Cannabidiol in Humans—The Quest for Therapeutic Targets Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Controlled clinical trial of cannabidiol in Huntington's disease Cannabinoids in the management of difficult to treat pain Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects Effect of Sublingual Application of Cannabinoids on Intraocular Pressure: A Pilot Study An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Interaction of cannabidiol and alcohol in humans Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids
Cannabidiol ( CBD ) , a major phytocannabinoid constituent of cannabis , is attracting growing attention in medicine for its anxiolytic , antipsychotic , antiemetic and anti-inflammatory properties . However , up to this point , a comprehensive literature review of the effects of CBD in humans is lacking . The aim of the present systematic review is to examine the r and omized and crossover studies that administered CBD  to healthy controls and to clinical patients . A systematic search was performed in the electronic data bases PubMed and EMBASE using the key word “ cannabidiol ” . Both monotherapy and combination studies ( e.g. , CBD + ∆9-THC ) were included . A total of 34 studies were identified : 16 of these were experimental studies , conducted in healthy subjects , and 18 were conducted in clinical population s , including multiple sclerosis ( six studies ) , schizophrenia and bipolar mania ( four studies ) , social anxiety disorder ( two studies ) , neuropathic and cancer pain ( two studies ) , cancer anorexia ( one study ) , Huntington ’s disease ( one study ) , insomnia ( one study ) , and epilepsy ( one study ) . Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC . Moreover , some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and /or intensify ∆9-THC-induced effects , whereas others suggest that it may inhibit ∆9-THC-induced effects . Finally , preliminary clinical trials suggest that high-dose oral CBD ( 150–600 mg/d ) may exert a therapeutic effect for social anxiety disorder , insomnia and epilepsy , but also that it may cause mental sedation . Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed 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 Objectives : Cannabis is the most commonly used illicit drug ; a substantial minority of users develop dependence . The current lack of pharmacological treatments for cannabis dependence warrants the use of novel approaches and further investigation of promising pharmacotherapy . In this case series , we assessed the use of self-titrated dosages of Sativex ( 1:1 , & Dgr;9-tetrahydrocannabinol [THC]/cannabidiol [ CBD ] combination ) and motivational enhancement therapy and cognitive behavioral therapy ( MET/CBT ) for the treatment of cannabis dependence among 5 treatment-seeking community-recruited cannabis-dependent subjects . Methods : Participants underwent a 3-month open-label self-titration phase with Sativex ( up to 113.4 of THC/105 mg of CBD ) and weekly MET/CBT , with a 3-month follow-up . Results : Sativex was well-tolerated by all participants ( average dosage 77.5 THC/71.7 mg CBD ) . The combination of Sativex and MET/CBT reduced the amount of cannabis use and progressively reduced craving and withdrawal scores . THC/CBD metabolite concentration indicated reduced cannabis use and compliance with medication . Conclusions : In summary , this pilot study found that with Sativex in combination with MET/CBT reduced cannabis use while preventing increases in craving and withdrawal in the 4 participants completing the study . Further systematic exploration of Sativex as a pharmacological treatment option for cannabis dependence should be performed 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 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 Based on encouraging preliminary findings , cannabidiol ( CBD ) , a major nonpsychotropic constituent of Cannabis , was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients with Huntington 's Disease ( HD ) . The effects of oral CBD ( 10 mg/kg/day for 6 weeks ) and placebo ( sesame oil for 6 weeks ) were ascertained weekly under a double-blind , r and omized cross-over design . A comparison of the effects of CBD and placebo on chorea severity and other therapeutic outcome variables , and on a Cannabis side effect inventory , clinical lab tests and other safety outcome variables , indicated no significant ( p greater than 0.05 ) or clinical ly important differences . Correspondingly , plasma levels of CBD  were assayed by GC/MS , and the weekly levels ( mean range of 5.9 to 11.2 ng/ml ) did not differ significantly over the 6 weeks of CBD administration . In summary , CBD , at an average daily dose of about 700 mg/day for 6 weeks , was neither symptomatically effective nor toxic , relative to placebo , in neuroleptic-free patients with HD 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 The main active ingredient in cannabis , delta-9-tetrahydrocannabinol ( THC ) , can acutely induce psychotic symptoms and impair episodic and working memory . Another major constituent , cannabidiol ( CBD ) , may attenuate these effects . This study aim ed to determine the effects of THC and CBD , both alone and in combination on psychotic symptoms and memory function . A r and omised , double-blind crossover design compared the effects of ( i ) placebo , ( ii ) THC 8 mg , ( iii ) CBD 16 mg and ( iv ) THC 8 mg + CBD 16 mg administered by inhalation through a vaporiser . Using an experimental medicine approach to predict treatment sensitivity , we selected 48 cannabis users from the community on the basis of ( 1 ) schizotypal personality question naire scores ( low , high ) and ( 2 ) frequency of cannabis use ( light , heavy ) . The Brief Psychiatric Rating Scale ( BPRS ) , Psychotomimetic States Inventory ( PSI ) , immediate and delayed prose recall ( episodic memory ) , 1- and 2-back ( working memory ) were assessed on each day . Results indicated that THC increased overall scores on the PSI , negative symptoms on BPRS , and robustly impaired episodic and working memory . Co-administration of CBD did not attenuate these effects . CBD alone reduced PSI scores in light users only . At a ratio of 2:1 , CBD does not attenuate the acute psychotic and memory impairing effects of vaporised THC . Frequent cannabis users may show a blunted anti- psychotic response to CBD , which is of concern due to the high rates of cannabis use disorders in patients with schizophrenia Cannabidiol ( CBD ) , a constituent of cannabis with few psychoactive effects , has been reported in some studies to attenuate certain aspects of Δ9-tetrahydrocannabinol ( THC ) intoxication . However , most studies have tested only one dose of CBD in combination with one dose of oral THC , making it difficult to assess the nature of this interaction . Further , the effect of oral CBD on smoked cannabis administration is unknown . The objective of this multi-site , r and omized , double-blind , within-subject laboratory study was to assess the influence of CBD ( 0 , 200 , 400 , 800 mg , p.o . ) pretreatment on the reinforcing , subjective , cognitive , and physiological effects of smoked cannabis ( 0.01 ( inactive ) , 5.30–5.80 % THC ) . Non-treatment-seeking , healthy cannabis smokers ( n=31 ; 17 M , 14 F ) completed eight outpatient sessions . CBD was administered 90 min prior to cannabis administration . The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session . A subset of participants ( n=8 ) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose ( 800 mg ) . Under placebo CBD conditions , active cannabis ( 1 ) was self-administered by significantly more participants than placebo cannabis and ( 2 ) produced significant , time-dependent increases in ratings of ‘ High ’ , ‘ Good Effect ’ , ratings of the cannabis cigarette ( eg , strength , liking ) , and heart rate relative to inactive cannabis . CBD , which alone produced no significant psychoactive or cardiovascular effects , did not significantly alter any of these outcomes . Cannabis self-administration , subjective effects , and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules . These findings suggest that oral CBD does not reduce the reinforcing , physiological , or positive subjective effects of smoked cannabis Generalized Social Anxiety Disorder ( SAD ) is one of the most common anxiety conditions with impairment in social life . Cannabidiol ( CBD ) , one major non-psychotomimetic compound of the cannabis sativa plant , has shown anxiolytic effects both in humans and in animals . This preliminary study aim ed to compare the effects of a simulation public speaking test ( SPST ) on healthy control ( HC ) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo .  A total of 24 never-treated patients with SAD were allocated to receive either CBD ( 600 mg ; n=12 ) or placebo ( placebo ; n=12 ) in a double-blind r and omized design 1 h and a half before the test . The same number of HC ( n=12 ) performed the SPST without receiving any medication . Each volunteer participated in only one experimental session in a double-blind procedure . Subjective ratings on the Visual Analogue Mood Scale ( VAMS ) and Negative Self-Statement scale ( SSPS-N ) and physiological measures ( blood pressure , heart rate , and skin conductance ) were measured at six different time points during the SPST . The results were su bmi tted to a repeated- measures analysis of variance . Pretreatment with CBD significantly reduced anxiety , cognitive impairment and discomfort in their speech performance , and significantly decreased alert in their anticipatory speech . The placebo group presented higher anxiety , cognitive impairment , discomfort , and alert levels when compared with the control group as assessed with the VAMS . The SSPS-N scores evidence d significant increases during the testing of placebo group that was almost abolished in the CBD group . No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment , discomfort , and alert factors of VAMS . The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD , result ing in a similar response as the HC Besides the psychoactive Delta(9)-tetrahydrocannabinol ( THC ) , hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol ( CBD ) and of the degradation product cannabinol ( CBN ) . The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC . Therefore , a method for the simultaneous quantitative determination of THC , its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol ( 11-OH-THC ) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol ( THC-COOH ) , CBD and CBN from plasma was developed . The method was based on automatic solid-phase extraction with C(18 ) ec columns , derivatization with N , O-bistrimethylsilyltrifluoroacetamide ( BSTFA ) , and gas chromatography-electron impact ionization-mass spectrometry ( GC-EI-MS ) with deuterated st and ards . The limits of detection were between 0.15 and 0.29 ng/mL for THC , 11-OH-THC , THC-COOH , and CBD and 1.1 ng/mL for CBN . The method was applied in a prospect i ve pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract . The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL ( mean 4.05 ng/mL ) for THC , 1.8 and 12.3 ng/mL ( mean 4.9 ng/mL ) for 11-OH-THC , 19 and 71 ng/mL ( mean 35 ng/mL ) for THC-COOH , and 0.2 and 2.6 ng/mL ( mean 0.95 ng/mg ) for CBD . The peak concentrations ( mean values ) of THC , 11-OH-THC , THC-COOH , and CBD were observed at 56 , 82 , 115 , and 60 min , respectively , after intake . CBN was not detected . Caused by the strong first-pass metabolism , the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking . Therefore , the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption 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 Purpose The purpose of this study was to assess the effect on intraocular pressure ( IOP ) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol ( Δ-9-THC ) and cannabidiol ( CBD ) . Patients and Methods A r and omized , double-masked , placebo-controlled , 4 way crossover study was conducted at a single center , using cannabis-based medicinal extract of Δ-9-THC and CBD .  Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg Δ-9-THC , 20 mg CBD , 40 mg CBD , or placebo . Main outcome measure was IOP . Secondary outcomes included visual acuity , vital signs , and psychotropic effects . Results Two hours after sublingual administration of 5 mg Δ-9-THC , the IOP was significantly lower than after placebo ( 23.5 mm Hg vs. 27.3 mm Hg , P=0.026 ) . The IOP returned to baseline level after the 4-hour IOP measurement . CBD administration did not reduce the IOP at any time . However , the higher dose of CBD ( 40 mg ) produced a transient elevation of IOP at 4 hours after administration , from 23.2 to 25.9 mm Hg ( P=0.028 ) . Vital signs and visual acuity were not significantly changed . One patient experienced a transient and mild paniclike reaction after Δ-9-THC administration . Conclusions A single 5 mg sublingual dose of Δ-9-THC reduced the IOP temporarily and was well tolerated by most patients . Sublingual administration of 20 mg CBD  did not reduce IOP , whereas 40 mg CBD produced a transient increase IOP rise 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 Objectives : To determine whether plant-derived cannabis medicinal extracts ( CME ) can alleviate neurogenic symptoms unresponsive to st and ard treatment , and to quantify adverse effects . Design : A consecutive series of double-blind , r and omized , placebo-controlled single-patient cross-over trials with two-week treatment periods . Setting : Patients attended as out patients , but took the CME at home . Subjects : Twenty-four patients with multiple sclerosis ( 18 ) , spinal cord injury ( 4 ) , brachial plexus damage ( 1 ) , and limb amputation due to neurofibromatosis ( 1 ) . Intervention : Whole-plant extracts of delta-9-tetrahydrocannabinol ( THC ) , cannabidiol ( CBD ) , 1:1 CBD : THC , or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5–120 mg/24 hours . Measures used : Patients recorded symptom , well-being and intoxication scores on a daily basis using visual analogue scales . At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales , administered st and ard measures of disability ( Barthel Index ) , mood and cognition , and recorded adverse events . Results : Pain relief associated with both THC and CBD was significantly superior to placebo . Impaired bladder control , muscle spasms and spasticity were improved by CME in some patients with these symptoms . Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME . Conclusions : Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to st and ard treatments . Unwanted effects are predictable and generally well tolerated . Larger scale studies are warranted to confirm these findings Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol ( THC ) but low in cannabidiol ( CBD ) are particularly hazardous for mental health . Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form , under controlled conditions . In a between-subjects design , we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment . Healthy participants were r and omised to receive oral CBD 600 mg ( n=22 ) or placebo ( n=26 ) , 210 min ahead of intravenous ( IV ) THC ( 1.5 mg ) . Post-THC , there were lower PANSS positive scores in the CBD group , but this did not reach statistical significance . However , clinical ly significant positive psychotic symptoms ( defined a priori as increases ≥3 points ) were less likely in the CBD group compared with the placebo group , odds ratio (OR)=0.22 ( χ2=4.74 , p<0.05 ) . In agreement , post-THC paranoia , as rated with the State Social Paranoia Scale ( SSPS ) , was less in the CBD group compared with the placebo group ( t=2.28 , p<0.05 ) . Episodic memory , indexed by scores on the Hopkins Verbal Learning Task-revised ( HVLT-R ) , was poorer , relative to baseline , in the placebo pre-treated group ( -10.6±18.9 % ) compared with the CBD group ( -0.4%±9.7 % ) ( t=2.39 , p<0.05 ) . These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health The object of the experiment was to verify whether cannabidiol ( CBD ) reduces the anxiety provoked by delta 9-THC in normal volunteers , and whether this effect occurs by a general block of the action of delta 9-THC or by a specific anxiolytic effect . Appropriate measurements and scales were utilized and the eight volunteers received , the following treatments in a double-blind procedure : 0.5 mg/kg delta 9-THC , 1 mg/kg CBD , a mixture containing 0.5 mg/kg delta 9-THC and 1 mg/kg CBD and placebo and diazepam ( 10 mg ) as controls . Each volunteer received the treatments in a different sequence . It was verified that CBD blocks the anxiety provoked by delta 9-THC , however this effect also extended to marihuana-like effects and to other subjective alterations induced by delta 9-THC . This antagonism does not appear to be caused by a general block of delta 9-THC effects , since no change was detected in the pulse-rate measurements . Several further effects were observed typical of CBD and of an opposite nature to those of delta 9-THC . These results suggest that the effects of CBD , as opposed to those of delta 9-THC , might be involved in the antagonism of effects between the two cannabinoids CONTEXT Cannabis use can both increase and reduce anxiety in humans . The neurophysiological substrates of these effects are unknown . OBJECTIVE To investigate the effects of 2 main psychoactive constituents of Cannabis sativa ( Delta9-tetrahydrocannabinol [ Delta9-THC ] and cannabidiol [ CBD ] ) on regional brain function during emotional processing . DESIGN Subjects were studied on 3 separate occasions using an event-related functional magnetic resonance imaging paradigm while viewing faces that implicitly elicited different levels of anxiety . Each scanning session was preceded by the ingestion of either 10 mg of Delta9-THC , 600 mg of CBD , or a placebo in a double-blind , r and omized , placebo-controlled design . PARTICIPANTS Fifteen healthy , English-native , right-h and ed men who had used cannabis 15 times or less in their life . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygenation level-dependent response ) , electrodermal activity ( skin conductance response [ SCR ] ) , and objective and subjective ratings of anxiety . RESULTS Delta9-Tetrahydrocannabinol increased anxiety , as well as levels of intoxication , sedation , and psychotic symptoms , whereas there was a trend for a reduction in anxiety following administration of CBD . The number of SCR fluctuations during the processing of intensely fearful faces increased following administration of Delta9-THC but decreased following administration of CBD . Cannabidiol attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing intensely fearful faces , and its suppression of the amygdalar and anterior cingulate responses was correlated with the concurrent reduction in SCR fluctuations . Delta9-Tetrahydrocannabinol mainly modulated activation in frontal and parietal areas . CONCLUSIONS Delta9-Tetrahydrocannabinol and CBD had clearly distinct effects on the neural , electrodermal , and symptomatic response to fearful faces . The effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety , whereas the anxiogenic effects of Delta9-THC may be related to effects in other brain regions Six male and four female healthy volunteers were given oral placebo ( glucose capsule and orange juice ) , cannabidiol ( CBD 200 mg capsule and orange juice ) , alcohol ( 1 g/kg in orange juice and glucose capsule ) , and CBD ( 200 mg capsule ) plus alcohol ( 1 g/kg in orange juice ) in a double-blind , crossover , r and omized design . Treatments were spaced one week apart . Parameters measured were a finger tap test ( motor performance ) , cancellation and differential aptitude tests ( psychomotor performance ) , a 1-min time production task , subjective effects ( 66 item adjective-pair semantic differential ) , and breathalyzer estimations of blood alcohol levels . Compared to placebo , alcohol and alcohol plus CBD , but not CBD alone , produced significant impairments of motor and psychomotor performances , overestimations of time production and subjective responses indicating an accurate self-perception of their intoxication and deficits . The combination of alcohol plus CBD result ed in significantly lower blood alcohol levels compared to alcohol given alone , however , there were few differences observed between the pharmacological effects of the two alcohol conditions . Thus , the inactivity of CBD , a major marijuana constituent , on motor and mental performance and effects also extends to its interaction with alcohol Cannabidiol ( CBD ) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects similar to diazepam in animal models of innate aversive behavior . However , the effects of CBD context ual conditioned fear have not been studied . Therefore , the aim of this work was to compare the behavioral and cardiovascular effects of CBD and diazepam , a prototype anxiolytic , in animals su bmi tted to a context ual conditioned fear paradigm . Male Wistar rats were su bmi tted to a 10min conditioning session ( six footshocks , 2.5 mA , 3s , delivered at pseudo-r and om intervals ) . The behavioral and cardiovascular responses to the context were measured 24h later in a 10 min test session . Diazepam ( 2.5 mg/kg ) , FG-7142 ( 8 mg/kg ) , a benzodiazepine inverse agonist , or CBD ( 10 mg/kg ) were administered i.p . before the test session . Conditioned rats su bmi tted to the aversive context exhibited more freezing behavior and a larger increase in blood pressure and heart rate as compared to non-conditioned animals . These effects were attenuated by CBD and diazepam in the conditioned animals . These drugs did not have any effect in non-conditioned rats . FG-7142 treatment failed to change the behavioral and cardiovascular responses to the aversive context . In conclusion , the results suggest that CBD has anxiolytic-like properties similar to those of diazepam in a rat model of conditioned fear to context OBJECTIVE Research in both animals and humans indicates that cannabidiol ( CBD ) has antipsychotic properties . The authors assessed the safety and effectiveness of CBD in patients with schizophrenia . METHOD In an exploratory double-blind parallel-group trial , patients with schizophrenia were r and omized in a 1:1 ratio to receive CBD ( 1000 mg/day ; N=43 ) or placebo ( N=45 ) alongside their existing antipsychotic medication . Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale ( PANSS ) , the Brief Assessment of Cognition in Schizophrenia ( BACS ) , the Global Assessment of Functioning scale ( GAF ) , and the improvement and severity scales of the Clinical Global Impressions Scale ( CGI-I and CGI-S ) . RESULTS After 6 weeks of treatment , compared with the placebo group , the CBD group had lower levels of positive psychotic symptoms ( PANSS : treatment difference=-1.4 , 95 % CI=-2.5 , -0.2 ) and were more likely to have been rated as improved ( CGI-I : treatment difference=-0.5 , 95 % CI=-0.8 , -0.1 ) and as not severely unwell ( CGI-S : treatment difference=-0.3 , 95 % CI=-0.5 , 0.0 ) by the treating clinician . Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance ( BACS : treatment difference=1.31 , 95 % CI=-0.10 , 2.72 ) and in overall functioning ( GAF : treatment difference=3.0 , 95 % CI=-0.4 , 6.4 ) . CBD was well tolerated , and rates of adverse events were similar between the CBD and placebo groups . CONCLUSIONS These findings suggest that CBD has beneficial effects  in patients with schizophrenia . As CBD 's effects do not appear to depend on dopamine receptor antagonism , this agent may represent a new class of treatment for the disorder BACKGROUND Peripheral neuropathic pain ( PNP ) associated with allodynia poses a significant clinical challenge . The efficacy of Δ(9 ) -tetrahydrocannabinol/cannabidiol ( THC/CBD ) oromucosal spray , a novel cannabinoid formulation , was investigated in this 15-week r and omized , double-blind , placebo-controlled parallel group study . METHODS In total , 303 patients with PNP associated with allodynia were screened ; 128 were r and omized to THC/CBD spray and 118 to placebo , in addition to their current analgesic therapy . The co- primary efficacy endpoints were the 30 % responder rate in PNP 0 - 10 numerical rating scale ( NRS ) score and the mean change from baseline to the end of treatment in this score . Various key secondary measures of pain and functioning were also investigated . RESULTS At the 30 % responder level , there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis ( intention-to-treat ) data set [ p = 0.034 ; 95 % confidence interval ( CI ) : 1.05 - 3.70 ] . There was also a reduction in mean PNP 0 - 10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group , but which failed to reach statistical significance . Secondary measures of sleep quality 0 - 10 NRS score ( p = 0.0072 ) and Subject Global Impression of Change ( SGIC ) ( p = 0.023 ) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment . CONCLUSIONS These findings demonstrate that , in a meaningful proportion of otherwise treatment-resistant patients , clinical ly important improvements in pain , sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray . THC/CBD spray was well tolerated and no new safety concerns were identified 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
In both rodent and cell culture models , CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus .
In rodent models , CBD was found to attenuate alcohol-induced hepatotoxicity , specifically , alcohol-induced steatosis .
Finally , findings from pre clinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking , alcohol self-administration , withdrawal-induced convulsions , and impulsive discounting of delayed rewards .
In human studies , CBD was well tolerated and did not interact with the subjective effects of alcohol .
Collectively , given its favorable effects on alcohol-related harms and addiction phenotypes in pre clinical models , CBD appears to have promise as a c and i date AUD pharmacotherapy .
This is further bolstered by the absence of abuse liability and its general tolerability .
There is substantial interest in the therapeutic potential of cannabidiol ( CBD ) , a nonpsychoactive cannabinoid found in plants of the genus Cannabis .
The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a c and i date pharmacotherapy for alcohol use disorder ( AUD ) .