Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids Psychomotor performance in relation to acute oral administration of Δ9-tetrahydrocannabinol and standardized cannabis extract in healthy human subjects Reinforcing and subjective effects of oral delta 9-THC and smoked marijuana in humans. Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans A double-blind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. Cannabidiol in Humans—The Quest for Therapeutic Targets Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms Safety, tolerability, and efficacy of orally administered cannabinoids in MS Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC) Acute psychotropic effects of oral cannabis extract with a defined content of Delta9-tetrahydrocannabinol (THC) in healthy volunteers. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. Using Ecological Momentary Assessment to Identify Mechanisms of Change: An Application From a Pharmacotherapy Trial With Adolescent Cannabis Users. Influence of cannabidiol on delta‐9‐tetrahydrocannabinol effects
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 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 The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol ( THC ) and smoked marijuana were studied in two groups of regular marijuana users . One group ( N = 10 ) was tested with smoked marijuana and the other ( N = 11 ) with oral THC .  Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions . Subjective effects and heart rate were measured before and after drug administration . Smoked active marijuana was chosen over placebo on both choice occasions by all subjects . Similarly , oral THC was chosen over placebo on both occasions by all but one subject . Both active drug treatments produced qualitatively and quantitatively similar subjective effects , and both significantly increased heart rate , although the time course of effects differed substantially between the two treatments . The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions . The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans 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 Δ9-Tetrahydrocannabinol ( Δ9-THC ) , the most prominent psychoactive cannabinoid in Cannabis sativa L. ( marijuana ) , has been reported to have properties of appetite stimulation , promotion of weight gain , and antiemetic efficacy in selected patient population s. In this 4-week , double-blind , crossover study , 11 female patients with primary anorexia nervosa ( PAN ) were evaluated on Δ9-THC and on an active placebo , diazepam . All patients participated in a st and ardized behavior modification treatment program . The following data were obtained : ( 1 ) daily weight , ( 2 ) daily caloric intake , and ( 3 ) weekly psychiatric assessment s. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales . The only significant differences found between the changes over time on Δ9-THC versus diazepam were more pathology on Δ9-THC for somatization , interpersonal sensitivity , and sleep disturbance . Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during Δ9-THC administration . One week after the study ended , each subject was given the highest dose level of Δ8-THC achieved in the study , and periodic blood sample s were obtained coincident with self-rated “ subjective high ” assessment s and pulse measurements . Quantitative analyses of these sample s indicated peak times of 1 to 5 hours postdose for Δ9- THC and for its primary active metabolite , 11-hydroxy-THC , which generally coincided with peak times for “ subjective high ” and pulse rate . The results of this clinical investigation suggest that Δ9-THC is not efficacious , in short-term administration , in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients 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 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 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 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 Abstract —The authors conducted a r and omized , double-blind , placebo-controlled , twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety , tolerability , and efficacy of oral & Dgr;9-Tetrahydrocannabinol ( THC ) and Cannabis sativa plant extract . Both drugs were safe , but adverse events were more common with plant-extract treatment . Compared with placebo , neither THC nor plant-extract treatment reduced spasticity . Both THC and plant-extract treatment worsened the participant ’s global impression BACKGROUND Cannabis can induce transient psychotic symptoms , but not all users experience these adverse effects . We compared the neural response to Δ9-tetrahydrocannabinol ( THC ) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms . Method In a double-blind , placebo-controlled , pseudor and omized design , 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo , orally . Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task . RESULTS The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic ( TP ; n = 11 ) and non-psychotic ( NP ; n = 10 ) groups . During the THC condition , TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus , the left and right middle temporal gyri and in the right cerebellum . In these regions , THC had opposite effects on activation relative to placebo in the two groups . The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum , independent of the effects of THC . CONCLUSIONS In this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC , we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum , suggesting that these regions mediate the effects of the drug on psychotic symptoms Rationale Δ9-Tetrahydrocannabinol ( THC ) is the main active constituent of cannabis . In recent years , the average THC content of some cannabis cigarettes has increased up to approximately 60 mg per cigarette ( 20 % THC cigarettes ) . Acute cognitive and psychomotor effects of THC among recreational users after smoking cannabis cigarettes containing such high doses are unknown . Objectives The objective of this study was to study the dose – effect relationship between the THC dose contained in cannabis cigarettes and cognitive and psychomotor effects for THC doses up to 69.4 mg ( 23 % ) . Material s and methods This double-blind , placebo-controlled , r and omised , four-way cross-over study included 24 non-daily male cannabis users ( two to nine cannabis cigarettes per month ) . Participants smoked four cannabis cigarettes containing 0 , 29.3 , 49.1 and 69.4 mg THC on four exposure days . Results The THC dose in smoked cannabis was linearly associated with a slower response time in all tasks ( simple reaction time , visuo-spatial selective attention , sustained attention , divided attention and short-term memory tasks ) and motor control impairment in the motor control task . The number of errors increased significantly with increasing doses in the short-term memory and the sustained attention tasks . Some participants showed no impairment in motor control even at THC serum concentrations higher than 40 ng/mL. High feeling and drowsiness differed significantly between treatments . Conclusions Response time slowed down and motor control worsened , both linearly , with increasing THC doses . Consequently , cannabis with high THC concentrations may be a concern for public health and safety if cannabis smokers are unable to titrate to a high feeling corresponding to a desired plasma THC level INTRODUCTION The medical use of cannabinoids is limited mainly by their undesirable effects . With respect to acute psychotropic effects , the aim of this study is the comparison of an oral cannabis extract and low-dose diazepam in a cross-over experiment in drug-naïve healthy women . METHODS Sixteen healthy females participated in this r and omized , double-blind , active comparator-controlled , single-dose , balanced 2-way cross-over study . Cannabis extract with st and ardised Delta (9)-tetrahydrocannabinol ( THC ) content ( 20 mg ) or active placebo ( 5 mg diazepam ) was administered orally . Subjects were assessed by self- and observer-rated visual analogue scales ( VAS ) , the BRIEF PSYCHIATRIC RATING SCALE ( BPRS ) and three psychomotor tests up to 6 h after administration . RESULTS VAS showed significantly elevated fatigue , drowsiness , dizziness , and " feeling high " after cannabis as compared to baseline and diazepam . BPRS scores were significantly higher after cannabis intake . Only in one psychomotor test a decrease of psychomotor activity after cannabis was evident . One subject in the cannabis condition experienced severe transient psychotic symptoms . DISCUSSION Orally administered cannabis produced significant central depressant side-effects compared to diazepam , mostly subjective effects ( VAS ) but marginal effects in psychomotor performance in 15 healthy females . Regarding the medical use of cannabis , a rigorous benefit-risk analysis and an exact psychiatric assessment before and during treatment are necessary UNLABELLED A r and omized , double-blinded , placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis . In a crossover design , each participant was exposed to 4 single dosing sessions of placebo or to low ( 1 % tetrahydrocannabinol [ THC ] ) , medium ( 4 % THC ) , or high ( 7 % THC ) doses of cannabis . Baseline spontaneous pain , evoked pain , and cognitive testing were performed . Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective " highness " score was measured at 5 , 15 , 30 , 45 , and 60 minutes and then every 30 minutes for an additional 3 hours . Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours . The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models . There was a significant difference in spontaneous pain scores between doses ( P < .001 ) . Specific significant comparisons were placebo versus low , medium , and high doses ( P = .031 , .04 , and < .001 , respectively ) and high versus low and medium doses ( both P < .001 ) . There was a significant effect of the high dose on foam brush and von Frey evoked pain ( both P < .001 ) . There was a significant negative effect ( impaired performance ) of the high dose on 2 of the 3 neuropsychological tests ( Paced Auditory Serial Addition Test , Trail Making Test Part B. PERSPECTIVE This small , short-term , placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain . This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain OBJECTIVE The present study used youth 's in vivo reports of subjective responses to cannabis while smoking in their natural environments to identify real-world mechanisms of topiramate treatment for cannabis misuse . METHOD Participants were 40 cannabis users ( ≥ twice weekly in past 30 days ) , ages 15 - 24 years ( 47.5 % female ) , with at least one cannabis use episode during the final 3 weeks of a 6-week , r and omized clinical trial . Youth reported subjective " high " while smoking , stimulation , sedation , stress , craving , and grams of marijuana used in the natural environment via wireless electronic devices . Bayesian multilevel structural equation modeling ( MSEM ) evaluated mediation via indirect effect tests . RESULTS Significant within ( daily ) and between ( person ) variability and distinctive within and between effects supported the MSEM approach . Subjective high while smoking was significantly reduced for youth in the topiramate condition , relative to placebo , and the indirect effect of reduced subjective high on total grams of cannabis smoked that day was significant . Indirect effects through other subjective responses were not significant . CONCLUSIONS The results of this initial study suggest that altering subjective responses to smoking , specifically subjective high , may be a key target for developing adjunctive pharmacotherapies for cannabis misuse . More generally , this work provides an example for applying ecological momentary assessment and analytic techniques to evaluate mechanisms of behavior change in longitudinal data Experiments investigating the possible interaction of tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , two major components of marihuana , were conducted under controlled laboratory conditions in a double‐blind manner . In one study , 15 male volunteers were given placebo or 25 µg/kg of THC together with either placebo or 150 µg/kg of CBD by inhalation of the smoke of a single cigarette . All four treatments were assigned to each subject according to a series of Latin‐square design s. CBD significantly attenuated the subjective euphoria of THC . Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD , but a trend indicating a decrease in THC‐like effects was observed after the combination . When administered alone CBD was inactive for all the parameters measured . In a second study , 8 male subjects were given CBD ( 0 or 150 µg/kg ) by smoke inhalation 30 min before THC ( 0 or 25 µg/kg ) in a second cigarette . In contrast to the simultaneous administration of both drugs , CBD pretreatment did not alter the effects of THC on the parameters observed
Of these , the metabolite produces the greatest psychoactive effects .
Cannabidiol ( CBD ) is not psychoactive but plays a modulating role on cannabis psychoactive effects .
The proportion of 9-THC in plant material is higher ( up to 40 % ) than in other cannabinoids ( up to 9 % ) .
Conclusions Findings reveal that 9-THC contributes the most to cannabis psychoactivity .
Due to lower psychoactive potency and smaller proportions in plant material , other psychoactive cannabinoids have a weak influence on cannabis final effects .
Objective This systematic review aims to summarize current evidence on which naturally present cannabinoids contribute to  cannabis psychoactivity  , considering their reported concentrations and pharmacodynamics in humans .