human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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 .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    