title: Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Naltrexone does not attenuate the effects of intravenous Δ9-tetrahydrocannabinol in healthy humans. Blunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis Does olanzapine inhibit the psychomimetic effects of Δ9-tetrahydrocannabinol? Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function
abstract: OBJECTIVE Research in both animals and humans indicates that cannabidiol ( CBD ) has antipsychotic properties . The authors assessed the safety and effectiveness of CBD in patients with schizophrenia . METHOD In an exploratory double-blind parallel-group trial , patients with schizophrenia were r and omized in a 1:1 ratio to receive CBD ( 1000 mg/day ; N=43 ) or placebo ( N=45 ) alongside their existing antipsychotic medication . Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale ( PANSS ) , the Brief Assessment of Cognition in Schizophrenia ( BACS ) , the Global Assessment of Functioning scale ( GAF ) , and the improvement and severity scales of the Clinical Global Impressions Scale ( CGI-I and CGI-S ) . RESULTS After 6 weeks of treatment , compared with the placebo group , the CBD group had lower levels of positive psychotic symptoms ( PANSS : treatment difference=-1.4 , 95 % CI=-2.5 , -0.2 ) and were more likely to have been rated as improved ( CGI-I : treatment difference=-0.5 , 95 % CI=-0.8 , -0.1 ) and as not severely unwell ( CGI-S : treatment difference=-0.3 , 95 % CI=-0.5 , 0.0 ) by the treating clinician . Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance ( BACS : treatment difference=1.31 , 95 % CI=-0.10 , 2.72 ) and in overall functioning ( GAF : treatment difference=3.0 , 95 % CI=-0.4 , 6.4 ) . CBD was well tolerated , and rates of adverse events were similar between the CBD and placebo groups . CONCLUSIONS These findings suggest that CBD has beneficial effects  in patients with schizophrenia . As CBD 's effects do not appear to depend on dopamine receptor antagonism , this agent may represent a new class of treatment for the disorder 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 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 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Recent advances in the underst and ing of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis . In a 3-day , double-blind , r and omized , and counterbalanced study , the behavioral , cognitive , and endocrine effects of 0 , 2.5 , and 5 mg intravenous delta-9-tetrahydrocannabinol ( Δ-9-THC ) were characterized in 22 healthy individuals , who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder . Prospect i ve safety data at 1 , 3 , and 6 months post study was also collected . Δ-9-THC ( 1 ) produced schizophrenia-like positive and negative symptoms ; ( 2 ) altered perception ; ( 3 ) increased anxiety ; ( 4 ) produced euphoria ; ( 5 ) disrupted immediate and delayed word recall , sparing recognition recall ; ( 6 ) impaired performance on tests of distractibility , verbal fluency , and working memory ( 7 ) did not impair orientation ; ( 8) increased plasma cortisol . These data indicate that Δ-9-THC produces a broad range of transient symptoms , behaviors , and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses . These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders 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 Although a wealth of pre clinical evidence indicates an interplay between the μ-opioid ( MOR ) and cannabinoid 1 receptor ( CB1R ) systems , the precise nature of the cross modulation in humans is unclear . The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist , naltrexone , on the subjective , behavioural and cognitive effects of the CB1R agonist , Δ9-tetrahydrocannabinol ( THC ) , in healthy human subjects . Healthy human subjects , screened carefully for any medical or psychiatric illness , were administered either placebo or active naltrexone ( 25 mg ) orally on each test day , followed 45 min later by placebo and 165 min later by active i.v . THC ( 0.025 mg/kg ) in a r and omized , fixed-order , double-blind manner . Subjective , behavioural and cognitive effects were assessed before and at several points after each drug administration . THC produced expected effects , including euphoria , anxiety , transient perceptual alterations , transient psychotomimetic effects and cognitive impairments .  However , naltrexone did not produce any effects alone , nor did it attenuate any of THC 's effects . Thus , in healthy human subjects who use cannabis intermittently , MOR antagonism does not modulate the common acute subjective , behavioural and cognitive effects of THC 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 Δ9-Tetrahydrocannabinol ( THC ) produces transient psychomimetic effects in healthy volunteers , constituting a pharmacological model for psychosis . The dopaminergic antagonist haloperidol has previously been shown to reduce these effects . This placebo-controlled , cross-over study in 49 healthy , male , mild cannabis users aim ed to further explore this model by examining the effect of a single oral dose of olanzapine ( with dopaminergic , serotonergic , adrenergic , muscarinergic and histaminergic properties ) or two oral doses of diphenhydramine ( histamine antagonist ) on the effects of intrapulmonarily administered THC .  Transient psychomimetic symptoms were seen after THC administration , as measured on the positive and negative syndrome scale ( 20.6 % increase on positive subscale , p<0.001 ) and the visual analogue scale for psychedelic effects ( increase of 10.7 mm on feeling high ) . Following the combination of THC and olanzapine , the positive subscale increased by only 13.7 % and feeling high by only 8.7 mm . This reduction of THC effects on the positive subscale failed to reach statistical significance ( p=0.066 ) . However , one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone . Within responders , olanzapine reduced the effects of THC on the positive subscale ( p=0.005 ) . Other outcome measures included pharmacokinetics , eye movements , postural stability , pupil/iris ratio , and serum concentrations of cortisol and prolactin Intravenous ( IV ) Δ9-tetrahydrocannabinol ( THC ) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients , but the psychotomimetic mechanism is unknown . One possibility is that THC stimulates dopamine ( DA ) release in the striatum . In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo . We also investigated whether DA release and positive psychotic symptoms were related . Eleven healthy male volunteers completed two 123I-iodobenzamide ( [123I]IBZM ) single photon emission tomography ( SPET ) sessions and received IV THC ( 2.5 mg ) or placebo in a r and omized counterbalanced order , under double-blind conditions . Analysable data were obtained from nine participants . The Positive and Negative Syndrome Scale ( PANSS ) was used to rate psychotomimetic effects . Striatal binding index values were calculated using the occipital cortex as a reference region . Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC . There were no significant differences in binding index in the cau date or putamen under THC compared to placebo conditions . Positive psychotic symptoms and DA release were unrelated . THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms . These findings do not support a central role for striatal DA in THC-elicited psychosis 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
target: 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: 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 .