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Cannabis and psychosis: What do we know and what should we do?

DOI:10.1192/bjp.2018.1
Authors:
Marco Colizzi at University of Udine
Marco Colizzi
Robin Murray at King's College London
Robin Murray
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Abstract

It is now incontrovertible that heavy use of cannabis increases the risk of psychosis. There is a dose–response relationship and high potency preparations and synthetic cannabinoids carry the greatest risk. It would be wise to await the outcome of the different models of legalisation that are being introduced in North America, before deciding whether or not to follow suit. Declaration of interest None.
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Editorial
Cannabis and psychosis: what do we
know and what should we do?
Marco Colizzi and Robin Murray
Summary
It is now incontrovertible that heavy use of cannabis increases
the risk of psychosis. There is a dose–response relationship and
high potency preparations and synthetic cannabinoids carry the
greatest risk. It would be wise to await the outcome of the dif-
ferent models of legalisation that are being introduced in North
America, before deciding whether or not to follow suit.
Declaration of interest
None.
Copyright and usage
© The Royal College of Psychiatrists 2018.
Marco Colizzi (pictured) is a psychiatrist and clinical researcher interested in psychosis
and addiction. He is studying the neurocognitive and neurochemical effects of canna-
binoids on the human brain. Robin Murray is a professor of psychiatric research and has
spent much of his life studying the causes of psychosis.
Cannabis is used by approximately 200 million people across the
world. The current trend to popularise its medicinal properties,
real and imagined,
1
and to decriminalise or legalise it in many coun-
tries, is likely to be followed by greater use.
2,3
However, cannabis is
not as safe as was once thought.
1,4
Just as longitudinal studies of
tobacco smokers versus non-smokers nailed the link between cigar-
ettes and lung cancer, so similar prospective studies have shown that
heavy cannabis use carries with it an increased risk of psychosis.
Of 13 longitudinal studies in the general population, 10 have
shown that cannabis users are at significant increased risk of subse-
quently developing psychotic symptoms or schizophrenia-like
psychotic illness. The remaining three studies showed a trend in
the same direction; two had a short follow-up period and the
third limited power.
4
A recent meta-analysis
5
reported that the
odds ratio for developing psychotic symptoms or a psychotic dis-
order in individuals who had used cannabis over non-users
reached 3.9 (95% CI 2.84–5.34) among the heaviest users.
Of course, association does not prove causation. However, one
by one, alternative explanations have gradually been disproved.
4
Patients do not start using cannabis to self-medicate their psychotic
or prodromal symptoms or side-effects of drugs, but rather use it for
the same reasons as the rest of the population, principally for its
‘high’. The risk of psychosis remains after controlling for personality
disorder and use of other psychotogenic drugs. Some overlap
between genes carrying susceptibility to schizophrenia and to
drug use has been reported but insufficient to explain more than
a fraction of the relationship.
4
Of course, the vast majority of people using cannabis do not
develop a psychotic disorder. Not surprisingly, people with a para-
noid or ‘psychosis-prone’personality are especially vulnerable,
alongside people with other risk factors for psychosis such as child-
hood trauma. Starting use in adolescence and having a family
history of psychosis also carry more risk; some evidence points to
variants of genes involved in the dopamine system conveying
susceptibility.
6
Neuroimaging studies have begun to clarify the neural under-
pinning of the psychotic symptoms induced by cannabinoids.
4
Unlike other drugs of misuse that have their maximum impact on
dopamine in the ventral striatum, long-term cannabis use induces
alterations in dopamine in the associative striatum, which recent
evidence pinpoints as the locus of abnormality underlying positive
psychotic symptoms.
The changing nature of recreational cannabinoids
Extract of Cannabis sativa contains over 80 different cannabinoids,
with delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol
(CBD) the most important. Δ9-THC is the main psychoactive ingre-
dient, and administering it experimentally to healthy volunteers can
induce transient psychotic symptoms.
4,7
CBD appears to counteract
Δ9-THC-induced psychotic symptoms and cognitive impairment,
and may even have antipsychotic properties.
7
Most traditional forms of cannabis such as marijuana or hashish
used in the 1960s and 1970s contained less than 4% of THC and
often an equal proportion of the ameliorating CBD. However,
these have been displaced by stronger varieties in many countries.
4
In the UK, the type colloquially known as skunk now dominates the
market; it contains on average 16% THC; CBD is barely detectable
as the plant cannot produce high concentrations of both cannabi-
noids. In Holland forms of Nederwiet containing up to 60% THC
can be lawfully smoked in coffee shops. In Colorado, where canna-
bis has been legalised for recreational use, preparations such as wax
dabs containing up to 90% THC can be bought.
In the last 5 years, synthetic cannabinoids, often termed collect-
ively spice, have hit the market. In contrast to THC which is a partial
agonist at the cannabinoid CB
1
receptor, most synthetic cannabi-
noids are full agonists and consequently more powerful. Acute
anxiety and paranoid reactions are common but because new mole-
cules are constantly being produced and few have been tested in
animals, incidental toxic reactions can be dangerous.
8
Difficulty in
detecting synthetic cannabinoids in urine has made them especially
popular in prisons.
Need for much more research
Little effort has been put into studying cannabis, compared with that
into alcohol or other recreational drugs. Effects of cannabis use on
other psychiatric disorders need to be further examined, with some
early reports claiming its use is beneficial for disorders such as post-
traumatic stress disorder and depression and others that it increases
their risk.
1
The role of cannabis composition needs to be further
examined in such studies, as it is still unclear whether at specific
concentrations CBD might outweigh any harmful effects of Δ9-
THC.
7
The role of cannabis dependence in perpetuating use
The British Journal of Psychiatry (2018)
212, 195–196. doi: 10.1192/bjp.2018.1
195
deserves more study as does the possible synergistic effects of
tobacco and cannabis, a major issue as the two are commonly
smoked together.
Research into the numerous components of cannabis should be
encouraged since, like research into opiates, it may produce drugs
with important medical uses. Individual cannabinoid components
can then be subject to trials measuring their effectiveness for a
variety of ailments (for example pain, childhood epilepsy) in the
same way any other proposed drug is evaluated. When effective, it
should be introduced for prescription by doctors; several cannabin-
oid drugs already have become available in this manner.
What should we do now?
We psychiatrists need to be more alert to cannabis use by our
patients and take as detailed a history of drug use as we do of
alcohol consumption. Certain characteristics should give rise to par-
ticular suspicion.
4
Patients who develop psychosis following misuse
of cannabis tend to have an earlier onset of illness and to have better
premorbid cognition and social function than other patients with
schizophrenia. We need to get better at detecting those patients
with established psychosis who continue to use cannabis, especially
high potency varieties, as this is associated with worse outcomes;
9
continued cannabis use and poor adherence to antipsychotics
tend to go together.
10
There is no strong evidence that any particular psychological
intervention is particularly helpful in aiding patients to stop using
cannabis. Nor have there been formal studies of which antipsychotic
is best although some evidence suggests that clozapine is less likely
to increase craving.
A curious divide has opened up between North America and the
UK. In the USA, cannabis use in young people has increased since
the mid-1990s as the number regarding use of cannabis as risky has
fallen; use and potency of the drug is greater in those states that have
legalised cannabis for medicinal or recreational purposes.
2
In con-
trast, use has fallen in England; in 1996, 25.8% of people aged 16–
24 admitted to having used cannabis in the previous year; by
2016, that number had declined to 16.4%.
This decline has occurred in spite of the fact that use of cannabis
has, in practice, been decriminalised in most parts of the UK. But,
should it be legalised? This was the policy of the Liberal
Democrats at the last election –although it did not turn out to be
a vote winner. Indeed, it is the case both in the USA and the UK
that much of the pressure to legalise is not coming from the
public but rather from investors keen to make a fast buck. Would
legalisation in the UK lead to an increase in consumption and can-
nabis tourism as evident in Amsterdam and Colorado, or could it be
combined with education so that consumption would actually fall?
The honest answer is that no one knows.
The sensible thing is to watch what happens in the next few
years as different models of legalisation are implemented in differ-
ent states in North America. The USA and Canada have embarked
on a major pharmaceutical experiment with the brains of their
youth, and we should wait and see the outcome of the experiment.
While we wait, we need public education to make the public aware
of the risks associated with heavy cannabis use. It would be a shame
when we are in sight of ridding the country of the scourge of tobacco
use, if it were to be replaced by use of a drug that, although less
harmful to the body, is more toxic to the mind.
Marco Colizzi, MD, National Institute for Health Research (NIHR) Biomedical Research
Centre (BRC), South London and Maudsley NHS Foundation Trust, UK; Department of
Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College
London, UK; Robin Murray, FRS, FRCPsych, National Institute for Health Research (NIHR)
Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust;
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience,
King’s College London, UK; Department of Psychiatry, Experimental Biomedicine and
Clinical Neuroscience (BIONEC), University of Palermo, Italy
Correspondence: Marco Colizzi, Department of Psychosis Studies, Institute of
Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK.
Email: marco.v.colizzi@kcl.ac.uk
First received 12 Sep 2017, accepted 13 Dec 2017
Acknowledgements
We thank Professor Wayne Hall for his comments on a draft.
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Colizzi & Murray
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... They stated that "the USA and Canada have embarked on a major pharmaceutical experiment with the brains of their youth." The caution urged by Colizzi and Murray (2018) and the nuanced conclusions from Babor et al. (2018) contrasts with the confidence indicated by Hughes et al. (2018) that penalties seem relatively unimportant. Before dismissing any impact of penalties upon use rates, we decided to revisit the penalty change events examined by Hughes et al. (2018), but to focus upon adolescents. ...
... Our analysis focuses on past month use among 16-year-olds, indicating current use. This group constitute an extremely important group from a population health perspective, based upon the known hazards of adolescent cannabis use (Colizzi & Murray, 2018;Murray & Hall, 2020;Volkow et al. 2014;Wilson et al. 2019). There is emerging evidence that even minimal cannabis use around this vulnerable stage of brain development may result in measurable alterations in brain morphology (Orr et al. 2019;Albaugh et al. 2021). ...
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Full-text available
  • Aug 2016
Background This study aimed to evaluate synthetic cannabinoid (SC)-induced psychosis in terms of patient profile and clinical characteristics with reference to concurrently hospitalized schizophrenic patients. Methods A total of 81 male patients diagnosed with psychotic disorder induced by the use of SCs (n=50; mean (standard deviation [SD]) age: 25.9 (5.5) years) or with schizophrenia (n=31, mean (SD) age: 42.9 (11.6) years) based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnosis criteria who were concurrently hospitalized at Erenköy Mental and Neurological Diseases Training and Research Hospital were included in this cross-sectional study. Data on sociodemographic characteristics, Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Frontal Assessment Battery (FAB), Hamilton Rating Scale for Depression (HRSD), and Hamilton Anxiety Rating Scale (HAM-A) were recorded in all the patients. Results Mean (SD) age at disease onset in SC-induced psychosis patients was 22.3 (5.6) years; 26.0% had suicidal ideation and 58.4% were hospitalized involuntarily. Marijuana was the most common first used substance (72.0%), and solitary use of SC was noted in 38.0% of patients. SC-induced psychosis patients had similar PANSS positive, BPRS, HRSD, and FAB scores and significantly lower PANSS negative scores (18.0 [6.5] vs 22.3 [6.0], P=0.004) than patients with schizophrenia, while they had similar HAM-A scores (17.8 [10.3] vs 21.6 [5.5], P=0.085) as young schizophrenics. Age at onset for SC (r=0.364, P=0.05) or substance (r=0.395, P=0.01) use was correlated positively with total FAB scores. Conclusion In conclusion, our findings revealed SC-induced psychosis to influence young individuals and be associated with remarkable rates of suicidal ideation and involuntary hospitalization as well as similar clinical picture with schizophrenia in terms of PANSS positive, BPRS, HRSD, HAM-A, and FAB scores. Younger age at onset was associated with poorer frontal lobe functions overall, regardless of the type of substance, and with poorer inhibitory control and programming performance in case of SC use.
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Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis
Article
Full-text available
  • Feb 2016
Cannabis use has been reported to induce long-lasting psychotic disorders and a dose-response relationship has been observed. We performed a systematic review of studies that investigate the association between the degree of cannabis consumption and psychosis and a meta-analysis to quantify the magnitude of effect. Published studies were identified through search of electronic databases, supplemented by manual searches of bibliographies. Studies were considered if they provided data on cannabis consumption prior to the onset of psychosis using a dose criterion (frequency/amount used) and reported psychosis-related outcomes. We performed random effects meta-analysis of individual data points generated with a simulation method from the summary data of the original studies. From 571 references, 18 studies fulfilled inclusion criteria for the systematic review and 10 were inserted in the meta-analysis, enrolling a total of 66 816 individuals. Higher levels of cannabis use were associated with increased risk for psychosis in all the included studies. A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers. Current evidence shows that high levels of cannabis use increase the risk of psychotic outcomes and confirms a dose-response relationship between the level of use and the risk for psychosis. Although a causal link cannot be unequivocally established, there is sufficient evidence to justify harm reduction prevention programs.
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Interaction between DRD2 and AKT1 genetic variations on risk of psychosis in cannabis users: A case-control study
Article
Full-text available
  • Jul 2015
Genetic factors may explain the differences in individual sensitivity to the psychosis-inducing effects of cannabis.1,2 In view of the converging data from candidate gene and genome-wide association studies that the D2-AKT1 signaling pathway is relevant for the pathophysiology and outcome of schizophrenia,3 and on the basis of previous association between cannabis-related psychosis and both DRD2 (rs1076560)1 and AKT1 (rs2494732),2 we hypothesized that these polymorphisms interact in increasing the risk of psychosis in cannabis users. We expected the genetic pathway × cannabis use interaction model to better predict the individual’s odds of psychotic disorder than the single candidate gene×cannabis use interaction model.
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Cannabis-associated psychosis: Neural substrate and clinical impact
Article
  • Jun 2017
Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia-like psychoses. Early onset of use, daily use of high-potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk-increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta-9-tetrahydrocannabinol (THC), can produce transient, dose-dependent, psychotic symptoms, as well as an array of psychosis-relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.
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US Adult Illicit Cannabis Use, Cannabis Use Disorder, and Medical Marijuana Laws: 1991-1992 to 2012-2013
Article
  • Apr 2017
Importance Over the last 25 years, illicit cannabis use and cannabis use disorders have increased among US adults, and 28 states have passed medical marijuana laws (MML). Little is known about MML and adult illicit cannabis use or cannabis use disorders considered over time. Objective To present national data on state MML and degree of change in the prevalence of cannabis use and disorders. Design, Participants, and Setting Differences in the degree of change between those living in MML states and other states were examined using 3 cross-sectional US adult surveys: the National Longitudinal Alcohol Epidemiologic Survey (NLAES; 1991-1992), the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001-2002), and the National Epidemiologic Survey on Alcohol and Related Conditions–III (NESARC-III; 2012-2013). Early-MML states passed MML between NLAES and NESARC (“earlier period”). Late-MML states passed MML between NESARC and NESARC-III (“later period”). Main Outcomes and Measures Past-year illicit cannabis use and DSM-IV cannabis use disorder. Results Overall, from 1991-1992 to 2012-2013, illicit cannabis use increased significantly more in states that passed MML than in other states (1.4–percentage point more; SE, 0.5; P = .004), as did cannabis use disorders (0.7–percentage point more; SE, 0.3; P = .03). In the earlier period, illicit cannabis use and disorders decreased similarly in non-MML states and in California (where prevalence was much higher to start with). In contrast, in remaining early-MML states, the prevalence of use and disorders increased. Remaining early-MML and non-MML states differed significantly for use (by 2.5 percentage points; SE, 0.9; P = .004) and disorder (1.1 percentage points; SE, 0.5; P = .02). In the later period, illicit use increased by the following percentage points: never-MML states, 3.5 (SE, 0.5); California, 5.3 (SE, 1.0); Colorado, 7.0 (SE, 1.6); other early-MML states, 2.6 (SE, 0.9); and late-MML states, 5.1 (SE, 0.8). Compared with never-MML states, increases in use were significantly greater in late-MML states (1.6–percentage point more; SE, 0.6; P = .01), California (1.8–percentage point more; SE, 0.9; P = .04), and Colorado (3.5–percentage point more; SE, 1.5; P = .03). Increases in cannabis use disorder, which was less prevalent, were smaller but followed similar patterns descriptively, with change greater than never-MML states in California (1.0–percentage point more; SE, 0.5; P = .06) and Colorado (1.6–percentage point more; SE, 0.8; P = .04). Conclusions and Relevance Medical marijuana laws appear to have contributed to increased prevalence of illicit cannabis use and cannabis use disorders. State-specific policy changes may also have played a role. While medical marijuana may help some, cannabis-related health consequences associated with changes in state marijuana laws should receive consideration by health care professionals and the public.
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Can we make cannabis safer?
Article
  • Mar 2017
Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm. Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use. Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.
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Evaluating the public health impacts of legalizing recreational cannabis use in the United States
Article
  • Oct 2016
Background and aims: Since 2012 four US states have legalized the retail sale of cannabis for recreational use by adults, and more are likely to follow. This report aimed to (1) briefly describe the regulatory regimes so far implemented; (2) outline their plausible effects on cannabis use and cannabis-related harm; and (3) suggest what research is needed to evaluate the public health impact of these policy changes. Method: We reviewed the drug policy literature to identify: (1) plausible effects of legalizing adult recreational use on cannabis price and availability; (2) factors that may increase or limit these effects; (3) pointers from studies of the effects of legalizing medical cannabis use; and (4) indicators of cannabis use and cannabis-related harm that can be monitored to assess the effects of these policy changes. Results: Legalization of recreational use will probably increase use in the long term, but the magnitude and timing of any increase is uncertain. It will be critical to monitor: cannabis use in household and high school surveys; cannabis sales; the number of cannabis plants legally produced; and the tetrahydrocannabinol (THC) content of cannabis. Indicators of cannabis-related harms that should be monitored include: car crash fatalities and injuries; emergency department presentations; presentations to addiction treatment services; and the prevalence of regular cannabis use among young people in mental health services and the criminal justice system. Conclusions: Plausible effects of legalizing recreational cannabis use in the United States include substantially reducing the price of cannabis and increasing heavy use and some types of cannabis-related harm among existing users. In the longer term it may also increase the number of new users.
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