesia in Healthy Volunteers Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. 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Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: A double-blind, placebo-controlled dose escalation study. Treatment of Tourette Syndrome with Delta-9-Tetrahydrocannabinol (Δ9-THC): No Influence on Neuropsychological Performance Benefits and risks of drug treatments: how to combine the best evidence on benefits with the best data about adverse effects. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study Safety and Efficacy of Acupuncture in Children: A Review of the Evidence Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC. Allergen immunotherapy for the treatment of allergic rhinitis and/or asthma: an umbrella review. The efficacy of single-session motivational interviewing in reducing drug consumption and perceptions of drug-related risk and harm among young people: results from a multi-site cluster randomized trial. Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial Naltrexone does not attenuate the effects of intravenous Δ9-tetrahydrocannabinol in healthy humans. Chapter 46 Pain following spinal cord injury. 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.
This article review s recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms , as well as r and omized clinical trials employing cannabinoids in pain treatment .  Tetrahydrocannabinol ( THC , Marinol ® ) and nabilone ( Cesamet ® ) are currently approved in the United States and other countries , but not for pain indications . Other synthetic cannabinoids , such as ajulemic acid , are in development . Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation . Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC ( partial CB1 receptor agonist ) and cannabidiol ( CBD , a non-euphoriant , anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects ) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis , and in 2007 for intractable cancer pain . Numerous r and omized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain , rheumatoid arthritis and cancer pain . An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006 . Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles . Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise Medicinal cannabis has already entered mainstream medicine in some countries . This systematic review ( SR ) aim ed at evaluating the efficacy , acceptability and safety of cannabis-based medicines for chronic pain management . Qualitative systematic review of SRs of r and omized controlled trials with cannabis-based medicines for chronic pain management . The Cochrane data bases of SRs , Data base of Abstract s of Review s of Effects and PubMed were search ed for SR published in the period January 2009 to January 2017 . Assessment of the method ological quality of SR was performed by the AMSTAR checklist . Out of 748 papers identified , 10 SRs met the inclusion criteria . The method ological quality was high in four and moderate in six SRs . There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis . There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases ( three SRs ) and in cancer pain ( two SRs ) . Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions . It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the st and ard of 21st century clinical care . SIGNIFICANCE We provide an overview of systematic review s on the efficacy , tolerability and safety of cannabis-based medicines for chronic pain management . There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis . There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain Worldwide cannabis dependence is increasing , as is the concentration of Δ9-tetrahydrocannabinol ( THC ) in street cannabis . At the same time , the concentration of the second most abundant cannabinoid in street cannabis ,  cannabidiol  ( CBD ) , is decreasing . These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory . No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans . A total of 94 cannabis users were tested 7 days apart , once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures . Using an unprecedented methodology , a sample of cannabis ( as well as saliva ) was collected from each user and analyzed for levels of cannabinoids . On the basis of CBD : THC ratios in the cannabis , individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs , explicit liking , and implicit attentional bias to drug stimuli . When intoxicated , smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC . Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days . Our findings suggest that CBD has potential as a treatment for cannabis dependence . The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders There is apressingneed todevelopnewmedications formany debilitating conditions . Novel approaches based onmarijuana or its constituent cannabinoids , if proven , could be added to the armamentarium of available treatments . In this issue of JAMA , review s byWhiting et al1 and Hill2 provide detailed assessment of thepharmacology , indications , benefits , adverseeffects , and laws related tomedicalmarijuana and thecannabinoids , and the results and conclusions are consistent . There is some evidence to support the use of marijuana for nausea and vomiting related tochemotherapy , specificpain syndromes , and spasticity from multiple sclerosis . However , for most other indications that qualifyby state lawforuseofmedicalmarijuana , suchashepatitis C , Crohn disease , Parkinson disease , or Tourette syndrome , the evidence supporting its use is of poor quality . State laws vary widely regarding conditions for which marijuana is approved and thedispensable legal limit . Both review sraise important issues worthy of further discussion . First , for most qualifying conditions , approval has relied on low- quality scientific evidence , anecdotal reports , individual testimonials , legislative initiatives , and public opinion . Imagine if other drugs were approved through a similar approach . The US Food and Drug Administration ( FDA ) requires evidence from at least 2 adequately powered r and omized clinical trials before approving a drug for any specific indication . For most of the conditions that qualify for medical marijuanause , the evidence fails tomeet FDA st and ards . It has beenargued that the lackof high- quality evidence reflects the difficulty inconductingmarijuana research intheUnitedStates . If so , the federal and state governments should support and encourage such research so that high- quality evidence canbe generated to guidedecisions aboutmedicalmarijuanause for the conditions forwhich the existing evidence is either insufficient or of poor quality . Second , there are inconsistencies in how medical conditionsarequalified formedicalmarijuanausewithina state and between states . For example , in Connecticut , psoriasis and sickle cell disease but not Tourette syndrome qualify , even though the supporting evidence for all 3 conditions is uniformly of very low quality . Similarly , posttraumatic stress disorder ( PTSD ) is approvedas aqualifying condition in somebut not all US states . These differences reflect inconsistencies in evaluating and applyingcurrent evidence towarddecisionmaking about qualifying indications for medical marijuana use . Third , unlikemost FDA -approveddrugs that typicallyhave 1or2activeconstituents , marijuanaisacomplexofmorethan400 compounds including flavonoids and terpenoids and approximately 70 cannabinoids other than Δ9-tetrahydrocannabinol (THC)3.Thesecannabinoidshaveindividual , interactive , and even entourageeffects(effectsofacompoundthatareonlyappreciable inthepresenceofothercompounds)thatarenotfullyunderstood and thatcontributetotheneteffectofmarijuana . Although clinical trials forsomeof thequalifyingconditions and studies inanimalmodelsof thoseconditionshavebeenconductedwith individual cannabinoids ( eg , THCor cannabidiol [ CBD ] ) , given that marijuanahas somanyconstituents , the results of studies with individualcannabinoids(eg , THCorCBD)cannotbeextrapolated tomarijuana and vice versa . In addition , unlike FDA -approved medicationsthathavearelativelyuniformcomposition , thecompositionofcannabispreparationscanvarysubstantiallyinitscontent of THC and CBD , such that precise dosingmaybe difficult . Giventhevariablecomposition , patients willhavetoexperiment with different strains and doses to achieve the desired effects , withoutmuch input or oversight by physicians . Fourth , some individual cannabinoids are already commercially available in the form of dronabinol and nabilone . Thesedrugs are administeredorally , and somepublished data are available to guide dosing . In contrast , there are few data on dosing smoked medical marijuana for many of the qualifying medical conditions for which it is used . Fifth , while theacuteadverseeffectsofmarijuanaarequite well known , the effects of repeated exposure , aswould occur withmedicalmarijuana , need further study . Approximately 1 in 10 adult users of marijuana  develops addiction , and this number is evenhigher amongadolescents.4Tolerance and dependence with accompanying down-regulation and desensitization of type 1 cannabinoid receptors occur with repeated exposure.5 Based on this profile , marijuana dosing will have to be increased over time to achieve the same effect . A distinct withdrawal syndrome is also well recognized . There is also a small but definite risk of psychotic disorder associated with marijuana use , as well as a significant risk of symptom exacerbations and relapse in patients with an establishedpsychoticdisorder.6Thus , explicitcontraindicationssuch as schizophrenia , bipolar disorder , or substance dependence need tobe identifiedalongwith measures tominimize the likelihoodthatpersonswithcontraindicationswouldbeable toobtain medical marijuana . Perhaps US states should establish clinical follow-upprogramstomonitor long-term outcomes prospect ively , especiallynegative outcomes ( eg , newcasesofpsychosis ) in patients with contraindications . Author Audio Interview at Objective : To test the effectiveness and long term safety of cannabinoids in multiple sclerosis ( MS ) , in a follow up to the main Cannabinoids in Multiple Sclerosis ( CAMS ) study . Methods : In total , 630 patients with stable MS with muscle spasticity from 33 UK centres were r and omised to receive oral Δ9-tetrahydrocannabinol ( Δ9-THC ) , cannabis extract , or placebo in the main 15 week CAMS study . The primary outcome was change in the Ashworth spasticity scale . Secondary outcomes were the Rivermead Mobility Index , timed 10 metre walk , UK Neurological Disability Score , postal Barthel Index , General Health Question naire-30 , and a series of nine category rating scales . Following the main study , patients were invited to continue medication , double blinded , for up to12 months in the follow up study reported here . Results : Intention to treat analysis of data from the 80 % of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months ( Δ9-THC mean reduction 1·82 ( n = 154 , 95 % confidence interval ( CI ) 0.53 to 3.12 ) , cannabis extract 0.10 ( n = 172 , 95 % CI −0.99 to 1.19 ) , placebo −0.23 ( n = 176 , 95 % CI −1.41 to 0.94 ) ; p = 0.04 unadjusted for ambulatory status and centre , p = 0.01 adjusted ) . There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability . There were no major safety concerns . Overall , patients felt that these drugs were helpful in treating their disease . Conclusions : These data provide limited evidence for a longer term treatment effect of cannabinoids . A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS Abstract —The authors conducted a r and omized , double-blind , placebo-controlled , twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety , tolerability , and efficacy of oral & Dgr;9-Tetrahydrocannabinol ( THC ) and Cannabis sativa plant extract . Both drugs were safe , but adverse events were more common with plant-extract treatment . Compared with placebo , neither THC nor plant-extract treatment reduced spasticity . Both THC and plant-extract treatment worsened the participant ’s global impression BACKGROUND Multiple sclerosis is associated with muscle stiffness , spasms , pain , and tremor . Much anecdotal evidence suggests that cannabinoids could help these symptoms . Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis . METHODS We did a r and omised , placebo-controlled trial , to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity . 630 participants were treated at 33 UK centres with oral cannabis extract ( n=211 ) , Delta9-tetrahydrocannabinol ( Delta9-THC ; n=206 ) , or placebo ( n=213 ) . Trial duration was 15 weeks . Our primary outcome measure was change in overall spasticity scores , using the Ashworth scale . Analysis was by intention to treat . FINDINGS 611 of 630 patients were followed up for the primary endpoint . We noted no treatment effect of cannabinoids on the primary outcome ( p=0.40 ) . The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 ( 95 % CI -1.04 to 1.67 ) , and for those taking Delta9-THC versus placebo it was 0.94 ( -0.44 to 2.31 ) . There was evidence of a treatment effect on patient-reported spasticity and pain ( p=0.003 ) , with improvement in spasticity reported in 61 % ( n=121 , 95 % CI 54.6 - 68.2 ) , 60 % ( n=108 , 52.5 - 66.8 ) , and 46 % ( n=91 , 39.0 - 52.9 ) of participants on cannabis extract , Delta9-THC , and placebo , respectively . INTERPRETATION Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale . However , though there was a degree of unmasking among the patients in the active treatment groups , objective improvement in mobility and patients ' opinion of an improvement in pain suggest cannabinoids might be clinical ly useful OBJECTIVE Pre clinical findings suggest that the over-the-counter supplement N-acetylcysteine ( NAC ) , via glutamate modulation in the nucleus accumbens , holds promise as a pharmacotherapy for substance dependence . The authors investigated NAC as a novel cannabis cessation treatment in adolescents , a vulnerable group for whom existing treatments have shown limited efficacy . METHOD In an 8-week double-blind r and omized placebo-controlled trial , treatment-seeking cannabis-dependent adolescents ( ages 15 - 21 years ; N=116 ) received NAC ( 1200 mg ) or placebo twice daily as well as a contingency management intervention and brief ( < 10 minutes ) weekly cessation counseling . The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo , in an intent-to-treat analysis . The primary tolerability measure was frequency of adverse events , compared by treatment group . RESULTS Participants receiving NAC had more than twice the odds , compared with those receiving placebo , of having negative urine cannabinoid test results during treatment ( odds ratio=2.4 , 95 % CI=1.1 - 5.2 ) . Exploratory secondary abstinence outcomes favored NAC but were not statistically significant . NAC was well tolerated , with minimal adverse events . CONCLUSIONS This is the first r and omized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis . Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents 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 . MATERIAL S 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 , r and omized 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:// clinical trials.gov/ct2/show/ study /NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http:// clinical trials.gov/ct2/show/NCT00678730 NCT00678730 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 , r and omized , 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 Δ9-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 BACKGROUND : Sleep disorders affect many patients with chronic pain conditions . Cannabis has been reported by several patient population s to help sleep . We evaluated the safety and efficacy of nabilone , a synthetic cannabinoid , on sleep disturbance in fibromyalgia ( FM ) , a disease characterized by widespread chronic pain and insomnia . METHODS : We conducted a r and omized , double-blind , active-control , equivalency crossover trial to compare nabilone ( 0.5–1.0 mg before bedtime ) to amitriptyline ( 10–20 mg before bedtime ) in patients with FM with chronic insomnia . Subjects received each drug for 2 wk with a 2-wk washout period . The primary outcome was sleep quality , measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Question naire . Secondary outcomes included pain , mood , quality of life , and adverse events ( AEs ) . RESULTS : Thirty-one subjects were enrolled and 29 completed the trial ( 26 women , mean age 49.5 yr ) . Although sleep was improved by both amitriptyline and nabilone , nabilone was superior to amitriptyline ( Insomnia Severity Index difference = 3.2 ; 95 % confidence interval = 1.2–5.3 ) . Nabilone was marginally better on the restfulness ( Leeds Sleep Evaluation Question naire difference = 0.5 [ 0.0–1.0 ] ) but not on wakefulness ( difference = 0.3 [ −0.2 to 0.8 ] ) . No effects on pain , mood , or quality of life were observed . AEs were mostly mild to moderate and were more frequent with nabilone . The most common AEs for nabilone were dizziness , nausea , and dry mouth . CONCLUSIONS : Nabilone is effective in improving sleep in patients with FM and is well tolerated . Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline . Longer trials are needed to determine the duration of effect and to characterize long-term safety BACKGROUND AND AIMS Between 2000 and 2005 the average percentage of Δ(9 ) -tetrahydrocannabinol ( THC ) in marijuana as sold in Dutch coffeeshops has increased substantially ; the potency of domestic products ( Nederwiet and Nederhasj ) has particularly increased . In contrast with imported marijuana , Nederwiet hardly contained any cannabidiol ( CBD ) , a cannabinoid that is thought to offset some of the adverse effects of THC . In 2005 , the THC content in Nederwiet was significantly lower than in 2004 . This study investigates the further decrease or increase of cannabinoids in these cannabis products . METHODS From 2005 to 2015 five different cannabis products were bought anonymously in 50 coffeeshops that were selected r and omly each year from all coffeeshops in the Netherl and s. A total of 2126 cannabis sample s were bought , consisting of 664 Nederwiet sample s ( most popular ) , 537 Nederwiet sample s ( supposed strongest varieties ) , 183 imported herbal cannabis sample s , 140 sample s of  cannabis resin made of Nederwiet and 602 sample s of imported cannabis resin . All sample s were analysed chemically for their THC , CBD and cannabinol ( CBN ) content . RESULTS Between 2005 and 2015 , the mean potencies of the most popular and the strongest Nederwiet and of imported cannabis resin were 16.0±4.0 % , 17.0±3,9 % and 16.5±6.3 % , respectively . Imported herbal cannabis ( 6.5±3.5 % ) and cannabis resin made from Nederwiet ( 30.2±16.4 % ) contained , respectively , less ( β=-10.0 , P<0.001 ) and more ( β=13.7 , P<0.001 ) THC than imported cannabis resin . Linear regression models were used to study the trends in THC of the different cannabis products over time . A marginal , but significant ( P<0.001 ) , overall decline of THC per year of 0.22 % was found in all cannabis products . However , no significant difference was found between the five products in the THC linear trajectories across time . Of all the cannabis products , only imported cannabis resin contained a relatively high CBD/THC ratio ( median 0.42 ) . CONCLUSION The average tetrahydrocannabinol ( THC ) content of the most popular herbal cannabis products in the Netherl and s has decreased slightly since 2005 . The popular Nederwiet type still has a relatively high THC to cannabidiol ratio Abnormalities in psychomotor performance are a consistent finding in schizophrenic patients as well as in chronic cannabis users . The high levels of central cannabinoid ( CB1 ) receptors in the basal ganglia , the cerebral cortex and the cerebellum indicate their implication in the regulation of motor activity . Based on the close relationship between cannabis use , the endogenous cannabinoid system and motor disturbances found in schizophrenia , we expected that administration of cannabinoids may change pattern of psychomotor activity like in schizophrenic patients . This prospect i ve , double-blind , placebo-controlled cross-over study investigated the acute effects of cannabinoids on psychomotor performance in 24 healthy right-h and ed volunteers ( age 27.9 ± 2.9 years , 12 male ) by comparing Δ9-tetrahydrocannabinol ( Δ9-THC ) and st and ardized cannabis extract containing Δ9-THC and cannabidiol .  Psychomotor performance was assessed by using a finger tapping test series . Cannabis extract , but not Δ9-THC , revealed a significant reduction of right-h and tapping frequencies that was also found in schizophrenia . As to the pure Δ9-THC condition , left-h and tapping frequencies were correlated with the plasma concentrations of the Δ9-THC metabolite 11-OH-THC . These effects are thought to be related to cannabinoid actions on CB1 receptors in the basal ganglia , the cerebral cortex and the cerebellum . Our data further demonstrate that acute CB1 receptor activation under the cannabis extract condition may also affect intermanual coordination ( IMC ) as an index of interhemispheric transfer . AIR-Scale scores as a measure of subjective perception of intoxication were dose-dependently related to IMC which was shown by an inverted U-curve . This result may be due to functional changes involving GABAergic and glutamatergic neurotransmission within the corpus callosum BACKGROUND Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders . METHODS In a 3-day , double-blind , r and omized , placebo-controlled study , the behavioral , cognitive , motor , and endocrine effects of 0 mg , 2.5 mg , and 5 mg intravenous Delta-9-tetrahydrocannabinol ( Delta-9-THC ) were characterized in 13 stable , antipsychotic-treated schizophrenia patients . These data were compared with effects in healthy subjects reported elsewhere . RESULTS Delta-9-tetrahydrocannabinol transiently increased 1 ) learning and recall deficits ; 2 ) positive , negative , and general schizophrenia symptoms ; 3 ) perceptual alterations ; 4 ) akathisia , rigidity , and dyskinesia ; 5 ) deficits in vigilance ; and 6 ) plasma prolactin and cortisol .  Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects . There were no serious short- or long-term adverse events associated with study participation . CONCLUSIONS Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia . These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis . Furthermore , Delta-9-THC might differentially affect schizophrenia patients relative to control subjects . Finally , the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia Weight gain is a major adverse effect of several second-generation antipsychotic medications . Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population . We conducted a 16-week , double-blind , placebo-controlled study of rimonabant ( 20 mg/d ) in people with schizophrenia or schizoaffective disorder , based on the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria , who were clinical ly stable on second-generation antipsychotics . Participants had a body mass index of 27 kg/m2 or higher with hyperlipidemia or body mass index of 30 kg/m2 or higher , and no current substance abuse/dependence ( except nicotine ) , more than weekly cannabis use , or recent depressive symptoms/suicidality . An exercise and dietary counseling group was offered weekly . Target enrollment was 60 ; the trial was terminated early because of withdrawal of rimonabant from the European market . Fifteen participants were r and omized ( 7 rimonabant  , 8 placebo ) ; 5 completed in each group . Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score  versus placebo ( mean ± SE difference , −1.9 ± 0.8 , P = 0.02 ) , driven by differences in the Brief Psychiatric Rating Scale anxiety/depression ( −1.4 ± 0.35 , P = 0.0004 ) and hostility ( −0.7 ± 0.3 , P = 0.02 ) factors . Group differences were not significant for the Calgary Depression Scale total score ( P = 0.24 ) , Scale for the Assessment of Negative Symptoms total score ( P = 0.13 ) , weight , blood pressure , or fasting lipids or glucose . Rimonabant was well tolerated with no significant adverse events . No significant weight loss , metabolic effects , or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia . The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity Recent advances in the underst and ing of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis . In a 3-day , double-blind , r and omized , and counterbalanced study , the behavioral , cognitive , and endocrine effects of 0 , 2.5 , and 5 mg intravenous delta-9-tetrahydrocannabinol ( Δ-9-THC ) were characterized in 22 healthy individuals , who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder . Prospect i ve safety data at 1 , 3 , and 6 months post study was also collected . Δ-9-THC ( 1 ) produced schizophrenia-like positive and negative symptoms ; ( 2 ) altered perception ; ( 3 ) increased anxiety ; ( 4 ) produced euphoria ; ( 5 ) disrupted immediate and delayed word recall , sparing recognition recall ; ( 6 ) impaired performance on tests of distractibility , verbal fluency , and working memory ( 7 ) did not impair orientation ; ( 8) increased plasma cortisol . These data indicate that Δ-9-THC produces a broad range of transient symptoms , behaviors , and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses . These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders BACKGROUND Interferon-based hepatitis C virus ( HCV ) therapy is safe and effective among people receiving opioid substitution therapy ( OST ) , but treatment uptake remains low . Our aim was to evaluate the impact of OST and drug use during therapy on completion , adherence , sustained virologic response ( SVR12 ) , and safety of ledipasvir/sofosbuvir ± ribavirin . METHODS The phase 3 ION studies evaluated a fixed-dose combination of ledipasvir/sofosbuvir ± ribavirin administered for 8 , 12 , or 24 weeks in patients with chronic HCV genotype 1 . People with clinical ly significant drug use ( prior 12 months ) or noncannabinoids detected at screening by urine drug tests ( not explained by prescriptions ) were ineligible . Stored sample s were available from ION-1 for retrospective testing for illicit drugs by enzyme-linked immunosorbent assay . RESULTS Among 1952 patients enrolled in the ION studies , 4 % ( n = 70 ) were receiving OST . Among those receiving ( n = 70 ) and not receiving OST ( n = 1882 ) , there was no difference in treatment completion ( 97 % vs 98 % ; P = .40 ) , ≥80 % adherence ( 93 % vs 92 % ; P = 1.00 ) , SVR12 ( 94 % vs 97 % ; P = .28 ) , and serious adverse events ( 4 % vs 3 % ; P = .43 ) , respectively . Among participants in the ION-1 trial , 23 % ( n = 196 ) used illicit drugs during therapy ( 15 % cannabinoids alone ; 8 % other illicit drugs ± cannabinoids ) . There was no difference in treatment completion , ≥80 % adherence , SVR12 , or serious AEs in those with no drug use during treatment compared with those who used cannabinoids and /or other illicit drugs . No cases of HCV reinfection were observed in the 24 weeks following treatment . CONCLUSIONS OST and drug use during HCV therapy did not impact treatment completion , adherence , SVR12 , or safety . CLINICAL TRIALS REGISTRATION ION-1 ( NCT01701401 ) ; ION-2 ( NCT01768286 ) ; and ION-3 ( NCT01851330 ) Cannabinoids have been used for pain relief for centuries and recent studies have investigated their analgesic and anti-inflammatory mechanisms , as well as clinical efficacy , in treating chronic pain . We report an open-label study addressed to evaluate the effect and adverse events of orally administered Δ -9-tetrahydrocannabinol ( Δ -9-THC ) in 13 patients with chronic nonmalignant pain ( CNMP ) unresponsive to conventional pharmacotherapy . The effect of the treatment was assessed on an eight-item HRQoL question naire . Five out of 13 patients reported adequate response to the treatment while eight patients reported inadequate or no response . Seven patients did not experience any adverse events ( AEs ) , six patients reported AEs , two of which discontinued the treatment . We conclude that oral THC may be a valuable therapeutic option for selected patients with CNMP that are unresponsive to previous treatments , though further research is warranted to characterize those patients BACKGROUND Cannabis use disorder ( CUD ) is a prevalent and impairing condition , and established psychosocial treatments convey limited efficacy . In light of recent findings supporting the efficacy of N-acetylcysteine ( NAC ) for CUD in adolescents , the objective of this trial was to evaluate its efficacy in adults . METHODS In a 12-week double-blind r and omized placebo-controlled trial , treatment-seeking adults ages 18 - 50 with CUD ( N=302 ) , enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites , were r and omized in a 1:1 ratio to a 12-week course of NAC 1200 mg ( n=153 ) or placebo ( n=149 ) twice daily . All participants received contingency management ( CM ) and medical management . The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment , compared between NAC and placebo participants . RESULTS There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence ( odds ratio=1.00 , 95 % confidence interval 0.63 - 1.59 , p=0.984 ) . Overall , 22.3 % of urine cannabinoid tests in the NAC group were negative , compared with 22.4 % in the placebo group . Many participants were medication non-adherent ; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group . CONCLUSIONS In contrast with prior findings in adolescents , there is no evidence that NAC 1200 mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM . This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development , cannabis use profiles , responses to embedded behavioral treatment , medication adherence , and other factors Introduction Taranabant is a cannabinoid 1 receptor inverse agonist that was in development for treatment of obesity . Because of central nervous system effects , the study was performed to assess the abuse potential and cognitive effects of taranabant in recreational polydrug users compared with phentermine , dronabinol , and placebo . Methods Stimulant- and cannabis-experienced polydrug users ( N = 30 ) were r and omized in a double-blind crossover study to receive taranabant 2 , 4 , 10 , and 20 mg ; phentermine 45 and 90 mg ; dronabinol 20 mg ; and placebo .  Subjective and neurocognitive measures were administered for 24 hours , and peak/peak change from baseline effects were analyzed using a linear mixed-effects model . Results Phentermine 45 and 90 mg showed abuse-related subjective effects versus placebo , including drug liking , overall drug liking , and other positive/stimulant effects , whereas dronabinol 20 mg showed abuse-related positive , cannabis-like , and sedative effects .  Taranabant was not significantly different from placebo on most of the subjective measures other than negative/dysphoric effects at the highest dose , and its effects were significantly less pronounced relative to phentermine and dronabinol on most measures . Phentermine  improved cognitive/motor performance and dronabinol impaired motor/cognitive performance on some measures , whereas taranabant 4 and 20 mg had minor impairment effects on manual tracking . Conclusions The phentermine and dronabinol results demonstrate the validity and sensitivity of the study . Taranabant did not consistently show stimulant/cannabis-like effects or abuse potential in recreational polydrug users , indicating that cannabinoid 1 receptor inverse agonists/antagonists are unlikely to be recreationally abused Objective : To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model . Methods : Prospect i ve r and omized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy . Patients were r and omly assigned to smoke either cannabis ( 3.56 % tetrahydrocannabinol ) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days . Primary outcome measures included ratings of chronic pain and the percentage achieving > 30 % reduction in pain intensity . Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model . Results : Fifty patients completed the entire trial . Smoked cannabis reduced daily pain by 34 % ( median reduction ; IQR = −71 , −16 ) vs 17 % ( IQR = −29 , 8) with placebo ( p = 0.03 ) . Greater than 30 % reduction in pain was reported by 52 % in the cannabis group and by 24 % in the placebo group ( p = 0.04 ) . The first cannabis cigarette reduced chronic pain by a median of 72 % vs 15 % with placebo ( p < 0.001 ) . Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli ( p ≤ 0.05 ) but appeared to have little effect on the painfulness of noxious heat stimulation . No serious adverse events were reported . Conclusion : Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy . The findings are comparable to oral drugs used for chronic neuropathic pain Objective : To test whether cannabinoids reduce urge incontinence episodes without affecting voiding in patients with multiple sclerosis . This was part of the multicentre trial of the Cannabinoids in Multiple Sclerosis ( CAMS ) study . Subjects and methods : The CAMS study r and omised 630 patients to receive oral administration of cannabis extract , Δ9-tetrahydrocannabinol ( THC ) or matched placebo . For this sub study subjects completed incontinence diaries . Results : All three groups showed a significant reduction , p<0.01 , in adjusted episode rate ( i.e. correcting for baseline imbalance ) from baseline to the end of treatment : cannabis extract , 38 % ; THC , 33 % ; and placebo , 18 % . Both active treatments showed significant effects over placebo ( cannabis extract , p=0.005 ; THC , p=0.039 ) . Conclusion : The findings are suggestive of a clinical effect of cannabis on incontinence episodes in patients with MS . This is in contrast to the negative finding of the CAMS study , where no difference was seen in the primary outcome of spasticity Objective Multiple sclerosis ( MS ) is associated with chronic symptoms , including muscle stiffness , spasms , pain and insomnia . Here we report the results of the Multiple Sclerosis and Extract of Cannabis ( MUSEC ) study that aim ed to substantiate the patient based findings of previous studies . Patients and methods Patients with stable MS at 22 UK centres were r and omised to oral cannabis extract ( CE ) ( N=144 ) or  placebo ( N=135 ) , stratified by centre , walking ability and use of antispastic medication . This double blind , placebo controlled , phase III study had a screening period , a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase . The primary outcome measure was a category rating scale ( CRS ) measuring patient reported change in muscle stiffness from baseline . Further CRSs assessed body pain , spasms and sleep quality . Three vali date d MS specific patient reported outcome measures assessed aspects of spasticity , physical and psychological impact , and walking ability . Results The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo ( 29.4 % vs 15.7 % ; OR 2.26 ; 95 % CI 1.24 to 4.13 ; p=0.004 , one sided ) . Similar results were found after 4 weeks and 8 weeks , and also for all further CRSs . Results from the MS scales supported these findings . Conclusion The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of  muscle stiffness in MS . This was supported by results for secondary efficacy variables . Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids . No new safety concerns were observed . Trial registration number NCT00552604 Although cannabis may have potential therapeutic value , inhalation of a combustion product is an undesirable delivery system . The aim of the study was to investigate vaporization using the Volcano ® device as an alternative means of delivery of inhaled Cannabis sativa . Eighteen healthy inpatient subjects enrolled to compare the delivery of cannabinoids by vaporization to marijuana smoked in a st and ard cigarette . One strength ( 1.7 , 3.4 , or 6.8 % tetrahydrocannabinol ( THC ) ) and delivery system was r and omly assigned for each of the 6 study days . Plasma concentrations of Δ‐9‐THC , expired carbon monoxide ( CO ) , physiologic and neuropsychologic effects were the main outcome measures . Peak plasma concentrations and 6‐h area under the plasma concentration – time curve of THC were similar . CO levels were reduced with vaporization . No adverse events occurred . Vaporization of cannabis is a safe and effective mode of delivery of THC . Further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system UNLABELLED Cannabis is widely used as a self-management strategy by patients with a wide range of symptoms and diseases including chronic non-cancer pain . The safety of cannabis use for medical purpose s has not been systematic ally evaluated . We conducted a prospect i ve cohort study to describe safety issues among individuals with chronic non-cancer pain . A st and ardized herbal cannabis product ( 12.5 % tetrahydrocannabinol ) was dispensed to eligible individuals for a 1-year period ; controls were individuals with chronic pain from the same clinics who were not cannabis users . The primary outcome consisted of serious adverse events and non-serious adverse events . Secondary safety outcomes included pulmonary and neurocognitive function and st and ard hematology , biochemistry , renal , liver , and endocrine function . Secondary efficacy parameters included pain and other symptoms , mood , and quality of life .  Two hundred and fifteen individuals with chronic pain were recruited to the cannabis group ( 141 current users and 58 ex-users ) and 216 controls ( chronic pain but no current cannabis use ) from 7 clinics across Canada . The median daily cannabis dose was 2.5 g/d . There was no difference in risk of serious adverse events ( adjusted incidence rate ratio = 1.08 , 95 % confidence interval = .57 - 2.04 ) between groups . Medical cannabis users were at increased risk of non-serious adverse events ( adjusted incidence rate ratio = 1.73 , 95 % confidence interval = 1.41 - 2.13 ) ; most were mild to moderate . There were no differences in secondary safety assessment s. Quality -controlled herbal cannabis , when used by patients with experience of cannabis use as part of a monitored treatment program over 1 year , appears to have a reasonable safety profile . Longer-term monitoring for functional outcomes is needed . STUDY REGISTRATION The study was registered with www.controlled-trials.com ( IS RCT N19449752 ) . PERSPECTIVE This study evaluated the safety of cannabis use by patients with chronic pain over 1 year . The study found that there was a higher rate of adverse events among cannabis users compared with controls but not for serious adverse events at an average dose of 2.5 g herbal cannabis per day INTRODUCTION The medical use of cannabinoids is limited mainly by their undesirable effects . With respect to acute psychotropic effects , the aim of this study is the comparison of an oral cannabis extract and low-dose diazepam in a cross-over experiment in drug-naïve healthy women . METHODS Sixteen healthy females participated in this r and omized , double-blind , active comparator-controlled , single-dose , balanced 2-way cross-over study . Cannabis extract with st and ardised Delta (9)-tetrahydrocannabinol ( THC ) content ( 20 mg ) or active placebo ( 5 mg diazepam ) was administered orally . Subjects were assessed by self- and observer-rated visual analogue scales ( VAS ) , the BRIEF PSYCHIATRIC RATING SCALE ( BPRS ) and three psychomotor tests up to 6 h after administration . RESULTS VAS showed significantly elevated fatigue , drowsiness , dizziness , and " feeling high " after cannabis as compared to baseline and diazepam . BPRS scores were significantly higher after cannabis intake . Only in one psychomotor test a decrease of psychomotor activity after cannabis was evident . One subject in the cannabis condition experienced severe transient psychotic symptoms . DISCUSSION Orally administered cannabis produced significant central depressant side-effects compared to diazepam , mostly subjective effects ( VAS ) but marginal effects in psychomotor performance in 15 healthy females . Regarding the medical use of cannabis , a rigorous benefit-risk analysis and an exact psychiatric assessment before and during treatment are necessary Cannabinoids and opioids share several pharmacologic properties and may act synergistically . The potential pharmacokinetics and the safety of the combination in humans are unknown . We therefore undertook a study to answer these questions . Twenty – one individuals with chronic pain , on a regimen of twice – daily doses of sustained – release morphine or oxycodone were enrolled in the study and admitted for a 5–day inpatient stay . Participants were asked to inhale vaporized cannabis in the evening of day 1 , three times a day on days 2–4 , and in the morning of day 5 . Blood sampling was performed at 12–h intervals on days 1 and 5 . The extent of chronic pain was also assessed daily . Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration – time curves for either morphine or oxycodone after exposure to cannabis . Pain was significantly decreased ( average 27 % , 95 % confidence interval ( CI ) 9 , 46 ) after the addition of vaporized cannabis . We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels . The combination may allow for opioid treatment at lower doses with fewer side effects & NA ; Adverse events in r and omized controlled trials of noninvasive , pharmacologic analgesics are frequently incompletely or inconsistently reported . A comprehensive reporting checklist is proposed to improve disclosure of adverse effects . & NA ; The development of valid and informative treatment risk – benefit profiles requires consistent and thorough information about adverse event ( AE ) assessment and participants ’ AEs during r and omized controlled trials ( RCTs ) . Despite a 2004 extension of the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement recommending the specific AE information that investigators should report , there is little evidence that analgesic RCTs adequately adhere to these recommendations . This systematic review builds on prior recommendations by describing a comprehensive checklist for AE reporting developed to capture clinical ly important AE information . Using this checklist , we coded AE assessment methods and reporting in all 80 double‐blind RCTs of noninvasive pharmacologic treatments published in the European Journal of Pain , Journal of Pain , and PAIN ® from 2006 to 2011 . Across all trials , reports of AEs were frequently incomplete , inconsistent across trials , and , in some cases , missing . For example , > 40 % of trials failed to report any information on serious adverse events . Trials of participants with acute or chronic pain conditions and industry‐sponsored trials typically provided more and better‐ quality AE data than trials involving pain‐free volunteers or trials that were not industry sponsored . The results of this review suggest that improved AE reporting is needed in analgesic RCTs . We developed an ACTTION ( Analgesic , Anesthetic , and Addiction Clinical Trial Translations , Innovations , Opportunities , and Networks ) AE reporting checklist that is intended to assist investigators in thoroughly and consistently capturing and reporting these critically important data in publications Context Because the same systems metabolize cannabinoids and protease inhibitors , cannabinoids might alter viral loads in HIV-infected patients taking protease inhibitors . Contribution In this r and omized trial , 62 HIV-infected patients taking indinavir or nelfinavir  received a marijuana cigarette , dronabinol capsule , or placebo capsule three times daily for 21 days . Half of the patients in all three groups had undetectable viral loads during the study , and average changes in viral load with marijuana and dronabinol , relative to placebo , were small . Caution s The findings of no large harmful effects on viral loads with either smoked or oral cannabinoids need to be confirmed in larger and longer trials . The Editors Marijuana has been smoked for medicinal purpose s for centuries ( 1 ) . Introduced into western medicine in 1842 , marijuana was used to treat various illnesses on the basis of its purported analgesic , anticonvulsant , sedative , hypnotic , and antispasmodic properties . With the passage of the Marihuana Tax Act in 1937 , use of marijuana as a therapeutic agent in the United States waned until the substance was removed from the U.S. Pharmacopoeia in 1942 . The Controlled Substances Act of 1970 placed marijuana in the Schedule I category along with other substances deemed to have no medicinal value and high potential for abuse . In 1986 , the U.S. Food and Drug Administration approved a synthetic , oral form of marijuana 's main psychoactive component , delta-9-tetrahydrocannabinol ( dronabinol , Marinol , Roxane Laboratories , Columbus , Ohio ) , for treating chemotherapy-induced nausea and vomiting ( 2 - 5 ) . A r and omized , controlled trial demonstrated that dronabinol increased self-reported appetite but not weight in patients with AIDS-related wasting syndrome ; these findings led to an expansion of the labeling indication for this use in 1992 ( 6 , 7 ) . Before the advent of highly active antiretroviral therapy in the 1990s , many patients infected with HIV-1 experienced wasting as a preterminal manifestation of the disease ( 8) . Patients with AIDS-related wasting syndrome often reported that they preferred smoked marijuana to dronabinol because it was easier to titrate the dose to achieve the desired effect ; smoked marijuana delivers cannabinoids to the bloodstream much more rapidly than dronabinol ( 9 ) . By the mid-1990s , cannabis buyers ' clubs in the San Francisco Bay area were reportedly selling marijuana to 11 000 patients with HIV infection ( 10 - 12 ) . With the increased availability of protease inhibitorcontaining antiretroviral regimens in the mid-1990s , the incidence of AIDS-related wasting syndrome decreased markedly , as did most of the other late-stage opportunistic manifestations of advanced HIV disease ( 13 - 15 ) . Protease inhibitors , which can inhibit or stimulate the hepatic cytochrome P-450 enzyme system , are subject to many significant drugdrug interactions with other agents used in treating HIV infection and its complications ( 16 , 17 ) . The potential for a drugdrug interaction between protease inhibitors and marijuana is worrisome since many HIV-infected patients continue to smoke marijuana as an appetite stimulant or to decrease nausea associated with their antiretroviral therapy ( 18 , 19 ) . The likelihood of such an interaction is supported by the facts that cannabinoids are metabolized by some of the same cytochrome P-450 enzyme isoforms that metabolize the more widely prescribed protease inhibitors and that tetrahydrocannabinol has been shown to inhibit the metabolism of other drugs ( 20 - 23 ) . Although few recent clinical trials have evaluated the potential therapeutic effects of smoked marijuana , significant progress has been made in underst and ing the pharmacology of cannabinoids in humans . Of the two cannabinoid receptors identified , CB1 ( found mainly in cells of the central nervous system ) is thought to be responsible for the neurologic and behavioral effects of marijuana ( 24 , 25 ) . The identification of a CB2 receptor , found predominantly on B lymphocytes and natural killer cells , suggests that cannabinoids may also affect the immune response . Some studies suggest that marijuana can impair the immune system through B-lymphocyte modulation , tumor necrosis factor inhibition , or changes in the phenotype and function of circulating lymphocytes ( 26 - 29 ) . The hallmark of successful antiretroviral therapy is sustained suppression of HIV RNA levels associated with increasing CD4 + cell counts ( 30 - 32 ) . Considering the potential for both a protease inhibitorcannabinoid interaction and an effect of smoked marijuana on the immune system , we design ed a study to determine the safety or toxicity profile of cannabinoids ( smoked and oral ) in persons with HIV infection . We chose HIV RNA levels as our primary outcome because an intervention that interacted unfavorably with either the antiretroviral agent pharmacokinetics or the immune system directly could cause a perturbation of viral suppression . We report the overall safety results of this r and omized , controlled inpatient clinical trial . Methods Study Group Study participants were recruited by referrals from local physicians and advertisements in newspapers . Volunteers from across the country telephoned to determine whether they might be eligible to participate . Participants were required to be at least 18 years of age , have documented HIV infection , and be receiving a stable antiretroviral treatment regimen of either indinavir ( Crixivan , Merck & Co. , Inc. , North Wales , Pennsylvania ) or nelfinavir ( Viracept , Agouron Pharmaceuticals , Inc. , La Jolla , California ) for at least 8 weeks before enrollment . When enrolled , participants who had been taking the recently recommended dose of nelfinavir  , 1250 mg twice daily , were switched to 750 mg three times daily for consistency of our pharmacokinetic evaluations ( 33 ) . No additional protease inhibitors were allowed for the duration of the study . Participants were also required to have a stable viral load , defined as less than a threefold ( 0.5 log10 ) change in HIV RNA level for the 16 weeks before enrollment . All participants were required to have previous experience smoking marijuana ( defined as six or more times ) to ensure that they knew how to inhale and what neuropsychiatric effects to expect . The institutional review board of the University of California , San Francisco , approved the study , and signed , informed consent was obtained from each participant before enrollment . Exclusion criteria included any active opportunistic infection or malignant condition requiring acute treatment , unintentional loss of 10 % or more of body weight during the previous 6 months , current substance dependence ascertained by completion of a confidential drug screening form and an alcohol screening form , methadone maintenance , use of tobacco or cannabinoids ( smoked or oral ) within 30 days of enrollment , history of serious pulmonary disease , pregnancy , or stage II or higher AIDS dementia complex . Laboratory exclusion criteria were hematocrit less than 0.25 and elevation of hepatic aminotransferase levels to greater than five times the upper limit of normal . Therapeutic exclusions were concurrent use within the past 8 weeks of anabolic hormones , prednisone , interleukin-2 , or other agents known to alter immune system function . Study Medications The National Institute on Drug Abuse provided prerolled marijuana cigarettes , weighing on average 0.9 g and containing 3.95 % delta-9-tetrahydrocannabinol . These cigarettes were kept in a locked and alarmed freezer until they were dispensed to a locked freezer in the General Clinical Research Center at the San Francisco General Hospital , where the inpatient study was conducted . The frozen marijuana cigarettes required rehydration overnight in a humidifier . Participants r and omly assigned to the smoked marijuana group were housed in a room with a fan ventilating to the outside . To maximize st and ardization of inhaled doses , research staff monitored participants while they followed the uniform puff procedure outlined by Foltin and colleagues ( 34 ) . Research staff weighed the marijuana cigarettes immediately before and after they were administered to participants and returned all leftover material to the pharmacy . Study participants smoked up to three complete marijuana cigarettes daily , as tolerated , 1 hour before meals . Study participants were r and omly assigned in a double-blind fashion to the oral regimens , which were given on the same schedule as the smoked marijuana . Research staff observed participants taking all treatments . Research Design and Procedures Study clinicians admitted study participants to the General Clinical Research Center for a 4-day lead-in period to obtain baseline variables . A urine sample obtained on the day of admission ( day 4 ) had to be negative for tetrahydrocannabinol . The second phase of the trial was a 21-day intervention period beginning with r and om assignment of treatments on day 0 . Patients were stratified by protease inhibitor ( indinavir or nelfinavir ) and then allocated with equal probability in blocks of 12 to the study agents ( marijuana , dronabinol , and placebo ) . The statistician generated the r and om allocation sequences , and the pharmacists maintained the sequences in a secure location and distributed the assignments to the study coordinator on day 0 . Study participants were not permitted to have visitors or to leave the General Clinical Research Center unless accompanied by research personnel during the 25-day study . All clinical laboratory tests and study procedures were obtained or performed in the center . Patients were weighed on the same calibrated scale each morning while wearing a hospital gown . Baseline blood specimens were collected on days 4 and 0 to examine within-participant variation in HIV RNA level in the absence of experimental therapies . Follow-up specimens were obtained on days 2 , 5 , 8 , 11 , 14 , 17 , 19 , and 21 . Sample s were stored at 70 C and batch-tested for HIV RNA at the end Rationale Cannabinoids have been shown to alter time perception , but existing literature has several limitations . Few studies have included both time estimation and production tasks , few control for subvocal counting , most had small sample sizes , some did not record subjects ’ cannabis use , many tested only one dose , and used either oral or inhaled administration of Δ9-tetrahydrocannabinol ( THC ) , leading to variable pharmacokinetics , and some used whole-plant cannabis containing cannabinoids other than THC . Our study attempted to address these limitations . Objectives This study aims to characterize the acute effects of THC and frequent cannabis use on seconds-range time perception . THC was hypothesized to produce transient , dose-related time overestimation and underproduction . Frequent cannabis smokers were hypothesized to show blunted responses to these alterations . Methods IV THC was administered at doses from 0.015 to 0.05 mg/kg to 44 subjects who participated in several double-blind , r and omized , counterbalanced , crossover , placebo-controlled studies . Visual time estimation and production tasks in the seconds range were presented to subjects three times on each test day . Results All doses induced time overestimation and underproduction . Chronic cannabis use had no effect on baseline time perception . While infrequent/nonsmokers showed temporal overestimation at medium and high doses and temporal underproduction at all doses , frequent cannabis users showed no differences . THC effects on time perception were not dose related . Conclusions A psychoactive dose of THC increases internal clock speed as indicated by time overestimation and underproduction . This effect is not dose related and is blunted in chronic cannabis smokers who did not otherwise have altered baseline time perception BACKGROUND The Cannabinoid Use in Progressive Inflammatory brain Disease ( CUPID ) trial aim ed to determine whether or not oral Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) slowed the course of progressive multiple sclerosis ( MS ) ; evaluate safety of cannabinoid administration ; and , improve methods for testing treatments in progressive MS . OBJECTIVES There were three objectives in the CUPID study : ( 1 ) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS ; ( 2 ) to assess the long-term safety of Δ(9)-THC ; and ( 3 ) to explore newer ways of conducting clinical trials in progressive MS . DESIGN The CUPID trial was a r and omised , double-blind , placebo-controlled , parallel-group , multicentre trial . Patients were r and omised in a 2 : 1 ratio to Δ(9)-THC or placebo . R and omisation was balanced according to Exp and ed Disability Status Scale ( EDSS ) score , study site and disease type . Analyses were by intention to treat , following a pre-specified statistical analysis plan . A cranial magnetic resonance imaging ( MRI ) sub study , Rasch measurement theory ( RMT ) analyses and an economic evaluation were undertaken . SETTING Twenty-seven UK sites . PARTICIPANTS Adults aged 18 - 65 years with primary or secondary progressive MS , 1-year evidence of disease progression and baseline EDSS 4.0 - 6.5 . INTERVENTIONS Oral Δ(9)-THC ( maximum 28 mg/day ) or matching placebo . ASSESSMENT VISITS Three and 6 months , and then 6-monthly up to 36 or 42 months . MAIN OUTCOME MEASURES Primary outcomes were time to EDSS progression , and change in Multiple Sclerosis Impact Scale-29 version 2 ( MSIS-29v2 ) 20-point physical subscale ( MSIS-29phys ) score . Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed . RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect . Economic evaluation estimated mean incremental costs and quality -adjusted life-years ( QALYs ) . RESULTS Effectiveness - recruitment targets were achieved . Of the 498 r and omised patients ( 332 to active and 166 to placebo ) , 493 ( 329 active and 164 placebo ) were analysed . PRIMARY OUTCOMES no significant treatment effect ; hazard ratio EDSS score progression ( active : placebo ) 0.92 [ 95 % confidence interval ( CI ) 0.68 to 1.23 ] ; and estimated between-group difference in MSIS-29phys score ( active-placebo ) -0.9 points ( 95 % CI -2.0 to 0.2 points ) . Secondary clinical and MRI outcomes : no significant treatment effects . Safety - at least one serious adverse event : 35 % and 28 % of active and placebo patients , respectively . RMT analyses - scale evaluation : MSIS-29 version 2 , MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments . There was no clear symptomatic or disease-modifying treatment effect . Economic evaluation - estimated mean incremental cost to NHS over usual care , over 3 years £ 27,443.20 per patient . No between-group difference in QALYs . CONCLUSIONS The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes . There were no major safety concerns , but unwanted side effects seemed to affect compliance . Participants were more disabled than in previous studies and deteriorated less than expected , possibly reducing our ability to detect treatment effects . RMT analyses supported performance of MS-specific rating scales as measures , enabled group- and individual person-level examination of treatment effects , but did not influence study inferences . The intervention had significant additional costs with no improvement in health outcomes ; therefore , it was dominated by usual care and not cost-effective . Future work should focus on determining further factors to predict clinical deterioration , to inform the development of new studies , and modifying treatments in order to minimise side effects and improve study compliance . The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection . TRIAL REGISTRATION Current Controlled Trials IS RCT N62942668 . FUNDING The National Institute for Health Research Health Technology Assessment programme , the Medical Research Council Efficacy and Mechanism Evaluation programme , Multiple Sclerosis Society and Multiple Sclerosis Trust . The report will be published in full in Health Technology Assessment ; Vol . 19 , No. 12 . See the NIHR Journals Library website for further project information Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis .  Delta-9-Tetrahydrocannabinol ( Δ-9-THC ) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals . Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established . In a 3-day , double-blind , r and omized , placebo-controlled study , the dose-related effects of 0 , 2.5 , and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls . Δ-9-THC ( 1 ) produced transient psychotomimetic effects and perceptual alterations ; ( 2 ) impaired memory and attention ; ( 3 ) increased subjective effects of ‘ high ’ ; ( 4 ) produced tachycardia ; and ( 5 ) increased serum cortisol in both groups . However , relative to controls , frequent users showed blunted responses to the psychotomimetic , perceptual altering , cognitive impairing , anxiogenic , and cortisol increasing effects of Δ-9-THC but not to its euphoric effects . Frequent users also had lower prolactin levels . These data suggest that frequent users of cannabis are either inherently blunted in their response to , and /or develop tolerance to the psychotomimetic , perceptual altering , amnestic , endocrine , and other effects of cannabinoids Although cannabinoids have anti‐hyperalgesic effects in animal models of nerve injury , there are currently very few prospect i ve trials of the efficacy of cannabinoids in neuropathic pain in humans . This open label prospect i ve study investigated the safety , tolerability and analgesic benefit of oral Δ‐9‐tetrahydrocannabinol ( THC ) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain .  Spontaneous ongoing and paroxysmal pain , allodynia and paresthesias were assessed . The sensory and affective components of pain using the McGill pain question naire , quality of life , mood , anxiety and functionality were also evaluated . Seven patients suffered from  side effects  necessitating premature arrest of the drug in 5 of them . THC ( mean dosage : 16.6 ± 6.5 mg/day ) did not induce any significant effects on ongoing and paroxysmal pain , allodynia , quality of life , anxiety/depression scores and functional impact of pain . These results do not support an overall benefit  of  THC in pain and quality of life in patients with refractory neuropathic pain PURPOSE To compare the effects of cannabis extract ( CE ) , delta-9-tetrahydrocannabinol ( THC ) , and placebo ( PL ) on appetite and quality of life ( QOL ) in patients with cancer-related anorexia-cachexia syndrome ( CACS ) . PATIENTS AND METHODS Adult patients with advanced cancer , CACS , weight loss ( > or = 5 % over 6 months ) , and Eastern Cooperative Oncology Group ( ECOG ) performance status ( PS ) < or = 2 were r and omly assigned ( 2:2:1 ) to receive CE ( st and ardized for 2.5 mg THC and 1 mg cannabidiol ) or THC ( 2.5 mg ) or PL orally , twice daily for 6 weeks . Appetite , mood , and nausea were monitored daily with a visual analog scale ( VAS ) ; QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( composite score : questions 29 and 30 ) . Cannabinoid-related toxicity was assessed every 2 weeks . RESULTS Of 289 patients screened , 243 were r and omly assigned and 164 ( CE , 66 of 95 patients ; THC , 65 of 100 patients ; and PL , 33 of 48 patients ) completed treatment . At baseline , groups were comparable for age ( mean , 61 years ) , sex ( 54 % men ) , weight loss ( 32 % > or = 10 % ) , PS ( 13 % ECOG = 2 ) , antineoplastic treatment ( 50 % ) , appetite ( mean VAS score , 31/100 mm ) , and QOL ( mean score , 30/100 ) . Intent-to-treat analysis showed no significant differences between the three arms for appetite , QOL , or cannabinoid-related toxicity . Increased appetite was reported by 73 % , 58 % , and 69 % of patients receiving CE , THC , or PL , respectively . An independent data review board recommended termination of recruitment because of insufficient differences between study arms . CONCLUSION CE at the oral dose administered was well tolerated by these patients with CACS . No differences in patients ' appetite or QOL were found either between CE , THC , and PL or between CE and THC at the dosages investigated Levonantradol is a cannabis derivative . Cannabinoid anti-emetics are being assessed in cancer chemotherapy but have been little used in radiotherapy to date . A pilot study and r and omised trial compared the anti-emetic effect of a st and ard drug ( Chlorpromazine 26 mg ) with Levonantradol at two doses ( 0.5 and 0.75 mg ) in patients receiving palliative single fraction radiotherapy to sites likely to cause nausea and vomiting . Most patients were out- patients . Both drugs were well tolerated . The frequency of vomiting was similar in all three groups in both the pilot study and r and omised trial UNLABELLED A r and omized , double-blinded , placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis . In a crossover design , each participant was exposed to 4 single dosing sessions of placebo or to low ( 1 % tetrahydrocannabinol [ THC ] ) , medium ( 4 % THC ) , or high ( 7 % THC ) doses of cannabis . Baseline spontaneous pain , evoked pain , and cognitive testing were performed . Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective " highness " score was measured at 5 , 15 , 30 , 45 , and 60 minutes and then every 30 minutes for an additional 3 hours . Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours . The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models . There was a significant difference in spontaneous pain scores between doses ( P < .001 ) . Specific significant comparisons were placebo versus low , medium , and high doses ( P = .031 , .04 , and < .001 , respectively ) and high versus low and medium doses ( both P < .001 ) . There was a significant effect of the high dose on foam brush and von Frey evoked pain ( both P < .001 ) . There was a significant negative effect ( impaired performance ) of the high dose on 2 of the 3 neuropsychological tests ( Paced Auditory Serial Addition Test , Trail Making Test Part B. PERSPECTIVE This small , short-term , placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain . This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain Background : The long-term treatment of Parkinson disease ( PD ) may be complicated by the development of levodopa-induced dyskinesia . Clinical and animal model data support the view that modulation of cannabinoid function may exert an antidyskinetic effect . The authors conducted a r and omized , double-blind , placebo-controlled crossover trial to examine the hypothesis that cannabis may have a beneficial effect on dyskinesia in PD . Methods : A 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six PD patients with levodopa-induced dyskinesia . Then a r and omized placebo-controlled crossover study ( RCT ) was performed , in which 19 PD patients were r and omized to receive oral cannabis extract followed by placebo or vice versa . Each treatment phase lasted for 4 weeks with an intervening 2-week washout phase . The primary outcome measure was a change in Unified Parkinson ’s Disease Rating Scale ( UPDRS ) ( items 32 to 34 ) dyskinesia score . Secondary outcome measures included the Rush scale , Bain scale , tablet arm drawing task , and total UPDRS score following a levodopa challenge , as well as patient-completed measures of a dyskinesia activities of daily living ( ADL ) scale , the PDQ-39 , on-off diaries , and a range of category rating scales . Results : Seventeen patients completed the RCT . Cannabis was well tolerated , and had no pro- or antiparkinsonian action . There was no evidence for a treatment effect on levodopa-induced dyskinesia as assessed by the UPDRS , or any of the secondary outcome measures . Conclusions : Orally administered cannabis extract result ed in no objective or subjective improvement in dyskinesias or parkinsonism Nabilone , a synthetic cannabinoid , and Prochlorperazine were compared in a double-blind crossover study of 34 patients with lung cancer undergoing a 3-day schedule of chemotherapy with Cyclophosphamide , Adriamycin and Etoposide .  Symptom scores were significantly better for patients on nabilone for nausea , retching and vomiting ( P less than 0.05 ) . Fewer subjects vomited with nabilone ( P = 0.05 ) and the number of vomiting episodes was lower ( P less than 0.05 ) ; no patients on nabilone required additional parenteral anti-emetic . More patients preferred nabilone for anti-emetic control ( P less than 0.005 ) . Adverse effects common with nabilone were drowsiness ( 57 % ) , postural dizziness ( 35 % ) and lightheadedness ( 18 % ) . Euphoria was seen in 14 % and a " high " in 7 % . Erect systolic blood pressure was lower in nabilone patients on Day 1 ( P = 0.05 ) but postural hypotension was a major problem in only 7 % . Nabilone is an effective oral anti-emetic drug for moderately toxic chemotherapy , but the range and unpredictability of its side-effects warrant caution in its use We conducted a review of systematic review s ( SRs ) and r and omized-controlled trials ( RCTs ) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders . Five data bases were systematic ally search ed ( 2006—August 2018 ) ; 4 SRs ( of 11 RCTs ) and 14 RCTs ( 1629 participants ) were included . Diagnoses were : dementia , cannabis and opioid dependence , psychoses/schizophrenia , general social anxiety , posttraumatic stress disorder , anorexia nervosa , attention-deficit hyperactivity disorder , and Tourette`s disorder . Outcome variables were too heterogeneous to conduct a meta- analysis . A narrative synthesis method was applied . The study quality was assessed using the risk-of-bias tool and SIGN-checklists . THC- and CBD-based medicines , given as adjunct to pharmaco- and psychotherapy , were associated with improvements of several symptoms of mental disorders , but not with remission . Side effects occurred , but severe adverse effects were mentioned in single cases only . In order to provide reliable treatment recommendations , more and larger RCTs with follow-up assessment s , consistent outcome measures and active comparisons are needed Background : Although the pre clinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects , efficacy in the human pain state remains unclear . Using a human experimental pain model , the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin . Methods : In a r and omized , double-blinded , placebo-controlled , crossover trial in 15 healthy volunteers , the authors evaluated concentration – response effects of low- , medium- , and high-dose smoked cannabis ( respectively 2 % , 4 % , and 8 % 9-&dgr;-tetrahydrocannabinol by weight ) on pain and cutaneous hyperalgesia induced by intradermal capsaicin . Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure , and pain , hyperalgesia , tetrahydrocannabinol plasma levels , and side effects were assessed . Results : Five minutes after cannabis exposure , there was no effect on capsaicin-induced pain at any dose . By 45 min after cannabis exposure , however , there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose . There was no effect seen with the low dose , nor was there an effect on the area of hyperalgesia at any dose . Significant negative correlations between pain perception and plasma & dgr;-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects . There was no significant difference in performance on the neuropsychological tests . Conclusions : This study suggests that there is a window of modest analgesia for smoked cannabis , with lower doses decreasing pain and higher doses increasing pain BACKGROUND Sativex ( ® ) , a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , is currently in phase III trials as an adjunct to opioids for cancer pain treatment , and recently received United Kingdom approval for treatment of spasticity . There are indications that CBD modulates THC 's effects , but it is unclear if this is due to a pharmacokinetic and /or pharmacodynamic interaction . METHODS Cannabis smokers provided written informed consent to participate in this r and omized , controlled , double-blind , double-dummy institutional review board-approved study . Participants received 5 and 15 mg synthetic oral THC , low-dose ( 5.4 mg THC and 5.0 mg CBD ) and high-dose ( 16.2 mg THC and 15.0 mg CBD ) Sativex , and placebo over 5 sessions . CBD , THC , 11-hydroxy-THC , and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS . Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions . Significant differences ( P < 0.05 ) in maximum plasma concentrations ( C(max ) ) and areas under the curve from 0 - 10.5 h postdose ( AUC(0→10.5 ) ) for all analytes were found between low and high doses of synthetic THC and Sativex . There were no statistically significant differences in C(max ) , time to maximum concentration or in the AUC(0→10.5 ) between similar oral THC and Sativex doses . Relative bioavailability was calculated to determine the relative rate and extent of THC absorption ; 5 and 15 mg oral THC bioavailability was 92.6 % ( 13.1 % ) and 98.8 % ( 11.0 % ) of low- and high-dose Sativex , respectively . CONCLUSION These data suggest that CBD modulation of THC 's effects is not due to a pharmacokinetic interaction at these therapeutic doses UNLABELLED Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge . Nabiximols ( Nabiximols is the U.S. Adopted Name [ USAN ] for Sativex [ GW Pharma Ltd , Wiltshire , U.K. ] , which does not yet have an INN ) , a novel cannabinoid formulation , is undergoing investigation as add-on therapy for this population . In a r and omized , double-blind , placebo-controlled , grade d-dose study , patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose ( 1 - 4 sprays/day ) , medium dose ( 6 - 10 sprays/day ) , or high dose ( 11 - 16 sprays/day ) . Average pain , worst pain and sleep disruption were measured daily during 5 weeks of treatment ; other question naires measured quality of life and mood .  A total of 360 patients were r and omized ; 263 completed . There were no baseline differences across groups . The 30 % responder rate primary analysis was not significant for nabiximols versus placebo ( overall P = .59 ) . A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall ( P = .035 ) , and specifically in the low-dose ( P = .008 ) and medium-dose ( P = .039 ) groups . In the low-dose group , results were similar for mean average pain ( P = .006 ) , mean worst pain ( P = .011 ) , and mean sleep disruption ( P = .003 ) . Other question naires showed no significant group differences . Adverse events were dose-related and only the high-dose group compared unfavorably with placebo . This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials . PERSPECTIVE Nabiximols , a novel cannabinoid formulation , may be a useful add-on analgesic for patients with opioid-refractory cancer pain . A r and omized , double-blind , placebo-controlled , grade d-dose study demonstrated efficacy and safety at low and medium doses The aim of the present study was to investigate the effects of nabilone on capsaicin‐induced pain and hyperalgesia , as well as on biomarkers of cannabinoid central nervous system ( CNS ) effects . A r and omized , double‐blind , placebo‐controlled , crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone ( 1 , 2 or 3 mg ) .  Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale ( 0–100 mm ) . Capsaicin cream was applied to the calf to induce hyperalgesia . Primary hyperalgesia was assessed by measuring heat pain thresholds , whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful . Pain and hyperalgesia were measured at baseline and 2–3.5 h after dosing . The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling ‘ stimulated ’ , ‘ anxious ’ , ‘ se date d ’ and ‘ down ’ . Plasma sample s for pharmacokinetic analysis were obtained up to 24 h after drug administration . Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia , whereas dose‐dependent CNS effects were observed from 1.5 to 6 h after dosing , being maximal at 4–6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1–2 h after dosing . Adverse events ( AE ) were common on nabilone treatment . Four subjects withdrew due to pronounced CNS AE ( anxiety , agitation , altered perception , impaired consciousness ) . Although nabilone had marked CNS effects , no analgesic or antihyperalgesic effects were observed CONTEXT The US Food and Drug Administration ( FDA ) licensed recombinant human coagulation factor VIIa ( rFVIIa ) on March 25 , 1999 , for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX . Use in patients without hemophilia has been increasing since licensure . OBJECTIVE To review serious thromboembolic adverse events ( AEs ) reported to the FDA 's Adverse Event Reporting System ( AERS ) . DESIGN , SETTING , AND PATIENTS The AERS data base was review ed from March 25 , 1999 , through December 31 , 2004 , for thromboembolic AE reports with rFVIIa . The AERS data base includes US and non-US spontaneous AE reports from both approved ( specific indications for patients with hemophilia ) and unlabeled uses . It also includes serious AEs in patients enrolled in postlicensure clinical trials who received rFVIIa . Manufacturer reporting to FDA is m and atory , but primary notification from clinicians and others to FDA or manufacturers is voluntary for spontaneous reports ; therefore , AERS underrepresents actual event occurrences . MAIN OUTCOME MEASURE Reported thromboembolic events occurring in patients administered rFVIIa . RESULTS A total of 431 AE reports for rFVIIa were found , of which 168 reports described 185 thromboembolic events . Seventeen events occurred in patients with hemophilia and 59 occurred in patients enrolled in postlicensure trials . Unlabeled indications accounted for 151 of the reports , most with active bleeding ( n = 115 ) . Reported AEs were thromboembolic cerebrovascular accident ( n = 39 ) , acute myocardial infa rct ion ( n = 34 ) , other arterial thromboses ( n = 26 ) , pulmonary embolism ( n = 32 ) , other venous thromboses ( including deep vein thrombosis ) ( n = 42 ) , and clotted devices ( n = 10 ) . In 36 ( 72 % ) of 50 reported deaths , the probable cause of death was the thromboembolic event . In 144 patients with timing information , 73 events ( 52 % ) occurred in the first 24 hours after the last dose ( 30 events within 2 hours ) . Sixty-four reports ( 38 % ) noted concomitant use of hemostatic agents . Most reports lacked sufficient information to evaluate potential dosage associations . CONCLUSIONS Most reported thromboembolic AEs followed the use of rFVIIa for unlabeled indications and occurred in arterial and venous systems , often result ing in serious morbidity and mortality . Analysis of the relationship between AEs and rFVIIa is hindered by concomitant medications , preexisting medical conditions , confounding by indication , and inherent limitations of passive surveillance . R and omized controlled trials are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia The antiemetic efficacy of i m levonantradol , a synthetic cannabinoid , given at a dose of 1 mg every 4 hours , was compared to oral delta-9-tetrahydrocannabinol ( THC ) given at a dose of 15 mg every 4 hours in a double-blind crossover study . Twenty-six patients receiving emetogenic cancer chemotherapy were evaluated . For each drug , 28 % of treated patients had no nausea . The median number of emetic episodes with levonantradol was 2.0 versus 3.0 for THC ( P = 0.06 ) . Side effects occurred in 91.7 % and 97.3 % of levonantradol and THC patients , respectively , with drowsiness and dizziness most commonly seen . Side effects were generally well-tolerated , with only 13.9 % of levonantradol and 21.6 % of THC patients discontinuing treatment because of side effects .  Levonantradol appears to be at least as effective an antiemetic as THC and is the only cannabinoid available for parenteral use Earlier this year my colleagues and I carried out a Cochrane review of the effects of  cholera vaccines .  The review was large , but because of the data available we concentrated mainly on the older killed whole cell ( KWC ) variety of vaccines . At the beginning of the review we were aware that cholera KWC vaccines have been discouraged since the 1970s in either endemic or epidemic areas on the grounds that they had low efficacy and short duration ( four to six months ) , required multiple doses , and were less effective in children under 5than in adults .  Important adverse effects were said to occur in 30 % of recipients of injected KWC vaccines . Our Cochrane review re-examined the evidence for these statements through a systematic review of r and omised and quasir and omised controlled  cholera vaccine  trials of over 2.5 m participants conducted world wide since 1963.The overall efficacy of vaccine compared with placebo was 57 % ( 95 % confidence Neuropathic pain ( NeP ) , generated by disorders of the peripheral and central nervous system , can be particularly severe and disabling . Prevalence estimates indicate that 2 % to 3 % of the population in the developed world suffer from NeP , which suggests that up to one million Canadians have this disabling condition . Evidence -based guidelines for the pharmacological management of NeP are therefore urgently needed . R and omized , controlled trials , systematic review s and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting . Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one method ologically sound , r and omized , controlled trial showing significant benefit relative to placebo or another relevant control group . Recommendations for treatment are based on degree of evidence of analgesic efficacy , safety , ease of use and cost-effectiveness .  Analgesic agents recommended for first-line treatments are certain antidepressants ( tricyclics ) and anticonvulsants ( gabapentin and pregabalin ) . Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine . Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain . Recommended fourth-line treatments include cannabinoids , methadone and anticonvulsants with lesser evidence of efficacy , such as lamotrigine , topiramate and valproic acid . Treatment must be individualized for each patient based on efficacy , side-effect profile and drug accessibility , including cost . Further studies are required to examine head-to-head comparisons among analgesics , combinations of analgesics , long-term outcomes , and treatment of pediatric and central OBJECTIVE Anorexia nervosa ( AN ) is characterised by complex neuroendocrine disturbances due to severe underweight , physical hyperactivity and purging behaviour . Cannabinoid agonists are used to palliate cachexia of various causes , but their interactions with the hormonal systems that are involved in energy metabolism have not been previously described in humans . Therefore we found it of interest to assess interactions between the synthetic cannabinoid agonist dronabinol and insulin-like growth factor I ( IGF-I ) , urinary free cortisol ( UFC ) and adipokines in patients with chronic AN . DESIGN This was a prospect i ve , double-blind r and omised crossover study , conducted at a specialised care centre for eating disorders . The results are based on twenty-four adult women with chronic AN , who completed the study . The participants received dronabinol ( oral capsules , 5 mg daily ) and matching placebo over four weeks , separated by a four-week washout period . Bioactive IGF was determined by a cell-based bioassay , whereas total IGF-I , IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays . The UFC excretion was determined by mass spectrometry . RESULTS As previously reported , dronabinol treatment caused a small , yet significant increase in BMI as compared to placebo ( + 0.23 kg/m(2 ) ; P = 0.04 ) . This modest weight gain predicted a corresponding increase in bioactive IGF-I , while the amount of daily energy expenditure due to physical activity had a comparable but opposite effect . Nevertheless , neither IGF-I , bioactive IGF nor the IGFBPs levels changed significantly during dronabinol intervention as compared to placebo . Adiponectin also remained unaffected by the weight gain , whereas plasma leptin showed a transient increase at three weeks ( P < 0.05 ) . UFC levels were decreased during dronabinol intervention . CONCLUSION Our results showed that low-dosage therapy with the synthetic cannabinoid agonist dronabinol affected neither the concentration nor the activity of the circulating IGF-system in women with severe and chronic AN . However , our results suggest that such treatment may alleviate the increased hypothalamic-pituitary-adrenal axis activity seen in these patients This was a double-blind , r and omised , placebo-controlled , crossover study of the acute cognitive and subjective effects of nabilone 1—3 mg in healthy male volunteers . The Cognitive Drug Research computerised system ( CDR system ) was used to assess changes in attention , working and episodic memory . In addition , a number of self-ratings were conducted including those of mood , alertness and perceived drug effects . Impairments to attention , working and episodic memory and self-ratings of alertness were evident . Volunteers also experienced a number of subjective drug effects . These data demonstrate that acute doses of nabilone in the range 1—3 mg produce clear cognitive and subjective effects in healthy volunteers , and therefore they may be used as reference data in the future study of peripherally acting cannabinoids believed to be free from such effects Drugs are important risk factors for traffic accidents . In Brazil , truck drivers report using amphetamines to maintain their extensive work schedule and stay awake . These drugs can be obtained without prescription easily on Brazilian roads . The use of these stimulants can result in health problems and can be associated with traffic accidents . There are Brazilian studies that show that drivers use drugs . However , these studies are question naire-based and do not always reflect real-life situations . The purpose of this study was to demonstrate the prevalence of drug use by truck drivers on the roads of Sao Paulo State , Brazil , during 2009 . Drivers of large trucks were r and omly stopped by police officers on the interstate roads during morning hours . After being informed of the goals of the study , the drivers gave written informed consent before providing a urine sample . In addition , a question naire concerning sociodemographic characteristics and health information was administered . Urine sample s were screened for amphetamines , cocaine , and cannabinoids by immunoassay and the confirmation was performed using gas chromatography-mass spectrometry ( GC-MS ) . Of the 488 drivers stopped , 456 ( 93.4 % ) provided urine sample s , and 9.3 % of them ( n=42 ) tested positive for drugs . Amphetamines were the most commonly found ( n=26 ) drug , representing 61.9 % of the positive sample s. Ten cases tested positive for cocaine ( 23.8 % ) , and five for cannabinoids ( 11.9 % ) . All drivers were male with a mean age of 40 ± 10.8 years , and 29.3 % of them reported some health problem ( diabetes , high blood pressure and /or stress ) . A high incidence of truck drivers who tested positive for drug use was found , among other reported health problems . Thus , there is an evident need to promote a healthier lifestyle among professional drivers and a need for preventive measures aim ed at controlling the use of drugs by truck drivers in Brazil Background Epidemiological , clinical , and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence . Moreover , clinical ly significant manic symptoms may occur even earlier , especially in children at familial risk . Lithium is the gold st and ard treatment for acute mania in adults , yet to our knowledge , there is no published systematic review assessing lithium treatment of mania in children or adolescents . This is a major gap in knowledge needed to inform clinical practice . Aim As a working group within the ISBD Task Force on Lithium Treatment ( http://www.isbd.org/active-task-forces ) , our aim is to complete a systematic review of the efficacy , tolerability , and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder . Methods We will include double- or single-blind r and omized controlled trials in patients aged less than 18 years . No restrictions will be made by study publication date or language . Several electronic data bases will be search ed along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies . Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome . Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts , respectively . Secondary outcomes will include rates of remission , severity of manic symptoms at different time points , and incidence of specific adverse events . Discussion Findings from this systematic review are critically needed to inform clinical practice . We should not generalize findings from adult studies , as children and adolescents are undergoing accelerated physiological and brain development . Therefore , efficacy , tolerability , and acceptability of lithium treatment of acute mania in children compared to adults may be very different . This systematic review has been registered in PROSPERO ( CRD42017055675 ) Objectives : Individuals with HIV constitute the largest group using cannabinoids for medicinal reasons ; yet , no studies have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol maintenance in HIV-positive marijuana smokers . This placebo-controlled within-subjects study evaluated marijuana and dronabinol across a range of behaviors : eating topography , mood , cognitive performance , physiologic measures , and sleep . Methods : HIV-positive marijuana smokers ( n = 10 ) completed 2 16-day inpatient phases . Each dronabinol ( 5 and 10 mg ) and marijuana ( 2.0 % and 3.9 % Δ9-tetrahydrocannabinol [ THC ] ) dose was administered 4 times daily for 4 days , but only 1 drug was active per day , thereby maintaining double-blind dosing . Four days of placebo washout separated each active cannabinoid condition . Results : As compared with placebo , marijuana and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive marijuana smokers . All cannabinoid conditions produced significant intoxication , except for low-dose dronabinol ( 5 mg ) ; the intoxication was rated positively ( eg , “ good drug effect ” ) with little evidence of discomfort and no impairment of cognitive performance . Effects of marijuana and dronabinol were comparable , except that only marijuana ( 3.9 % THC ) improved ratings of sleep . Conclusions : These data suggest that for HIV-positive marijuana smokers , both dronabinol ( at doses 8 times current recommendations ) and marijuana were well tolerated and produced substantial and comparable increases in food intake Rationale Many neuropsychological studies have documented deficits in working memory among recent heavy cannabis users . However , little is known about the effects of cannabis on brain activity . Objective We assessed brain function among recent heavy cannabis users while they performed a working memory task . Methods Functional magnetic resonance imaging was used to examine brain activity in 12 long-term heavy cannabis users , 6–36 h after last use , and in 10 control subjects while they performed a spatial working memory task .  Regional brain activation was analyzed and compared using statistical parametric mapping techniques . Results Compared with controls , cannabis users exhibited increased activation of brain regions typically used for spatial working memory tasks ( such as prefrontal cortex and anterior cingulate ) . Users also recruited additional regions not typically used for spatial working memory ( such as regions in the basal ganglia ) . These findings remained essentially unchanged when re-analyzed using subjects ’ ages as a covariate . Brain activation showed little or no significant correlation with subjects ’ years of education , verbal IQ , lifetime episodes of cannabis use , or urinary cannabinoid levels at the time of scanning . Conclusions Recent cannabis users displayed greater and more widespread brain activation than normal subjects when attempting to perform a spatial working memory task . This observation suggests that recent cannabis users may experience subtle neurophysiological deficits , and that they compensate for these deficits by “ working harder”—calling upon additional brain regions to meet the dem and s of the task CONTEXT Chronic pain in patients with advanced cancer poses a serious clinical challenge . The Δ9-tetrahydrocannabinol (THC)/cannabidiol ( CBD ) oromucosal spray ( U.S. Adopted Name , nabiximols ; Sativex ( ® ) ) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group . OBJECTIVES This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer . METHODS In total , 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing , who had participated in a previous three-arm ( THC/CBD spray , THC spray , or placebo ) , two-week parent r and omized controlled trial , entered this open-label , multicenter , follow-up study . Patients self-titrated THC/CBD spray ( n=39 ) or THC spray ( n=4 ) to symptom relief or maximum dose and were regularly review ed for safety , tolerability , and evidence of clinical benefit . RESULTS The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for " pain severity " and " worst pain " domains showed a decrease ( i.e. , improvement ) at each visit in the THC/CBD spray patients . Similarly , the European Organization for Research and Treatment of Cancer Quality of Life Question naire-C30 scores showed a decrease ( i.e. , improvement ) from baseline in the domains of insomnia , pain , and fatigue . No new safety concerns associated with the extended use of THC/CBD spray arose from this study . CONCLUSION This study showed that the long-term use of THC/CBD spray was generally well tolerated , with no evidence of a loss of effect for the relief of cancer-related pain with long-term use . Furthermore , patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time , suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit IMPORTANCE There are no medications approved for treating cannabis dependence or withdrawal . The cannabis extract nabiximols ( Sativex ) , developed as a multiple sclerosis treatment , offers a potential agonist medication for cannabis withdrawal . OBJECTIVE To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal . DESIGN , SETTING , AND PARTICIPANTS A 2-site , double-blind r and omized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales , Australia . Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers . INTERVENTIONS A 6-day regimen of nabiximols ( maximum daily dose , 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol ) or placebo with st and ardized psychosocial interventions during a 9-day admission . MAIN OUTCOMES AND MEASURES Severity of cannabis withdrawal and cravings ( Cannabis Withdrawal Scale ) , retention in withdrawal treatment , and adverse events . Secondary outcomes include postwithdrawal cannabis use , health outcomes , and psychosocial outcomes . RESULTS Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo ( F8,377.97 = 2.39 ; P = .01 ) , including effects on withdrawal-related irritability , depression , and cannabis cravings . Nabiximols had a more limited , but still positive , therapeutic benefit on sleep disturbance , anxiety , appetite loss , physical symptoms , and restlessness . Nabiximols patients remained in treatment longer during medication use ( unadjusted hazard ratio , 3.66 [ 95 % CI , 1.18 - 11.37 ] ; P = .02 ) , with 2.84 the number needed to treat to achieve successful retention in treatment . Participants could not reliably differentiate between nabiximols and placebo treatment ( χ21 = 0.79 ; P = .67 ) , and those receiving nabiximols did not report greater intoxication ( F1,6 = 0.22 ; P = .97 ) . The number ( F1,50 = 0.3 ; P = .59 ) and severity ( F1,50 = 2.69 ; P = .10 ) of adverse events did not differ significantly between groups . Both groups showed reduced cannabis use at follow-up , with no advantage of nabiximols over placebo for self-reported cannabis use ( F1,48 = 0.29 ; P = .75 ) , cannabis-related problems ( F1,49 = 2.33 ; P = .14 ) , or cannabis dependence ( F1,50 < 0.01 ; P = .89 ) . CONCLUSIONS AND RELEVANCE In a treatment-seeking cohort , nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment . However , placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation . The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal  in treatment-seeking population s. TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12611000398909 BACKGROUND Epicutaneous allergen administration using a patch may be an alternative to subcutaneous or sublingual immunotherapy . OBJECTIVE To optimize treatment dose and to demonstrate the efficacy and safety of epicutaneous immunotherapy . METHODS This monocentric , placebo-controlled , double-blind trial included 132 patients with grass pollen-induced rhinoconjunctivitis . In February 2008 , patients were r and omly allocated to receive placebo or 3 different doses of allergen . Before and during the pollen season 2008 , patients received 6 weekly patches . Efficacy was assessed 4 to 5 months later ( n = 110 ) and during the pollen season of the treatment-free follow-up year in 2009 ( n = 93 ) . The primary outcome was patient-reported changes in hay fever symptoms assessed by a visual analog scale . Secondary outcome measures were weekly visual analog scale symptom scores during pollen season , use of rescue medication , changes in conjunctival and skin reactivity , as well as safety . RESULTS Hay fever symptoms during the pollen season were reduced by more than 30 % in 2008 and by 24 % in 2009 in the high-dose group as compared with that in the placebo group , and the alleviation of symptoms in the follow-up year was dependent on the treatment dose . Higher allergen doses were associated with drug-related adverse events ( AEs ) , predominantly manifested by pruritus , erythema , wheal , or eczema . Eleven systemic AEs of grade s 1 to 2 required treatment and led to study exclusion . The dropout rate due to AEs was 8.3 % . No drug-related serious AE was recorded . CONCLUSION Epicutaneous immunotherapy is safe and efficacious in a dose-dependent manner after 6 patches only Previous studies provide evidence that marijuana ( Cannabis sativa ) and delta-9-tetrahydrocannabinol ( Δ9-THC ) , the major psychoactive ingredient of marijuana , respectively , are effective in the treatment of tics and behavioral problems in Tourette syndrome ( TS ) . It , therefore , has been speculated that the central cannabinoid receptor system might be involved in TS pathology . However , in healthy marijuana users there is an ongoing debate as to whether the use of cannabis causes acute and /or long-term cognitive deficits . In this r and omized double-blind placebo-controlled study , we investigated the effect of a treatment with up to 10 mg Δ9-THC over a 6-week period on neuropsychological performance in 24 patients suffering from TS . During medication and immediately as well as 5–6 weeks after withdrawal of Δ9-THC treatment , no detrimental effect was seen on learning curve , interference , recall and recognition of word lists , immediate visual memory span , and divided attention . Measuring immediate verbal memory span , we even found a trend towards a significant improvement during and after treatment . Results from this study corroborate previous data suggesting that in patients suffering from TS , treatment with Δ9-THC  causes neither acute nor long-term cognitive deficits . Larger and longer- duration controlled studies are recommended to provide more information on the adverse effect profile of THC in patients suffering from TS THE CENTRAL THEME OF THE INSTITUTE OF MEDICINE report on the US drug safety system was the need for a life cycle approach to drug evaluation : both the benefits and the risks need to be evaluated and integrated during the entire market life of a drug . The Food and Drug Administration Amendments Act of 2007 also called on the agency to improve its methods of communicating risks and benefits to patients and physicians . The Institute of Medicine recommendation to “ develop and continually improve a systematic approach to risk-benefit analysis for use throughout the [ Food and Drug Administration ] in the preapproval and postapproval setting s ” specifically acknowledges the need for and the challenges of the development of new methods of combining evidence about risks and benefits . Information that combines the best evidence on benefits with the best data on risks is also needed for daily clinical practice . Whenever a patient and physician decide on a particular course of treatment , they do so because they expect that the likely benefits will exceed potential harms . For the benefits of drug treatments , they often have authoritative sources to provide information : r and omized trials and systematic review s and meta-analyses of such trials . For adverse effects , the situation is different . Given the average duration of r and omized trials ( often months to 1 or 2 years ) and the average number of patients in r and omized trials ( often dozens to a few hundred ) , such trials are at most able to detect and quantify frequent adverse events that occur only early during treatment . Moreover , the adverse effect has to be known beforeh and or anticipated to be recorded systematic ally in the trials . The study population in trials , which often includes young persons with a single diagnosis and without concurrent disease , is often not representative of those who will eventually use the drug in the community . The situation does not much improve in meta- analysis : the typical meta- analysis of r and omized trials covers 1000 to 2500 individuals , only half of whom will have taken the new drug . The sample size precludes good quantification of adverse effects unless they occur at least with a frequency of about 1 per 200 person-years . Meta-analyses of trials do not solve the problem of late adverse effects or the problem of the narrow population included in the trials . The information on harms from trials is incomplete , and the possibility of using and combining such information across trials in systematic review s is limited . Thus , to underst and the full spectrum of adverse effects — those that occur late , that were not known beforeh and , and that are rare but nevertheless serious— and to be able to investigate the true incidence of known adverse effects in circumstances of actual prescribing , well- design ed observational studies will always be necessary . It follows that systematic review s of drug treatments must include not only the results of r and omized trials on benefits but also evidence from observational research on harms . Although the idea to turn to observational data for evidence may be a surprise , the idea makes sense in view of what r and omization does and what r and omized trials are good at doing . R and omized trials are uniquely superior to evaluate the benefits , the intended or hoped-for effects of treatments . The r and om allocation mechanism is able to overcome the strong tendency of physicians to selectively prescribe treatments based on the perceived prognosis and likely outcomes of patients . Although prescriptions that are tailored to individual prognoses constitute desired medical practice , this effort also makes it difficult to compare the benefits of different treatments because patients who receive different treatments will have different prognoses , called “ confounding by indication . ” In general , data from routine daily practice can therefore not be used to assess the benefits of treatment , especially for the comparison between users and nonusers of a drug Symptoms relating to spasticity are common in multiple sclerosis ( MS ) and can be difficult to treat . We have investigated the efficacy , safety and tolerability of a st and ardized oromucosal whole plant cannabis-based medicine ( CBM ) containing delta-9 tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , upon spasticity in MS . A total of 189 subjects with definite MS and spasticity were r and omized to receive daily doses of active preparation ( n = 124 ) or placebo ( n = 65 ) in a double blind study over 6 weeks . The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity . Secondary endpoints included a measure of spasticity ( Ashworth Score ) and a subjective measure of spasm . The primary efficacy analysis on the intention to treat ( ITT ) population ( n = 184 ) showed the active preparation to be significantly superior ( P = 0.048 ) . Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance . The responder analysis favoured active preparation , 40 % of subjects achieved > 30 % benefit ( P = 0.014 ) . Eight withdrawals were attributed to adverse events ( AEs ) ; six were on active preparation and two on placebo . We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain . Design R and omised , double blind , crossover trial of 14 weeks ’ duration comparing dihydrocodeine and nabilone . Setting Outpatient units of three hospitals in the United Kingdom . Participants 96 patients with chronic neuropathic pain , aged 23 - 84 years . Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain , as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period . Secondary outcomes were changes in mood , quality of life , sleep , and psychometric function . Side effects were measured by a question naire . Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks . Treatment periods were separated by a 2 week washout period . Results Mean baseline visual analogue score was 69.6 mm ( range 29.4 - 95.2 ) on a 0 - 100 mm scale . 73 patients were included in the available case analysis and 64 patients in the per protocol analysis . The mean score was 6.0 mm longer for nabilone than for dihydrocodeine ( 95 % confidence interval 1.4 to 10.5 ) in the available case analysis and 5.6 mm ( 10.3 to 0.8 ) in the per protocol analysis . Side effects were more frequent with nabilone . Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects , although no major adverse events occurred for either drug . Trial registration Current Controlled Trials IS RCT N15330757 Acupuncture has been used therapeutically in China for thous and s of years and is growing in prominence in Europe and the United States . In a recent review of complementary and alternative medicine use in the US population , an estimated 2.1 million people or 1.1 % of the population sought acupuncture care during the past 12 months . Four percent of the US population used acupuncture at any time in their lives . We review ed 31 different published journal articles , including 23 r and omized controlled clinical trials and 8 meta- analysis / systematic review s. We found evidence of some efficacy and low risk associated with acupuncture in pediatrics . From all the conditions we review ed , the most extensive research has looked into acupuncture 's role in managing postoperative and chemotherapy-induced nausea/vomiting . Postoperatively , there is far more evidence of acupuncture 's efficacy for pediatrics than for children treated with chemotherapy . Acupuncture seems to be most effective in preventing postoperative induced nausea in children . For adults , research shows that acupuncture can inhibit chemotherapy-related acute vomiting , but conclusions about its effects in pediatrics can not be made on the basis of the available published clinical trials data to date . Besides nausea and vomiting , research conducted in pain has yielded the most convincing results on acupuncture efficacy . Musculoskeletal and cancer-related pain commonly affects children and adults , but unfortunately , mostly adult studies have been conducted thus far . Because the manifestations of pain can be different in children than in adults , data can not be extrapolated from adult research . Systematic review s have shown that existing data often lack adequate control groups and sample sizes . Vas et al , Alimi et al , and Mehling et al demonstrated some relief for adults treated with acupuncture but we could not find any well-conducted r and omized controlled studies that looked at pediatrics and acupuncture exclusively . Pain is often unresolved from drug therapy , thus there is a need for more studies in this setting . For seasonal allergic rhinitis , we review ed studies conducted by Ng et al and Xue et al in children and adults , respectively . Both population s showed some relief of symptoms through acupuncture , but questions remain about treatment logistics . Additionally , there are limited indications that acupuncture may help cure children afflicted with nocturnal enuresis . Systematic review s show that current published trials have suffered from low trial quality , including small sample sizes . Other areas of pediatric afflictions we review ed that suffer from lack of research include asthma , other neurologic conditions , gastrointestinal disorders , and addiction . Acupuncture has become a dominant complementary and alternative modality in clinical practice today , but its associated risk has been question ed . The National Institutes of Health Consensus Statement states “ one of the advantages of acupuncture is that the incidence of adverse effects is substantially lower than that of many drugs or other accepted procedures for the same conditions . ” A review of serious adverse events by White et al found the risk of a major complication occurring to have an incidence between 1:10,000 and 1:100,000 , which is considered “ very low . ” Another study found that the risk of a serious adverse event occurring from acupuncture therapy is the same as taking penicillin . The safety of acupuncture is a serious concern , particularly in pediatrics . Because acupuncture 's mechanism is not known , the use of needles in children becomes question able . For example , acupoints on the vertex of infants should not be needled when the fontanel is not closed . It is also advisable to apply few needles or delay treatment to the children who have overeaten , are overfatigued , or are very weak . Through our review of pediatric adverse events , we found a 1.55 risk of adverse events occurring in 100 treatments of acupuncture that coincides with the low risk detailed in the studies mentioned previously . The actual risk to an individual patient is hard to determine because certain patients , such as an immunosuppressed patient , can be predisposed to an increased risk , acupuncturist 's qualifications differ , and practice s vary in certain parts of the world . Nevertheless , it seems acupuncture is a safe complementary/alternative medicine modality for pediatric patients on the basis of the data we review ed Objective : Cannabis may alleviate some symptoms associated with multiple sclerosis ( MS ) . This study investigated the effect of an orally administered st and ardized Cannabis sativa plant extract in MS patients with poorly controlled spasticity . Methods : During their inpatient rehabilitation programme , 57 patients were enrolled in a prospect i ve , r and omized , double-blind , placebo-controlled crossover study of cannabis-extract capsules st and ardized to 2.5 mg tetrahydrocannabinol ( THC ) and 0.9 mg cannabidiol ( CBD ) each . Patients in group A started with a drug escalation phase from 15 to maximally 30 mg THC by 5 mg per day if well tolerated , being on active medication for 14 days before starting placebo . Patients in group B started with placebo for seven days , crossed to the active period ( 14 days ) and closed with a three-day placebo period ( active drug dose escalation and placebo sham escalation as in group A ) . Measures used included daily self-report of spasm frequency and symptoms , Ashworth Scale , Rivermead Mobility Index , 10-m timed walk , nine-hole peg test , paced auditory serial addition test ( PASAT ) , and the digit span test . Results : In the 50 patients included into the intention-to-treat analysis set , there were no statistically significant differences associated with active treatment compared to placebo , but trends in favour of active treatment were seen for spasm frequency , mobility and getting to sleep . In the 37 patients ( per- protocol set ) who received at least 90 % of their prescribed dose , improvements in spasm frequency ( P- 0.013 ) and mobility after excluding a patient who fell and stopped walking were seen ( P- 0.01 ) . Minor adverse events were slightly more frequent and severe during active treatment , and toxicity symptoms , which were generally mild , were more pronounced in the active phase . Conclusion : A st and ardized Cannabis sativa plant extract might lower spasm frequency and increase mobility with tolerable side effects in MS patients with persistent spasticity not responding to other drugs CONTEXT Neuropathic pain caused by chemotherapy limits dosing and duration of potentially life-saving anti-cancer treatment and impairs quality of life . Chemotherapeutic neuropathy responds poorly to conventional treatments , and there is an urgent medical need for new treatments . Recent pre clinical studies demonstrate that cannabinoid agonists suppress established chemotherapy-evoked neuropathy . OBJECTIVES This was a pilot trial to begin to investigate a currently available cannabinoid agent , nabiximols ( oral mucosal spray containing cannabinoids ) , in the treatment of chemotherapy-induced neuropathic pain . METHODS A r and omized , placebo-controlled crossover pilot study was done in 16 patients with established chemotherapy-induced neuropathic pain . A 0 - 10 point numeric rating scale for pain intensity ( NRS-PI ) was used as the primary outcome measure . RESULTS When examining the whole group , there was no statistically significant difference between the treatment and the placebo groups on the NRS-PI . A responder analysis demonstrated that there were five participants who reported a two-point or greater reduction in pain that trended toward statistical significance and the number needed to treat was five . CONCLUSION Chemotherapy-induced neuropathic pain is particularly resistant to currently available treatments . This pilot trial found a number needed to treat of five and an average decrease of 2.6 on an 11-point NRS-PI in five " responders " ( as compared with a decrease of 0.6 with placebo ) and supports that it is worthwhile to study nabiximols in a full r and omized , placebo-controlled trial of chemotherapy-induced neuropathic pain BACKGROUND Our previous research suggested the involvement of γ-aminobutyric acid ( GABA ) , in particular the GABAB receptor subtype , in the interoceptive effects of Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . The aim of the present study was to determine the potential involvement of the GABAA receptor subtype by assessing the separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ(9)-THC using pharmacologically selective drug-discrimination procedures . METHODS Ten cannabis users learned to discriminate 30 mg oral Δ(9)-THC from placebo and then received diazepam ( 5 and 10 mg ) , Δ(9)-THC ( 5 , 15 and 30 mg ) and placebo , alone and in combination  . Self-report , task performance and physiological measures were also collected . RESULTS Δ(9)-THC functioned as a discriminative stimulus , produced subjective effects typically associated with cannabinoids ( e.g. , High , Stoned , Like Drug ) and elevated heart rate . Diazepam alone impaired performance on psychomotor performance tasks and increased ratings on a limited number of self-report question naire items ( e.g. , Any Effect , Se date d ) , but did not substitute for the Δ(9)-THC discriminative stimulus or alter the Δ(9)-THC discrimination dose-response function . Similarly , diazepam had limited impact on the other behavioral effects of Δ(9)-THC . CONCLUSIONS These results suggest that the GABAA receptor subtype has minimal involvement in the interoceptive effects of Δ(9)-THC , and by extension cannabis , in humans BACKGROUND Allergic rhinitis and asthma are important public health concerns , yet there is no consensus about the benefits and harms of allergen-specific immunotherapy to treat these conditions . We performed an umbrella review of systematic review s summarizing the current evidence for the benefits and harms of subcutaneous immunotherapy ( SCIT ) and sublingual immunotherapy ( SLIT ) . METHODS We search ed MEDLINE , Embase , the Cochrane Library and the grey literature from Jan. 1 , 2010 to Nov. 20 , 2016 for systematic review s of r and omized controlled trials or prospect ively controlled studies involving children or adults with allergic rhinitis or asthma . Outcomes were summarized narratively ( benefits : total combined symptom-medication score , symptom score , medication score , disease-specific quality of life , adherence ; harms : anaphylaxis , death , local and systemic reactions ) . RESULTS Twenty-three systematic review s were included . SCIT and SLIT were more effective than placebo for most outcomes . SCIT was better than SLIT at improving medication and symptom scores , with no differences in quality of life ; however , data were limited for this comparison . Anaphylaxis and death were infrequently reported . Few review s assessed benefits or harms among children . INTERPRETATION Allergen immunotherapy appears to be effective among patients with allergic rhinitis and asthma . The safety of allergen immunotherapy is not conclusively established , although death and anaphylaxis appear to be rare . PROSPERO no. : CRD42015024590 AIM To test whether a single session of motivational interviewing ( discussing alcohol , tobacco and illicit drug use ) would lead successfully to reduction in use of these drugs or in perceptions of drug-related risk and harm among young people . DESIGN Cluster r and omized trial , allocating 200 young people in the natural groups in which they were recruited to either motivational interviewing  ( n=105 ) or non-intervention education-as-usual control condition ( n=95 ) . SETTING Ten further education colleges across inner London . PARTICIPANTS Two hundred young people ( age range 16 - 20 years ) currently using illegal drugs , with whom contact was established through peers trained for the project . INTERVENTION The intervention was adapted from the literature on motivational interviewing in the form of a 1-hour single-session face-to-face interview structured by a series of topics . MEASUREMENTS Changes in self-reported cigarette , alcohol , cannabis and other drug use and in a range of drug-specific perceptions and other indicators of risk and harm . Measurement at recruitment and follow-up interview 3 months later . FINDINGS A good follow-up rate ( 89.5 % ; 179 of 200 ) was achieved . In comparison to the control group , those r and omized to motivational interviewing reduced their of use of cigarettes , alcohol and cannabis , mainly through moderation of ongoing drug use rather than cessation . Effect sizes were 0.37 ( 0.15 - 0.6 ) , 0.34 ( 0.09 - 0.59 ) and 0.75 ( 0.45 - 1.0 ) for reductions in the use of cigarettes , alcohol and cannabis , respectively . For both alcohol and cannabis , the effect was greater among heavier users of these drugs and among heavier cigarette smokers . The reduced cannabis use effect was also greater among youth usually considered vulnerable or high-risk according to other criteria . Change was also evident in various indicators of risk and harm , but not as widely as the changes in drug consumption . CONCLUSIONS This study provides the first substantial evidence of non-treatment benefit to be derived among young people involved in illegal drug use in receipt of motivational interviewing . The targeting of multiple drug use in a generic fashion among young people has also been supported Despite management with opioids and other pain modifying therapies , neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals . Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception . We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV . This was a phase II , double-blind , placebo-controlled , crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy ( DSPN ) . Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes ; they continued on their pre study analgesic regimens throughout the trial . Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting . Treatments were placebo and active cannabis ranging in potency between 1 and 8 % Δ-9-tetrahydrocannabinol , four times daily for 5 consecutive days during each of 2 treatment weeks , separated by a 2-week washout . The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale ( DDS ) from a pretreatment baseline to the end of each treatment week . Secondary measures included assessment s of mood and daily functioning . Of 127 volunteers screened , 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments . Among the completers , pain relief was greater with cannabis than placebo ( median difference in DDS pain intensity change , 3.3 points , effect size=0.60 ; p=0.016 ) . The proportions of subjects achieving at least 30 % pain relief  with cannabis versus placebo were 0.46 ( 95%CI 0.28 , 0.65 ) and 0.18 ( 0.03 , 0.32 ) . Mood and daily functioning improved to a similar extent during both treatment periods . Although most side effects were mild and self-limited , two subjects experienced treatment-limiting toxicities . Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN Although a wealth of pre clinical 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 r and omized , 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 Publisher Summary This chapter explores that spinal cord injury ( SCI ) has a number of severe and disabling consequences . Although loss of function is often considered the primary issue , pain is also a major problem . In central pain conditions , small r and omized trials have shown the effectiveness of amitriptyline and lamotrigine in central post-stroke pain and of dronabinol , a cannabinoid , in pain in multiple sclerosis . It is not known whether the efficacy of drugs in other central or peripheral neuropathic pain conditions can be anticipated to have similar effects in SCI neuropathic pain . Central neuropathic pain is often considered more refractory than peripheral neuropathic pain . It has been suggested that central post-stroke pain responds better to antidepressants than SCI pain . The chapter also review s that because of the lack of sufficient data in neuropathic SCI pain , efficacy in other neuropathic pain conditions has to be considered in choosing treatment 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 )
Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials .
There was an increased risk of short-term AEs with cannabinoids , including serious AEs .
Common AEs included dizziness , dry mouth , nausea , fatigue , somnolence , euphoria , vomiting , disorientation , drowsiness , confusion , loss of balance , and hallucination .
CONCLUSIONS AND RELEVANCE There was moderate- quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity .
There was low- quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy , weight gain in HIV infection , sleep disorders , and Tourette syndrome .
Cannabinoids were associated with an increased risk of short-term AEs
IMPORTANCE Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms , but their efficacy for specific indications is not clear .
OBJECTIVE To conduct a systematic review of the benefits and adverse events ( AEs ) of cannabinoids .