Cannabis and Psychosis – Cause and Cure

Elinor Bradley

Verity Williams

Abstract

Professionals working in mental health services frequently see individuals who have comorbid substance misuse. The relationship between mental health and substance use is complex, particularly for cannabis, which remains the most prevalent illicit substance used globally. Professionals are often asked questions regarding the role of cannabis as a causative factor in psychotic illness. As cannabis-derived products become more widely available, questions are also being asked regarding its role as a treatment for psychosis. This paper discusses the evidence for cannabis as an etiological factor in psychotic disorders, and the potential that cannabis-derived products, namely cannabidiol, have in treating psychosis. We aim to provide evidence for discussion with patients and their carers about this complex field.

Introduction

Cannabis is the most widely used illicit substance globally, and its use is increasing. In the UK, 40% of 15–16-year-olds have used cannabis [1], and the age at first use has been steadily decreasing [2]. The Crime Survey for England and Wales (2020) found that 18.7% of UK young adults (aged 16-24) had used cannabis within the last year [3]. This may be understood in the context of the ‘prevalent view of its harmlessness’ [4], the legalisation of use of cannabis in some jurisdictions (e.g., multiple states in the USA), and with cannabis- derived products, such as the non-psychoactive component cannabidiol (CBD) being widely marketed [5].

The three main types of street cannabis are derived from differing parts of the cannabis plant: ‘hash’ is made from the plants’ resin and the most prevalent type on the market up to 2000; herbal cannabis, also known as ‘weed’, ‘grass’ or ‘marijuana’, is made from the dried leaves and flowers of the pollinated plant; high-potency cannabis or ‘skunk’ is made from the unpollinated plant. These types vary in the content of the psychoactive cannabinoid tetrahydrocannabinol (THC) [6]. ‘Hash’ contains 2-4% of both THC and CBD; herbal cannabis contains 2-4% THC and less than 1.5% CBD; and ‘skunk’ contains 12-18% THC and less than 1.5% CBD [7,8]. ‘Skunk’ now accounts for 70% of the street market; the potency of street cannabis has increased over recent decades, containing three times more THC than in the 1960s [4].

Cannabis use is prevalent in people with mental illness compared with the general population. Estimates of its use in people with severe mental illness within the UK vary from 20- 70% [9,10]. Adults with mental illness used more than twice as much cannabis in the last year compared to adults without [11,12]. Reasons reported by people with mental illness for using cannabis include: to reduce boredom and to enjoy the positive mood; to get relief from dysphoria, agitation, and poor sleep; and to manage symptoms of mental illness [13].

Does cannabis cause or worsen psychosis?

 Research dating from the late 1980s highlighted that the relative risk of schizophrenia among high consumers of cannabis (use on more than fifty occasions) was six times higher than non-users (95% CI 4·0—8·9) [14]. Arseneault (2002) conducted a population-based longitudinal study in New Zealand, collecting data on prodromal symptoms at age 11, and drug use at age 15 and 18. Those that had used cannabis by the age of 15 were four times more likely to develop a schizophreniform disorder at age 26 than controls [15].

Diverse evidence has since confirmed an association between cannabis use and psychosis. Semple (2005) investigated the association between preceding cannabis use and schizophrenia or schizophrenia-like psychosis, and found that individuals who used cannabis during adolescence, had baseline psychotic symptoms, or were at high genetic risk, were particularly vulnerable [16].

Further studies have since added to the evidence of an association between cannabis use and psychosis. Barnett et al (2007) examined substance misuse in an ‘Early Intervention in Psychosis’ service in the UK [17]. He found that the lifetime prevalence of cannabis use in patients was 83%, with 51% meeting the criteria for cannabis abuse or dependence. The prevalence of cannabis use in the previous 30 days was higher than age-adjusted use for the general population: 29% of patients compared with 12%. The onset of substance use usually took place several years prior to the first psychotic symptoms [17]. Similarly, a longitudinal study of patients within a Canadian ‘early psychosis programme’ identified that 33% of patients met the criteria for cannabis substance misuse disorder [18].

Di Forti et al (2009) compared patients experiencing first episode psychosis with controls from the local UK population [19]. Whilst no significant association was found between individuals having ‘ever taken’ cannabis and psychosis, patients were more likely to be current daily users and to have smoked cannabis for more than 5 years compared to the controls. Among those who had used cannabis, 78% of patients used high-potency cannabis compared to 37% of the controls [19].

A Finnish population-based longitudinal study gathered information on prodromal psychotic symptoms and cannabis use at age 15–16 years [20]. Cannabis users received higher rates of psychotic diagnosis during the 15-year follow-up, compared to non-cannabis users (4.8% vs 1.7%). There was a dose–response effect with elevated risk in individuals who had tried cannabis more than five times (HR 6.5, 95% CI 3.0–13.9) [20].

There is also evidence that cannabis use worsens the prognosis of established psychotic illness. Individuals with first episode psychosis who persist in using cannabis have higher levels of positive psychotic symptoms [18]. Preceding use of cannabis in patients admitted to a ‘psychiatric intensive care unit’ is associated with more severe illness, requiring longer periods in hospital than non-users [10]. Cannabis also leads to increased behavioural disturbances such as violence [9]. A recent review found converging lines of evidence indicating that patients with existing psychosis, or those at high risk of developing psychosis, are at increased risk of harm from using THC-containing compounds [21].

Is the association causative?

 The nature of the association between cannabis and psychotic illness has been widely debated. Some contend that it is due to being a confounding factor; an independent factor which is associated with both the exposure to cannabis and the outcome of psychosis, but which does not lie on the causative pathway [22]. However, several studies had controlled for a wide range of potential confounding factors [23].

Others support the ‘self-medication hypothesis’, or reverse causality, and highlight the subjective view that cannabis use is secondary to mental health symptoms, either as a coping strategy or to alleviate side effects from prescribed psychotropics.  This has not been supported by research, as studies adjusting for prodromal symptoms have shown clear evidence of a temporal relationship with cannabis use predating psychosis [15,17,20]. As intravenous THC induces positive psychotic symptoms in patients with schizophrenia [24] and controls [25] the biological plausibility of the mechanism by which cannabis use would ameliorate these symptoms lacks credibility.

A further hypothesis regarding this association is of ‘effect modification’, a phenomenon where an exposure has a different effect among different subgroups. Research supports this with cannabis being particularly linked with psychosis in vulnerable subgroups, such as individuals with prodromal symptoms, family history of psychosis [20], and those with certain genetic variants of the dopamine regulating catechol-O-methyltransferase (COMT) gene [26].

Could cannabinoids alleviate psychosis?

 Dopamine antagonists remain the mainstay of treatment for psychotic illness. However, treatment resistance, lack of efficacy for negative symptoms and adverse effects contributing to non-adherence are barriers to the treatment. Novel interventions that act outside of the dopaminergic system are thus needed, and CBD is seen as a possible candidate. CBD has opposite effects to THC on striatal brain activation, and pre-treatment with CBD attenuates THC induced psychotic symptoms [27].

The first single case study investigating the effects of CBD monotherapy, titrated up to 1500 mg/day, for a patient suffering acute exacerbation of schizophrenia, resulted in reduction of psychotic symptoms [28]. However, the subsequent case series examining the effects of CBD monotherapy, titrated up to 1280 mg/day, found improvements in only one of three patients with treatment-resistant schizophrenia [29].

One of the first landmark randomised controlled trials [30] compared up to 800 mg/day of CBD with the antipsychotic Amisulpride as treatment for patients with an acute exacerbation of schizophrenia. There was a significant and comparable reduction in positive symptoms in both groups [30].

CBD has also been investigated as an adjunct treatment. A randomised controlled trial in patients with schizophrenia, comparing CBD (1000 mg/day) as an add-on treatment to existing antipsychotic with add-on placebo, found a significant reduction in positive symptoms with CBD [31]. However, a second study using similar methodology, with a lower dose of 600 mg/day add-on CBD versus add-on placebo, failed to replicate these findings [32].

While CBD has been found to be well tolerated in short-term clinical trials [29, 30, 31, 32], the total volume of data regarding adverse effects is too small to conclude it as a safe treatment. Research on CBD, for indications other than psychosis, also suggest it has a favourable safety profile with no adverse effects on physiological, psychomotor or psychological functions [33,34]. However, CBD is not entirely free from adverse effects such as diarrhea, nausea and headaches [31], and in vitro work suggesting possible impact on cell viability and fertilisation potential [35]. CBD is also associated with significantly increased hepatic aminotransferases [36], and its potent inhibitory effect on the cytochrome P450 family (CYP3A4 and CYP2D6) indicates it may affect circulating concentrations of concomitant psychotropics [37].

Discussion

Mental health professionals are frequently asked difficult questions regarding the role of cannabis as a causative factor in psychotic illness. Additionally, in the context of increasing use of off licence medical cannabinoids, questions are also asked regarding its role as treatment for psychosis. Woo (2002) makes the case for ‘more transparency and humility’ by clinicians when counselling patients, acknowledging that ‘our current knowledge of cannabinoids is quite limited’ within an ‘evolving’ evidence base [38].

We can advise with relative confidence that whilst most people who use cannabis do not develop psychosis, there is convincing evidence that individuals who use cannabis regularly from an early age and use high potency cannabis are at increased risk of developing psychosis. The risk is especially seen in those individuals with vulnerabilities such as prodromal symptoms or a family history of psychosis. There is also evidence that the outcomes for patients with established psychotic illness are worse when cannabis use is ongoing.

We can let our patients know that, at this time, there is only limited evidence regarding cannabinoids’ efficacy in treating psychotic illness. There is also insufficient data to make conclusions regarding its long-term safety. In addition, off licence medical cannabinoids carry risks as they are unregulated, not of pharmaceutical quality, with high risk of contamination with other cannabinoids [39]. The dosage of cannabidiol products is also highly variable and typically lower than doses used in clinical studies. Off licence medical cannabinoids are thus ‘at best an expensive placebo, but at worst may be actively harmful’ [39]. We must also acknowledge that research in this area is ongoing and the advice may change in future.

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About the authors

Dr Rhian Bradley is a Consultant Psychiatrist in general adult psychiatry at Kent and Medway NHS Trust (KMPT). Dr Bradley is actively involved in medical education at KMPT, and at Kent and Medway Medical School, and Canterbury Christchurch University.

 Dr Verity Williams is a higher trainee (ST5) in general adult psychiatry at Kent and Medway NHS Trust (KMPT).