UK Medical Research Council, Maudsley Charity, Brain and Behavior Research Foundation, Wellcome Trust, and the UK National Institute for Health Research.

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. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes.

15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified. Compared with placebo, THC significantly increased total symptom severity with a large effect size (assessed in nine studies, with ten independent samples, involving 196 participants: SMC 1·10 [95% CI 0·92–1·28], p<0·0001); positive symptom severity (assessed in 14 studies, with 15 independent samples, involving 324 participants: SMC 0·91 [95% CI 0·68–1·14], p<0·0001); and negative symptom severity with a large effect size (assessed in 12 studies, with 13 independent samples, involving 267 participants: SMC 0·78 [95% CI 0·59–0·97], p<0·0001). In the systematic review, of the four studies evaluating CBD's effects on THC-induced symptoms, only one identified a significant reduction in symptoms.

In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published in English between database inception and May 21, 2019, with a within-person, crossover design. Inclusion criteria were studies reporting symptoms using psychiatric scales (the Brief Psychiatric Rating Scale [BPRS] and the Positive and Negative Syndrome Scale [PANSS]) following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants, and presenting data that allowed calculation of standardised mean change (SMC) scores for positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms. We did a random-effects meta-analysis to assess the main outcomes of the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo. Because the number of studies to do a meta-analysis on CBD's moderating effects was insufficient, this outcome was only systematically reviewed. This study is registered with PROSPERO, CRD42019136674.

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 understand its risks, including the acute induction of psychotic and other psychiatric symptoms. We aimed to investigate the effect of the cannabis constituent Δ 9 -tetrahydrocannabinol (THC) alone and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy people.

We aimed to investigate the psychotomimetic effects of THC and CBD alone and in combination on healthy volunteers to determine the magnitude and consistency of the psychiatric effects of THC and CBD, to investigate the moderating effects of CBD on THC-induced symptoms, and to evaluate the moderating effects of demographic and clinical factors on the induction of symptoms.

There is increasing interest in the effects of cannabidiol (CBD), another constituent of cannabis.CBD does not induce schizophreniform symptoms itself.Cannabis containing higher proportions of CBD has been associated with fewer subclinical psychotic symptoms in people who use cannabis recreationally in naturalistic studies.This finding has led to suggestions that CBD has antipsychotic properties, with some promising results in people with schizophrenia.However, results from controlled studies evaluating whether CBD can attenuate THC-induced psychiatric symptoms are mixed.As the THC-to-CBD ratio of street cannabis continues to increase,clarification of the moderating effects of CBD is needed.

Potency of Δ 9 THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology.

Effects and interaction of delta-9-tetrahydrocannabidiol and cannabidiol on psychopathology, neurocognition, and endocannabinoids in serum of healthy volunteers: influence on psychopathology.

Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.

Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function.

Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial.

Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis.

Cannabis with high cannabidiol content is associated with fewer psychotic experiences.

Modulation of mediotemporal and ventrostriatal function in humans by Δ9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis.

Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function.

The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and Δ 9 tetrahydrocannabivarin.

Our finding that THC induces positive and other psychiatric symptoms highlights the risks associated with the use of cannabis products, which should be factored into risk–benefit discussions between patients and medical practitioners. This work will inform regulators, public health initiatives, and policy makers considering the medical use of cannabis products or their legalisation for recreational use. Our findings also have implications for mental health policy in terms of education on risks and harm minimisation strategies for products containing THC, and for research into effects in people who might be vulnerable to mental illness.

Implications of all the available evidence

In this meta-analysis of 15 studies, we determined that the acute administration of THC induces positive, negative, and other symptoms associated with schizophrenia and other mental disorders in healthy adults with large effect sizes. Evidence of CBD's modifying effect is inconclusive. We also found lower induction of psychotic symptoms by THC in studies with more tobacco smokers, and that cannabis use did not moderate the induction of symptoms by THC. These findings extend the literature by systematically showing that THC induces psychotic and other psychiatric symptoms across a range of forms, routes of administration, doses, and settings.

Added value of this study

Studies in healthy people indicate that the cannabis constituent Δ 9 -tetrahydrocannabinol (THC) can induce positive and negative symptoms but findings have been inconsistent. Thus, the magnitude, consistency, and moderators of the induction of schizophreniform and other symptoms by THC remain unclear, including the role of other cannabis constituents such as cannabidiol (CBD). MEDLINE (from Jan 1, 1946, to May 21, 2019), Embase (from Jan 1, 1974, to May 21, 2019), and PsycINFO (from Jan 1, 1806, to May 21, 2019) were searched using the following keywords: (“THC” OR “tetrahydrocannabinol” OR “9THC” OR “9tetrahydrocannabinol” OR “delta9THC” OR “d9THC” OR “delta9tetrahydrocannabinol” OR “dronabinol” OR “marinol” OR “bedrobinol” OR “anandamide” OR “methanandamide” OR “WIN,55,212-2” OR “ACPA” OR “CP55940” OR “bedrocan” OR “spice” OR “JWH-018” OR “AM251” OR “SR161716A” OR “rimonabant” OR “cannabidiol” OR “CBD” OR “cannabinoid”) AND (“BPRS” OR “brief psychiatric rating scale” OR “PANSS” OR “positive and negative syndrome scale”).

J J Moreaufirst described an association between cannabis use and psychotic symptoms, such as paranoia and hallucinations, more than 150 years ago. Subsequently, the main psychoactive constituent of cannabis, Δ-tetrahydrocannabinol (THC), was shown to induce a significant increase in psychotic (also referred to as positive) symptoms as well as negative symptoms, such as poor rapport, and general psychiatric symptoms, such as depression, relative to placebo.Multiple independent studies have explored the psychotomimetic properties of THC since.Although most of these studies support the original findings, discrepancies exist,highlighting the need to determine the consistency and magnitude of these effects. Furthermore, potential modifiers of these effects, such as dose, previous cannabis use, route of administration, age, sex, tobacco use, and type of THC, have not been systematically evaluated.

Central nervous system effects of haloperidol on THC in healthy male volunteers.

Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function.

Central nervous system effects of haloperidol on THC in healthy male volunteers.

Does olanzapine inhibit the psychomimetic effects of Δ 9 tetrahydrocannabinol?.

Dose-related modulation of event-related potentials to novel and target stimuli by intravenous Δ 9 THC in humans.

Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans.

Blunted psychotomimetic and amnestic effects of Δ-9-tetrahydrocannabinol in frequent users of cannabis.

Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis.

Modulation of mediotemporal and ventrostriatal function in humans by Δ9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis.

Naltrexone does not attenuate the effects of intravenous Δ 9 tetrahydrocannabinol in healthy humans.

Disruption of frontal θ coherence by Δ 9 tetrahydrocannabinol is associated with positive psychotic symptoms.

The acute effects of synthetic intravenous Δ 9 tetrahydrocannabinol on psychosis, mood and cognitive functioning.

Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function.

The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis.

The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis.

Cannabis is one of the most widely used psychoactive substances worldwide, with 6–7% of the population in Europe and 15·3% of the population in the USA using it each year.There is a global trend towards decriminalisation and legalisation,with 11 US states, Canada, and Uruguay now permitting the sale and recreational use of cannabis in addition to its medicinal use.Given the projected increase in rates of cannabis use,the increasing potency of cannabis and cannabis-based products, and the burgeoning interest in the therapeutic potential of cannabinoids,it is timely to assess the psychiatric effects of cannabis constituents.

Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis.

Association of state recreational marijuana laws with adolescent marijuana use.

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

This study is registered with PROSPERO, CRD42019136674.

The significance level for all statistical tests was p<0·05 (two tailed). All raw data are provided in the appendix (pp 4–7) . All code used in the analysis can be requested from the corresponding author. Statistical analyses were done with the metafor package (version 1.9-9) in the statistical programming language R (version 3.3.1).

We assessed inconsistency across studies using the Cochran Q statistic and the Istatistic.An Ivalue of less than 25% was considered to have low inconsistency, 25% to 75% indicated medium inconsistency, and greater than 75% indicated high inconsistency.We also did leave-one-out sensitivity analyses. Publication bias and selective reporting were assessed using Egger's regression testand represented diagrammatically with funnel plots. If missing studies were identified, they were imputed using trim-and-fill analyses. We did meta-regression and subgroup analyses to evaluate the potential modifying effect of age (mean), sex (proportion of male participants), proportion of tobacco smokers, dose (mg), current cannabis use (studies in which participants' recent use was confirmed with a positive urine drug screen for cannabis vs studies in which participants had confirmed abstinence from recent cannabis with a negative urine drug screen for cannabis at screening),frequency of cannabis use (mean total exposures >100 vs mean total exposures <100),route of administration (oral vs inhaled vs intravenous),type of THC (purified vs synthetic), symptom scale (BPRS vs PANSS), study quality (Newcastle-Ottawa Scale score), and study author (D'Souza group vs other).Finally, we did an exploratory analysis comparing the magnitude of the effect of THC effects on positive, negative, and general symptoms (see appendix p 2 for further details). Because of the range of timepoints reported by each study and the variation in half-life according to route of administration, we were unable to meta-analyse duration of symptoms. Given the clinical relevance of this issue, we summarise the findings of the included studies in the appendix (pp 3, 20)

The positive and negative syndrome scale and the brief psychiatric rating scale: reliability, comparability, and predictive validity.

Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking.

Genetic predisposition vs individual-specific processes in the association between psychotic-like experiences and cannabis use.

Genetic predisposition vs individual-specific processes in the association between psychotic-like experiences and cannabis use.

Does tobacco use cause psychosis? Systematic review and meta-analysis.

Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics.

where Mand Mare the mean scores for the THC and placebo conditions, respectively, and SD, and SDare the standard deviations for the THC and placebo conditions, respectively; r denotes the between-condition correlation for symptom scores under the THC and placebo conditions. An SMC value of less than 0·40 was considered a small effect, 0·40–0·70 a moderate effect, and more than 0·70 a large effect.The correlation coefficient (r) was set to 0·5 for all studies in our main analysis on the basis of previous literature.We did a sensitivity analysis to evaluate the influence of this assumption on our main results by refitting our model using r values of 0·1 and 0·7 ( appendix p 20 ).

Heterogeneity and homogeneity of regional brain structure in schizophrenia: a meta-analysis.

We used random-effects models based on restricted maximum likelihood estimation in all analyses, since between-study heterogeneity was expected because of the variability in experimental methods and sample characteristics. Given that we were examining within-person studies, the SMC was calculated as a measure of the magnitude of placebo–THC differences. We also calculated the 95% CI of the SMC. The SMC was defined for each study as follows:

We assessed risk of bias using the Newcastle-Ottawa Scale.Disagreements were resolved by discussion between GH, KB, and ODH. Studies with scores of 7 or more were considered to have low risk of bias.If duplicate data were suspected, the authors were contacted for confirmation and the study with the largest sample size or the largest number of required variables was chosen, with sample size taking precedence.

Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis.

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.

If more than one dose or timepoint was reported, the data for the maximum dose or the timepoint associated with the highest mean symptom score for the THC condition with the corresponding placebo score were extracted because we aimed to determine the maximum possible effect. Variables extracted were author, year of publication, number of participants, mean age, proportion of males, proportion of current tobacco smokers, mean total lifetime cannabis exposures, details of control condition and randomisation procedure, inclusion and exclusion criteria, route and dose of THC, symptom measure used and subscales reported, timing of measure relative to administration of THC, and mean and SD of symptom scales. If dose was presented as mg/kg, the mean dose delivered was calculated by multiplying the dose per kg by the mean weight in kg of participants.

GH and KB independently extracted data from studies. Data extraction was cross-checked to ensure accuracy. Where there were discrepancies, these were resolved by discussion with ODH. The main outcome measures were the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo.

Two authors (GH and KB) independently did the search and data extraction ( appendix p 2 ). MEDLINE (from Jan 1, 1946, to May 21, 2019), Embase (from Jan 1, 1974, to May 21, 2019), and PsycINFO (from Jan 1, 1806, to May 21, 2019) were searched. The following keywords were used: (“THC” OR “tetrahydrocannabinol” OR “9THC” OR “9tetrahydrocannabinol” OR “delta9THC” OR “d9THC” OR “delta9tetrahydrocannabinol” OR “dronabinol” OR “marinol” OR “bedrobinol” OR “anandamide” OR “methanandamide” OR “WIN,55,212-2” OR “ACPA” OR “CP55940” OR “bedrocan” OR “spice” OR “JWH-018” OR “AM251” OR “SR161716A” OR “rimonabant” OR “cannabidiol” OR “CBD” OR “cannabinoid”) AND (“BPRS” OR “brief psychiatric rating scale” OR “PANSS” OR “positive and negative syndrome scale”). Meta-analyses, review articles, and included manuscripts were hand-searched for missing studies. Abstracts were screened and the full texts of suitable studies were obtained. If studies used BPRS or PANSS, but data for any of three scales (total, negative, or positive) or additional variables of interest were missing, the authors were contacted for data. Two authors (GH and KB) selected the final studies included in the systematic review and meta-analysis. Conflicts were resolved by discussion between these two authors and ODH where necessary. We contacted study authors to confirm that studies had independent samples. We did the meta-analysis according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) framework.The protocol is available online .

Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.

To ensure comparable and reliable outcome measures, we focused on studies that used standardised, well validated rating scales of psychotic, negative and general psychiatric symptoms (the Brief Psychiatric Rating Scale [BPRS] and the Positive and Negative Syndrome Scale [PANSS]).These tools are designed to measure change in symptoms across psychopathological symptom domains relevant to schizophrenia, including positive (psychotic-like) symptoms such as hallucinations, delusions, and thought disorder, as well as negative symptoms such as blunted affect, anhedonia and amotivation, and general psychopathology, including depressive, cognitive, and anxiety symptoms. Additional searches were made for other well validated scales (Scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, and Community Assessment of Psychic Experience), details of which can be found in the ( appendix p 2 ). These searches were not in the original protocol and were done at the request of reviewers.

The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation.

Exclusion criteria were studies not involving a control condition, using an active control, or administering concurrent medication (besides CBD for the systematic review of CBD plus THC); studies with absence of measures in either the THC or control condition; studies not written in English; studies not reporting original data; studies only providing p or t values, change measurements, or effect sizes; studies with two or fewer participants in each group; and studies involving concurrent administration of other pharmacological compounds.

For this systematic review and meta-analysis, inclusion criteria were double-blind studies that included healthy participants; reported symptom changes in response to acute administration of intravenous, oral, or inhaled THC or CBD; contained either a placebo condition (for the effects of THC or CBD alone) or concurrent administration of THC plus CBD or placebo CBD (for the moderation of THC effects by CBD); used a within-person, crossover design; reported total, positive, or negative symptoms using BPRS or PANSS; and presented data allowing the calculation of the standardised mean difference and deviation between the THC and placebo condition.

Results

15 D'Souza DC

Pittman B

Perry E

Simen A Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Figure 2 Forest plot of total psychiatric symptom severity following THC relative to placebo Show full caption 9-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. The size of the squares reflects the weight attributed to each study. Exact study weights are presented in the appendix (p 13) . The diamond denotes the summary effect size for the random-effects model for all studies, and the width of the diamond depicts the overall 95% CI. THC=Δ-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. Total symptoms were assessed in nine studies with ten samples (two independent samples included from D'Souza et al), involving 196 participants. THC significantly increased total symptom severity compared with placebo, with a large effect size (SMC 1·10 [95% CI 0·92–1·28], p<0·0001; figure 2 ). The result remained significant in all iterations of the leave-one-out analysis (SMC ranged from 1·03 [95% CI 0·92–1·36] to 1·15 [0·95–1·35]; appendix p 21 ).

2=0%, Cochran's Q=9·27, p=0·41). Egger's test did not identify evidence of publication bias (p=0·14). However, trim-and-fill analysis estimated two missing studies on the left-hand side. The SMC was reduced but remained significant after imputation of the two missing studies (SMC 1·02 [95% CI 0·78–1·25], p<0·0001; No between-sample inconsistency was detected (I=0%, Cochran's Q=9·27, p=0·41). Egger's test did not identify evidence of publication bias (p=0·14). However, trim-and-fill analysis estimated two missing studies on the left-hand side. The SMC was reduced but remained significant after imputation of the two missing studies (SMC 1·02 [95% CI 0·78–1·25], p<0·0001; appendix p 14 ).

There were no significant linear relationships between the magnitude of placebo–THC differences and age (n=10, β=0·02 [95% CI −0·07 to 0·11], p=0·68), sex (n=10, β=–0·01 [–0·02 to 0·00], p=0·10), tobacco smoking (n=6, β=–0·02 [–0·06 to 0·02], p=0·30), THC dose (n=6, β=–0·05 [–0·26 to 0·16], p=0·65; including studies of intravenous THC only because of insufficient data for analysis for other routes of administration), or study quality (n=10, β=–0·07 [–0·40 to 0·26], p=0·69). Moreover, the induction of total symptoms was not modified by the use of intravenous or inhaled THC (intravenous vs inhaled: Z=–0·90, p=0·37), frequent cannabis use (Z=35, p=0·73), current cannabis use (Z=0·07, p=0·95) or study author (Z=1·06, p=0·29). An insufficient number of studies used BPRS, synthetic THC, or oral THC to enable a moderator analysis of these variables.

Figure 3 Forest plot of positive symptom severity following THC relative to placebo Show full caption 9-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. The size of the squares reflects the weight attributed to each study. Exact study weights are presented in the appendix (p 13) . The diamond denotes the summary effect size for the random-effects model for all studies, and the width of the diamond depicts the overall 95% CI. THC=Δ-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. Positive symptoms were assessed in 14 studies (15 independent samples) involving 324 participants. THC increased positive symptom severity compared with placebo (SMC 0·91 [95% CI 0·68–1·14], p<0·0001; figure 3 ). The result remained significant in all iterations of the leave-one-out analysis (SMC ranged from 0·85 [95% CI 0·63–1·07] to 0·96 [0·75–1·18]; appendix p 22 ).

2=65·70%, Cochran's Q=43·73, p<0·0001). Egger's test implied significant publication bias (p=0·0007). Trim-and-fill analysis estimated one missing study on the left-hand side ( There was medium between-sample inconsistency (I=65·70%, Cochran's Q=43·73, p<0·0001). Egger's test implied significant publication bias (p=0·0007). Trim-and-fill analysis estimated one missing study on the left-hand side ( appendix p 14 ). The SMC was reduced but remained significant after imputation of the missing study (SMC 0·87 [95% CI 0·63–1·11], p<0·0001).

Intravenous THC induced more severe positive symptoms than did inhaled THC (Z=2·34, p=0·014; appendix p 15 ), and studies completed by the D'Souza group were also associated with more severe positive symptoms than studies by other authors (Z=2·89, p=0·0038; appendix p 15 ). There was an insufficient number of studies to evaluate the effect of oral THC. There was a negative association between tobacco smoking and positive symptoms induced by THC (n=10, β=–0·01 [95% CI −0·02 to 0·00], p=0·019; appendix p 16 ). Studies with higher quality were associated with a greater effect on positive symptoms (n=15, β=0·26 [95% CI 0·06–0·47], p=0·011; appendix p 16 ).

By contrast, there were no significant linear relationships between the magnitude of THC–placebo differences and age (n=15, β=0·09 [95% CI −0·01 to 0·19], p=0·069), sex (n=15, β=–0·01 [–0·02 to 0·01], p=0·27), or dose of THC (n=10, β=–0·01 [–0·21 to 0·18], p=0·91; only reported for studies using intravenous administration). Similarly, frequent cannabis use (Z=0·87, p=0·38), current cannabis use (Z=–1·10, p=0·27), and type of THC (synthetic vs purified; Z=–0·73, p=0·47) did not significantly moderate the induction of positive symptoms. An insufficient number of studies used BPRS to enable a moderator analysis of symptom scale used.

Figure 4 Forest plot of negative symptom severity following THC relative to placebo Show full caption 9-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. The size of the squares reflects the weight attributed to each study. Exact study weights are presented in the appendix (p 13) . The diamond denotes the summary effect size for the random-effects model for all studies, and the width of the diamond depicts the overall 95% CI. THC=Δ-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. Negative symptoms were assessed in 12 studies (13 independent samples) involving 267 participants. THC increased the severity of negative symptoms compared with placebo, with a large effect size (SMC 0·78 [95% CI 0·59–0·97], p<0·0001; figure 4 ). The result remained significant in all iterations of the leave-one-out analysis (SMC ranged from 0·72 [95% CI 0·55–0·90] to 0·83 [0·66–1·00]; appendix p 22 ). THC induced a greater effect on positive symptoms than on negative symptoms (Z=2·06, p=0·039), although this finding did not remain significant when refitting the model with a lower between-symptom correlation coefficient (r=0·1, Z=1·53, p=0·13; appendix p 20 ).

2=40·57%, Cochran's Q=24·24, p=0·019). Egger's test implied significant publication bias (p=0·0069). Trim-and-fill analysis did not identify any missing studies ( There was medium between-sample inconsistency (I=40·57%, Cochran's Q=24·24, p=0·019). Egger's test implied significant publication bias (p=0·0069). Trim-and-fill analysis did not identify any missing studies ( appendix p 17 ).

As with positive symptoms, intravenous THC induced greater negative symptoms than did inhaled THC (Z=2·43, p=0·015; appendix p 17 ). An insufficient number of studies used oral THC to evaluate its modifying effects. Higher mean age of the sample predicted greater negative symptoms induced by THC (n=13, β=0·08 [95% CI 0·01–0·15], p=0·022; appendix p 18 ).

There were no significant linear relationships between the magnitude of THC–placebo differences and sex (n=13, β=–0·00 [95% CI −0·01 to 0·01], p=0·89), tobacco smoking (n=8, β=–0·00 [–0·01 to 0·01], p=0·41), THC dose (n=9, β=0·03 [–0·12 to 0·18], p=0·73; only assessed in studies of intravenous THC), or study quality (n=13, β=–0·00 [–0·21 to 0·20], p=0·99). Similarly, frequent cannabis use (Z=–0·23, p=0·82), current cannabis use (Z=–0·94, p=0·35), type of THC (synthetic vs purified; Z=–1·35, p=0·18), and study author (Z=0·062, p=0·95) did not significantly moderate the induction of negative symptoms. An insufficient number of studies used BPRS to enable a moderator analysis of symptom scale used.

Figure 5 Forest plot of general psychiatric symptom severity following THC relative to placebo Show full caption 9-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. The size of the squares reflects the weight attributed to each study. Exact study weights are presented in the appendix (p 13) . The diamond denotes the summary effect size for the random-effects model for all studies, and the width of the diamond depicts the overall 95% CI. THC=Δ-tetrahydrocannabinol. *Low cannabis use sample. †High cannabis use sample. General symptoms were assessed in eight studies (nine independent samples) involving 162 participants. THC significantly increased general symptoms compared with placebo with a large effect size (SMC 1·01 [95% CI 0·77–1·25], p<0·0001; figure 5 ). The result remained significant in all iterations of the leave-one-out analysis (SMC ranged from 0·90 [95% CI 0·70–1·11] to 1·08 [0·81–1·35]; appendix p 22 ). No significant differences were found between the effect on general symptoms and positive (Z=0·44, p=0·66) or negative symptoms (Z=1·90, p=0·058), although the latter became significant when refitting the model with a higher between-symptom correlation coefficient (r=0·7, Z=2·01, p=0·044; appendix p 20 ).

2 value of 28·90% (Cochran's Q=20·67, p=0·0081). Egger's test implied significant publication bias (p=0·0002). Trim-and-fill analysis estimated three missing studies on the left side ( There was medium between-sample inconsistency, with an Ivalue of 28·90% (Cochran's Q=20·67, p=0·0081). Egger's test implied significant publication bias (p=0·0002). Trim-and-fill analysis estimated three missing studies on the left side ( appendix p 18 ). The SMC was reduced but remained significant after imputation of the missing study (SMC 0·85 [95% CI 0·53–1·17], p<0·0001).

There were no significant linear relationships between the magnitude of THC–placebo differences in general symptoms and age (n=9, β=–0·00 [95% CI −0·13 to 0·13], p=0·95), sex (n=9, β=–0·00 [–0·02 to 0·01], p=0·72), tobacco smoking (n=6, β=–0·01 [–0·04 to 0·03], p=0·67), THC dose (n=7, β=–0·08 [–0·33 to 0·17], p=0·52; only assessed in studies of intravenous THC), or study quality (n=9, β=–0·02 [–0·48 to 0·45], p=0·95). Similarly, intravenous and inhaled THC (Z=–0·31, p=0·76), frequent cannabis use (Z=–0·068, p=0·95), current cannabis use (Z=–0·84, p=0·38), and study author (Z=1·06, p=0·29) did not significantly moderate the induction of general symptoms. An insufficient number of studies used BPRS, oral THC, or synthetic THC to enable moderator analyses of these variables.

The effect of CBD on psychopathology compared with placebo was evaluated in two within-person studies and one between-person study ( figure 1 ), with one further study that used the CAPE scale identified by our additional searches ( appendix p 19 ). In the systematic review, there were no significant differences between CBD and placebo in any of the subscales reported ( appendix p 11 ).