Psychomotor performance in relation to acute oral administration of Δ9-tetrahydrocannabinol and standardized cannabis extract in healthy human subjects Cannabinoids in the management of difficult to treat pain FAAH selectively influences placebo effects The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia The interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information Medical Marijuana: Is the Cart Before the Horse? Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia: A Randomized, Double-Blind, Pilot Study 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 Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial. Is pigment epithelium-derived factor level in cerebrospinal fluid a promising biomarker for early diagnosis of Alzheimer's disease? Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis 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. Can we clinically diagnose dementia with Lewy bodies yet? Nabilone produces marked impairments to cognitive function and changes in subjective state in healthy volunteers
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 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 Endogenous opioid and cannabinoid systems are thought to act synergistically regulating antinociceptive and reward mechanisms . To further underst and the human implication s of the interaction between these two systems , we investigated the role of the common , functional missense variant Pro129Thr of the gene coding fatty acid amide hydrolase ( FAAH ) , the major degrading enzyme of endocannabinoids , on psychophysical and neurotransmitter ( dopaminergic , opioid ) responses to pain and placebo-induced analgesia in humans . FAAH Pro129/Pro129 homozygotes , who constitute nearly half of the population , reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration ; no effects on pain report in the absence of placebo were observed . Pro129/Pro129 homozygotes also showed greater placebo-induced μ-opioid , but not D2/3 dopaminergic , enhancements in neurotransmission in regions known involved in placebo effects . These results show that a common genetic variation affecting the function of the cannabinoid system is serving as a probe to demonstrate the involvement of cannabinoid and opioid transmitters on the formation of placebo effects 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 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 Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today . Current treatment options are few and limited due to substantial side effects . Objectives The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity . Methods In an open-label pilot study , six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances — five patients with Alzheimer ’s disease and one patient with vascular dementia — were treated with 2.5 mg dronabinol daily for 2 weeks . Motor activity was measured objective ly using actigraphy . Results Compared to baseline , dronabinol led to a reduction in nocturnal motor activity ( P=0.028 ) . These findings were corroborated by improvements in Neuropsychiatric Inventory total score ( P=0.027 ) as well as in subscores for agitation , aberrant motor , and nighttime behaviors ( P<0.05 ) . No side effects were observed . Conclusions The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients . Thus , it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia BACKGROUND Interactions between glutamatergic and endocannabinoid systems may contribute to schizophrenia , dissociative states , and other psychiatric conditions . Cannabidiol ( CBD ) , a cannabinoid-1/2 ( CB1/2 ) receptor weak partial agonist or antagonist , may play a role in the treatment of schizophrenia . OBJECTIVE This study tested the hypothesis that CBD would attenuate the behavioral effects of the NMDA receptor antagonist , ketamine , in healthy human subjects . METHODS Ten male healthy volunteers were evaluated twice in a r and omized order . In both sessions they received ketamine ( bolus of 0.26 mg/kg/1 min followed by IV infusion of 0.25mg/kg over 30 min ) preceded by either CBD ( 600 mg ) or placebo . Psychopathology was assessed using the Brief Psychiatric Rating Scale ( BPRS ) and the CADSS ( Clinician Administered Dissociative States Scale ) at regular intervals from 30 min before to 90 min after ketamine administration . RESULTS CBD significantly augmented the activating effects of ketamine , as measured by the activation subscales of the BPRS . However , CBD also showed a non-significant trend to reduce ketamine-induced depersonalization , as measured by the CADSS . CONCLUSION These data describe a complex pattern of psychopharmacologic interactions between CBD and ketamine at the doses of each agent studied in this experiment 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 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 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 The endocannabinoid system , consisting of two cannabinoid receptors ( CB1 and CB2 ) and the endogenous lig and s an and amide ( arachidonoylethanolamide ( AEA ) ) and 2-arachidonoylglycerol ( 2-AG ) , has been shown to control food intake in both animals and humans , modulating either rewarding or quantitative aspects of the eating behavior . Moreover , hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis . Therefore , alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders , where a deranged leptin signalling has been also reported . In order to verify this hypothesis , we measured plasma levels of AEA , 2-AG , and leptin  in 15 women with anorexia nervosa ( AN ) , 12 women with bulimia nervosa ( BN ) , 11 women with binge-eating disorder ( BED ) , and 15 healthy women .  Plasma levels of AEA result ed significantly enhanced in both anorexic and BED women , but not in bulimic patients . No significant change occurred in the plasma levels of 2-AG in all the patients ' groups . Moreover , circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women . These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED . Although the pathophysiological significance of this alteration awaits further studies to be clarified , it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED 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 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 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 Alzheimer 's disease ( AD ) is the most common cause of dementia in Western countries and in Japan . Early diagnosis and treatment is needed to slow down the degenerative process and dementia in AD . The main histopathological characteristics of AD are senile plaques and neurofibrillary tangles . Based on the disease pathology , numerous blood and cerebrospinal fluid ( CSF ) tests have been proposed for early detection of AD . However , there is no definite clinical method to determine in which patients with mild cognitive impairment will progress to AD with dementia . Since pigment epithelium-derived factor ( PEDF ) has been recently shown to protect various types of cells including neuronal cells against oxidative stress- or glutamate-induced injury through its anti-oxidative properties , we examined here the expression levels of PEDF in AD 's brain . PEDF was found to have the strong immunoreactivity in cortical neurons and astrocytes in the brains of AD . Further , the distribution of PEDF proteins was good concordance with RAGE proteins , one of the receptors for amyloid beta peptides , which are involved in neuronal cell death and microglial activation in AD . These results suggest that PEDF overexpression may indicate a compensation mechanism to fight against neuronal cell injury in AD . Our present observations suggest that PEDF in CSF might reflect cerebral PEDF turnover and provide a means for monitoring neuronal perturbation induced by oxidative stress in the early stage of AD . Clinical use of CSF-PEDF as a biomarker for AD might enable more effective diagnosis and treatment of patients with this disorder 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 This study investigated the contribution of different cannabinoids to the subjective , behavioral and neurophysiological effects of smoked marijuana . Healthy marijuana users ( 12 men , 11 women ) participated in four sessions . They were r and omly assigned to a low or a high Δ9-tetrahydrocannabinol group ( THC ; 1.8 % versus 3.6 % ) . In the four sessions under blinded conditions subjects smoked marijuana cigarettes containing placebo ( no active cannabinoids ) , or cigarettes containing THC with low or high levels of cannabichromene ( CBC ; 0.1 % versus 0.5 % ) and low or high levels of cannabidiol ( CBD ; 0.2 % versus 1.0 % ) . Dependent measures included subjective reports , measures of cognitive task performance and neurophysiological measures [ electroencephalographic ( EEG ) and event-related potential ( ERP ) ] . Compared to placebo , active THC cigarettes produced expected effects on mood , behavior and brain activity . A decrease in performance , reduction in EEG power and attenuation of ERP components reflecting attentional processes were observed during tests of working memory and episodic memory . Most of these effects were not dose-dependent . Varying the concentrations of CBC and CBD did not change subjects ' responses on any of the outcome measures . These findings are consistent with previous studies indicating that THC and its metabolites are the primary active constituents of marijuana . They also suggest that neurophysiological EEG and ERP measures are useful biomarkers of the effects of THC 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 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 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 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 ) Dementia with Lewy Bodies ( DLB ) was initially identified and confirmed primarily by pathology , but is soon to be incorporated into the Diagnostic and Statistical Manual criteria as a clinical disease entity . Despite these advances over more than 20 years , current data suggest that the sensitivity of accurate clinical diagnosis of DLB is still very low , although there is mounting evidence that supportive features may increase diagnostic accuracy . Although DLB remains easy to identify pathologically with different cellular pathologies differentiating it from other dementia syndromes , pathological identification using only Lewy body pathology has been shown to be inaccurate due to overlap with patients without dementia symptoms . A number of studies now suggest that a combination of cellular pathologies , which include α-synuclein and β-amyloid deposition as well as dopamine denervation , assist with differentiating this dementia syndrome from others . The clinical and pathological overlap with the tauopathy of Alzheimer ’s disease still remains to be clarified . To determine more robust and independent clinicopathological correlates from Alzheimer ’s disease , longitudinal prospect i ve studies , using specific clinical batteries on dementia patients reaching the proposed criteria for DLB , with post-mortem assessment of the multiple pathologies associated with dementia , are required . Identifying genetic causes for DLB is another approach to investigate the pathogenesis of DLB . However this approach has been hindered to date by difficulties with identifying DLB clinical ly . The use of novel techniques is likely to advance knowledge on the pathogenesis of DLB and assist with redefining clinical and pathologic diagnostic criteria . To achieve the goal of more accurate clinical diagnosis of DLB , breakthroughs are necessary on the pathogenesis of DLB 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
This review finds no evidence that cannabinoids are effective in the improvement of disturbed behaviour in dementia or in the treatment of other symptoms of dementia .
BACKGROUND Following the discovery of an endogenous cannabinoid system and the identification of specific cannabinoid receptors in the central nervous system , much work has been done to investigate the main effects of these compounds .
There is increasing evidence that the cannabinoid system may regulate neurodegenerative processes such as excessive glutamate production , oxidative stress and neuroinflammation .
Neurodegeneration is a feature common to the various types of dementia and this has led to interest in whether cannabinoids may be clinical ly useful in the treatment of people with dementia .
Recent studies have also shown that cannabinoids may have more specific effects in interrupting the pathological process in Alzheimer 's disease .
OBJECTIVES To determine from available research whether cannabinoids are clinical ly effective in the treatment of dementia .