Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15. Acute psychotropic effects of oral cannabis extract with a defined content of Delta9-tetrahydrocannabinol (THC) in healthy volunteers. Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. 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. Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC) 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
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 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 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 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 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 CONTEXT Cannabis sativa use can impair verbal learning , provoke acute psychosis , and increase the risk of schizophrenia . It is unclear where C. sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms . OBJECTIVES To investigate the effects of 2 main psychoactive constituents of C. sativa , Delta9-tetrahydrocannabinol ( Delta9-THC ) and cannabidiol , on regional brain function during verbal paired associate learning . DESIGN Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task . Each imaging session was preceded by the ingestion of Delta9-THC ( 10 mg ) , cannabidiol ( 600 mg ) , or placebo in a double-blind , r and omized , placebo-controlled , repeated- measures , within-subject design . SETTING University research center . PARTICIPANTS Fifteen healthy , native English-speaking , right-h and ed men of white race/ethnicity who had used C. sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygen level-dependent response ) , performance in a verbal learning task , and objective and subjective ratings of psychotic symptoms , anxiety , intoxication , and sedation . RESULTS Delta9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety , intoxication , and sedation , whereas no significant effect was noted on these parameters following administration of cannabidiol .  Performance in the verbal learning task was not significantly modulated by either drug . Administration of Delta9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident . Delta9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs , which was directly correlated with concurrently induced psychotic symptoms . In contrast , administration of cannabidiol had no such effect . CONCLUSION The modulation of mediotemporal and ventrostriatal function by Delta9-THC may underlie the effects of C. sativa on verbal learning and psychotic symptoms , respectively 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 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 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 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 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 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
INTERPRETATION A single THC administration induces psychotic , negative , and other psychiatric symptoms with large effect sizes .
There is no consistent evidence that CBD induces symptoms or moderates the effects of THC .
BACKGROUND Approximately 188 million people use cannabis yearly worldwide , and it has recently been legalised in 11 US states , Canada , and Uruguay for recreational use .
The potential for increased cannabis use highlights the need to better underst and its risks , including the acute induction of psychotic and other psychiatric symptoms .
We aim ed to investigate the effect of the cannabis constituent Δ9-tetrahydrocannabinol ( THC ) alone and in combination with cannabidiol ( CBD ) compared with placebo on psychiatric symptoms in healthy people .