title: Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids Cognitive and subjective dose-response effects of acute oral Δ9-tetrahydrocannabinol (THC) in infrequent cannabis users Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC) Comparative studies in man and in laboratory animals on 8 - and 9 -trans-tetrahydrocannabinol. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Interactions in man of delta‐9‐tetrahydrocannabinol; II. Cannabinol and cannabidiol Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC Cannabidiol in Humans—The Quest for Therapeutic Targets Blunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15. Strong increase in total delta‐THC in cannabis preparations sold in Dutch coffee shops Influence of cannabidiol on delta‐9‐tetrahydrocannabinol effects
abstract: 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 Abstract Rationale . Although some aspects of memory functions are known to be acutely impaired by Δ9-tetrahydrocannabinol ( Δ9-THC ; the main active constituent of marijuana ) , effects on other aspects of memory are not known and the time course of functional impairments is unclear . Objective . The present study aim ed to detail the acute and residual cognitive effects of Δ9-THC in infrequent cannabis users . Methods . A balanced , double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg Δ9-THC with matched placebo  in 15 male volunteers . Participants were assessed pre and 1 , 2 , 4 , 6 , 8 , 24 and 48 h post-drug . Results . Δ9-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration ( 2 h post-drug ) . At the same time point , performance on an implicit memory task was preserved intact . The higher dose of Δ9-THC result ed in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by Δ9-THC . In several tasks , Δ9-THC increased both speed and error rates , reflecting " riskier " speed-accuracy trade-offs . Subjective effects were also most marked at 2 h but often persisted longer , with participants rating themselves as " stoned " for 8 h. Participants experienced a strong drug effect , liked this effect and , until 4 h , wanted more oral Δ9-THC . No effects of Δ9-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral Δ9-THC are minimal . Conclusions . These data demonstrate that oral Δ9-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory 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 The pharmacological activity of several doses of △ 8-THC and △ 9-TΗC was studied comparatively using rats ( climbing rope test ) , mice ( catatonia and spontaneous motor activity tests ) and rabbits ( Gayer test ) and also human volunteers ( pulse rate , time discrimination and subjective symptoms ) .  △ 9-TΗC was twice as active as △ 8-THC in rats and mice ; both compounds were equiactive in rabbits . In man △ 9-THC revealed to be nearly twice as active as its isomer . There were no qualitative differences between both drugs neither in man nor in the laboratory animals 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 Oral doses of delta‐9‐tetrahydrocannabinol ( THC ) 20 mg , combined with placebo or with 40 mg doses of cannabinol ( CBN ) and cannabidiol ( CBD ) , were given to volunteers . The combination of THC with CBN produced no detectable changes in the quality , intensity , or duration of the effects of THC alone . The THC‐CBD combination tended to delay onset and prolong effects of THC , while making them somewhat more intense . Even this interactive effect was slight , providing no reason to ab and on the current practice of basing doses of marihuana for clinical studies solely on THC content 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 ) . The pharmacokinetics of THC after smoking cannabis cigarettes containing more than approximately 35 mg THC ( 3.55 % THC cigarettes ) is unknown . To be able to perform suitable exposure risk analysis , it is important to know if there is a linear relation at higher doses . Objectives The present study aim ed to characterise the pharmacokinetics of THC , the active metabolite 11-OH-THC and the inactive metabolite THC-COOH after smoking a combination of tobacco and cannabis containing high THC doses . Material s and methods This double-blind , placebo-controlled , four-way , cross-over study included 24 male non-daily cannabis users ( two to nine joints per month ) . Participants were r and omly assigned to smoke cannabis cigarettes containing 29.3 , 49.1 and 69.4 mg THC and a placebo . Serial serum sample s collected over a period of 0–8 h were analysed by liquid chromatography electrospray t and em mass spectrometry . Effects on heart rate , blood pressure and ‘ high ’ feeling were also measured . Results Mean maximal concentrations ( Cmax ) were 135.1 , 202.9 and 231.0 μg/L for THC and 9.2 , 16.4 and 15.8 μg/L for 11-OH-THC after smoking a 29.3- , 49.1- and 69.4-mg THC cigarette , respectively . A large inter-individual variability in Cmax was observed . Heart rate and ‘ high ’ feeling significantly increased with increasing THC dose . Conclusions This study demonstrates that the known linear association between THC dose and THC serum concentration also applies for high THC doses 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 Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis .  Delta-9-Tetrahydrocannabinol ( Δ-9-THC ) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals . Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established . In a 3-day , double-blind , r and omized , placebo-controlled study , the dose-related effects of 0 , 2.5 , and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls . Δ-9-THC ( 1 ) produced transient psychotomimetic effects and perceptual alterations ; ( 2 ) impaired memory and attention ; ( 3 ) increased subjective effects of ‘ high ’ ; ( 4 ) produced tachycardia ; and ( 5 ) increased serum cortisol in both groups . However , relative to controls , frequent users showed blunted responses to the psychotomimetic , perceptual altering , cognitive impairing , anxiogenic , and cortisol increasing effects of Δ-9-THC but not to its euphoric effects . Frequent users also had lower prolactin levels . These data suggest that frequent users of cannabis are either inherently blunted in their response to , and /or develop tolerance to the psychotomimetic , perceptual altering , amnestic , endocrine , and other effects of cannabinoids The purpose of this study was to determine whether marijuana produced dose-dependent antinociception in humans and , if so , whether endogenous opiates modulate this effect . A total of five male regular marijuana users participated in three test sessions during which they smoked cigarettes containing 0 % ( placebo ) and 3 . 55 % Delta(9)-tetrahydrocannabinol ( Delta(9)-THC ) ( active ) . Each of four controlled smoking bouts per session , spaced at 40-min intervals , consisted of nine puffs from active and placebo cigarettes ( three cigarettes , three puffs per cigarette , one puff per min ) . During successive bouts , participants smoked 0 , 3 , 6 and 9 ( 0 , 3 , 9 and 18 cumulative ) puffs from active marijuana cigarettes , with the remainder of puffs from placebo cigarettes . Test sessions were identical , except for naltrexone 0 , 50 or 200 mg p.o . ( r and omized , double-blind ) administration 1 h before the first smoking bout on the different days . Before smoking , between smoking bouts and postsmoking , participants completed an assessment battery that included antinociceptive ( finger withdrawal from radiant heat stimulation ) , biological , subjective , observer-rated signs and performance measures . Marijuana produced significant dose-dependent antinociception ( increased finger withdrawal latency ) and biobehavioral effects . Naltrexone did not significantly influence marijuana dose-effect curves , suggesting no role of endogenous opiates in marijuana-induced antinociception under these conditions 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 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 The total concentration of THC has been monitored in cannabis  preparations sold in Dutch coffee shops since 1999 . This annual monitoring was issued by the Ministry of Health after reports of increased potency . The level of the main psychoactive compound , Δ 9 ‐tetrahydrocannabinol ( THC ) , is measured in marijuana and hashish . A comparison is made between imported and Dutch preparations , and between seasons . Sample s of  cannabis preparations from r and omly selected coffee shops were analyzed using gas chromatography ( GC‐FID ) for  THC , CBD  and  CBN  . In 2004 , the average THC level of Dutch home‐grown marijuana ( Nederwiet ) ( 20.4 % THC ) was significantly higher than that of imported marijuana ( 7.0 % THC ) . Hashish derived from Dutch marijuana ( Nederhasj ) contained 39.3 % THC in 2004 , compared with 18.2 % THC in imported hashish . The average THC percentage of Dutch marijuana , Dutch hashish and imported hashish was significantly higher than in previous years . It nearly doubled over 5 years . During this period , the THC percentage in imported marijuana remained unchanged . A higher price had to be paid for cannabis with higher levels of THC . Whether the increase in THC levels causes increased health risks for users can only be concluded when more data are available on adjusted patterns of use , abuse liability , bioavailability and levels of THC in the brain 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
target: 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 .
background: 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 .