Cannabis and its constituents

The Cannabis genus of plants contains over 100 unique compounds called phytocannabinoids, or cannabinoids. One of the principal psychoactive cannabinoids, Δ-9-tetrahydrocannabinol (referred to herein as THC unless otherwise noted), confers acute psychological effects including intoxication, positive subjective drug effects, sedation, introspection, impaired working memory, appetite stimulation, anxiety, and psychotic-like experiences. Another highly prevalent cannabinoid is cannabidiol (CBD). CBD is non-intoxicating, though investigations of potential anxiolytic, antipsychotic, and anticonvulsant applications are promising (Amminger et al., Reference Amminger, Lin, Kerr, Weller, Spark, Pugh and McGorry2022; Bhattacharyya et al., Reference Bhattacharyya, Morrison, Fusar-Poli, Martin-Santos, Borgwardt, Winton-Brown and McGuire2010; McGuire et al., Reference McGuire, Robson, Cubala, Vasile, Morrison, Barron and Wright2018; White, Reference White2019). Also present in cannabis are hundreds of other compounds, such as terpenes, and minor cannabinoids, concentrations of which vary between chemovars (Ferber et al., Reference Ferber, Namdar, Hen-Shoval, Eger, Koltai, Shoval and Weller2020). This variability makes it challenging to disentangle each compound's contributions to outcomes in higher-order mental states.

As cannabis' commercial marketplace has expanded in recent decades and as producers refine agricultural and extraction techniques, availability and use of high-potency THC cannabis and cannabis-based products is increasing (Cash, Cunnane, Fan, & Romero-Sandoval, Reference Cash, Cunnane, Fan and Romero-Sandoval2020). The US Drug Enforcement Agency data on seizures of unregulated cannabis indicate that samples increased from approximately 4% to 15% THC on average from 1995 to 2021, while CBD levels remained negligible (See Fig. 1; National Institute on Drug Abuse, 2022).

Figure 1. Percentage of THC and CBD in cannabis samples seized by DEA (1995–2001). Adapted from National Institute on Drug Abuse, 2022. Retrieved 02/05/2023 from https://nida.nih.gov/research-topics/marijuana/cannabis-marijuana-potency

Mechanism of psychoactive effects relevant to CHR-P

THC produces psychoactive effects via the endocannabinoid (eCB) system – a family of signaling molecules and receptors associated with learning and memory, reward, motivation, pain processing, and emotion regulation. Endocannabinoids modulate the release of other neurotransmitters (Covey, Mateo, Sulzer, Cheer, & Lovinger, Reference Covey, Mateo, Sulzer, Cheer and Lovinger2017). Thus, as a partial agonist of the cannabinoid 1 (CB1) receptor, THC disrupts neural circuits supporting diverse functions. eCB system dysregulation has often been observed in patients with idiopathic psychotic disorders (Garani, Watts, & Mizrahi, Reference Garani, Watts and Mizrahi2021). Many have speculated how cannabinoid-induced neurobiological alterations could potentially contribute to development of chronic psychotic disorders, but no consensus currently exists (Bossong & Niesink, Reference Bossong and Niesink2010; Malone, Hill, & Rubino, Reference Malone, Hill and Rubino2010). Within the heterogeneous CHR-P population we lack knowledge of the molecular and cellular factors influencing divergent clinical trajectories and how they may interface with cannabis exposure. As the eCB system plays a central role in brain maturation, adolescents may be particularly vulnerable to its effects (Ellgren et al., Reference Ellgren, Artmann, Tkalych, Gupta, Hansen, Hansen and Hurd2008). In animal models chronic exposure to exogenous cannabinoids during adolescence especially disrupts eCB-mediated cortical development (Dow-Edwards & Silva, Reference Dow-Edwards and Silva2017; Miller et al., Reference Miller, Chadwick, Dickstein, Purushothaman, Egervari, Rahman and Hurd2019). Yet it remains unclear whether such changes occur in humans, or whether they drive psychosis. Investigating the potential contribution of cannabis use upon vulnerable brain development may improve our understanding of overall psychosis risk (Collins et al., Reference Collins, Ji, Chung, Lympus, Afriyie-Agyemang, Addington and Cannon2023; Howes & Onwordi, Reference Howes and Onwordi2023).

The mechanisms linking THC's pharmacology to its phenomenological effects remain unclear. The mesolimbic D2 dopamine receptor hyperactivity hypothesis (i.e., that excessive signaling through D2 receptors in subcortical and limbic regions drives positive psychotic symptoms, most strongly supported by the efficacy of antidopaminergic antipsychotic medications) has long been invoked to explain both THC's rewarding properties and the positive symptoms of idiopathic psychosis (Bloomfield, Ashok, Volkow, & Howes, Reference Bloomfield, Ashok, Volkow and Howes2016; Brisch et al., Reference Brisch, Saniotis, Wolf, Bielau, Bernstein, Steiner and Gos2014). Recent work supports a more nuanced model, in which mesolimbic dopamine changes occur via modulation of presynaptic GABA/glutamatergic neurons – on whose axon terminals CB1 receptors reside (Covey et al., Reference Covey, Mateo, Sulzer, Cheer and Lovinger2017; Radhakrishnan et al., Reference Radhakrishnan, Skosnik, Cortes-Briones, Sewell, Carbuto, Schnakenberg and D'Souza2015). The resultant excitation-inhibition imbalance feeding onto mesolimbic dopamine neurons is hypothesized to generate the observed decreases in cortical synchrony (Cortes-Briones et al., Reference Cortes-Briones, Skosnik, Mathalon, Cahill, Pittman, Williams and D'Souza2015), as well as impaired information processing and associative functions, mimicking idiopathic psychosis (Sherif, Radhakrishnan, D'Souza, & Ranganathan, Reference Sherif, Radhakrishnan, D'Souza and Ranganathan2016).

Differential effects of CBD relevant to CHR-P

CBD is hypothesized to utilize dozens of distinct mechanisms of action. Its psychoactive effects are unlike THC's, characterized primarily by slight drowsiness and reduced anxiety under some conditions (Freeman et al., Reference Freeman, Petrilli, Lees, Hindocha, Mokrysz, Curran and Freeman2019). There is currently mixed evidence for CBD attenuating THC-induced psychotic-like symptoms in healthy individuals. Two RCTs in healthy adults found that high-dose CBD pre-administration attenuated intravenous THC's acute psychotomimetic effect (Bhattacharyya et al., Reference Bhattacharyya, Morrison, Fusar-Poli, Martin-Santos, Borgwardt, Winton-Brown and McGuire2010; Englund et al., Reference Englund, Morrison, Nottage, Hague, Kane, Bonaccorso and Kapur2013). Similarly, a large cross-sectional, web-based study reported a subtle but significant inverse relationship between CBD concentration and self-reported positive symptoms (Schubart et al., Reference Schubart, Sommer, van Gastel, Goetgebuer, Kahn and Boks2011). Conversely, two RCTs revealed no attenuating effect of CBD at concentrations present in recreational cannabis (Englund et al., Reference Englund, Oliver, Chesney, Chester, Wilson, Sovi and McGuire2022; Lawn et al., Reference Lawn, Trinci, Mokrysz, Borissova, Ofori, Petrilli and Curran2023), and another noted attenuation of THC-induced psychotic symptoms only for low-frequency cannabis users (Morgan et al., Reference Morgan, Freeman, Hindocha, Schafer, Gardner and Curran2018). Thus, CBD's acute psychosis attenuation may depend on THC dose and cannabis use frequency. Small-scale clinical trials have demonstrated safety and efficacy of oral CBD use as a potential antipsychotic, though larger trials would be needed to support formal recommendations (Leweke et al., Reference Leweke, Piomelli, Pahlisch, Muhl, Gerth, Hoyer and Koethe2012; McGuire et al., Reference McGuire, Robson, Cubala, Vasile, Morrison, Barron and Wright2018; Zuardi et al., Reference Zuardi, Crippa, Hallak, Pinto, Chagas, Rodrigues and Tumas2009, Reference Zuardi, Hallak, Dursun, Morais, Sanches, Musty and Crippa2006). A large-scale RCT in CHR-P participants assessing CBD's efficacy in reducing positive symptoms of psychosis is also currently underway (Amminger et al., Reference Amminger, Lin, Kerr, Weller, Spark, Pugh and McGorry2022).

THC and acute exacerbation of psychotic-like experiences

There is substantial overlap between some of THC's acute adverse effects and psychosis spectrum symptoms, including paranoia, distorted audiovisual and time perception, disorganized cognition, and anxiety. Initial clinical studies demonstrated that intravenously administered THC transiently induces positive and negative symptoms of psychosis in healthy individuals and those with schizophrenia, in a dose-dependent manner (D'Souza et al., Reference D'Souza, Abi-Saab, Madonick, Forselius-Bielen, Doersch, Braley and Krystal2005, Reference D'Souza, Perry, MacDougall, Ammerman, Cooper, Wu and Krystal2004). Many subsequent clinical experiments in healthy adults have replicated these findings with inhaled and oral-use THC (Bhattacharyya et al., Reference Bhattacharyya, Atakan, Martin-Santos, Crippa, Kambeitz, Malhi and McGuire2015, Reference Bhattacharyya, Fusar-Poli, Borgwardt, Martin-Santos, Nosarti, O'Carroll and McGuire2009; Kleinloog et al., Reference Kleinloog, Liem-Moolenaar, Jacobs, Klaassen, de Kam, Hijman and van Gerven2012; Liem-Moolenaar et al., Reference Liem-Moolenaar, te Beek, de Kam, Franson, Kahn, Hijman and van Gerven2010; Morgan et al., Reference Morgan, Freeman, Hindocha, Schafer, Gardner and Curran2018).

To our knowledge, as of April 2023 only one double-blinded, placebo-controlled study of cannabis in CHR-P participants has been published. In this exploratory study, CHR-P participants smoked cannabis and temporarily experienced significant exacerbations of paranoia, visual illusions, time distortions, feelings of strangeness, cognitive impairment, and anxiety – effects not observed in people not at risk for psychosis (Vadhan, Corcoran, Bedi, Keilp, & Haney, Reference Vadhan, Corcoran, Bedi, Keilp and Haney2017). Observational CHR-P studies similarly report transient exacerbations of anxiety, depression, and positive symptoms shortly following cannabis use (Corcoran et al., Reference Corcoran, Kimhy, Stanford, Khan, Walsh, Thompson and Colibazzi2008; Peters et al., Reference Peters, De Koning, Dingemans, Becker, Linszen and De Haan2009). Notably, an observational study found that CHR-P individuals who experience acute psychotic-like symptoms during cannabis use were 4.9 times more likely to eventually develop psychosis than CHR-P individuals who are cannabis users who do not experience these symptoms during cannabis use (see Fig. 2; McHugh et al., Reference McHugh, McGorry, Yung, Lin, Wood, Hartmann and Nelson2017). CHR-P individuals who experience psychotic-like symptoms in the context of cannabis use may represent a subpopulation with a distinct clinical trajectory, warranting dedicated early intervention and greater research attention. The existence of subpopulations with divergent responses to cannabis may account for variable results of prior analyses of cannabis use among the inherently heterogeneous overall CHR-P population.

Figure 2. Survival functions modeling time to transition to psychotic disorder based on presence of psychotic-like symptoms during cannabis use (n = 190) (McHugh et al., Reference McHugh, McGorry, Yung, Lin, Wood, Hartmann and Nelson2017). Adapted from Fig. 1 of ‘Cannabis-induced attenuated psychotic symptoms: implications for prognosis in young people at ultra-high risk for psychosis’, by McHugh et al., Reference McHugh, McGorry, Yung, Lin, Wood, Hartmann and Nelson2017, Psychological Medicine, 47, p. 616–626. Copyright 2017 by Cambridge University Press.

Similarly, observational studies of healthy individuals who use cannabis reveal that individuals scoring highly on schizotypal personality measures reported higher levels of psychotic-like symptoms during and shortly after using cannabis (Mason et al., Reference Mason, Morgan, Dhiman, Patel, Parti, Patel and Curran2009; Stirling et al., Reference Stirling, Barkus, Nabosi, Irshad, Roemer, Schreudergoidheijt and Lewis2008). Frequency of use is positively related to schizotypy among these individuals, which authors speculated may arise from a gradient of heightened dopamine system sensitivity along the psychosis spectrum (Stirling et al., Reference Stirling, Barkus, Nabosi, Irshad, Roemer, Schreudergoidheijt and Lewis2008).

Epidemiological evidence for a relationship between cannabis use and psychosis risk

Several large-scale epidemiological studies revealed an association between cannabis use and risk for psychotic disorder. Among the first reports was a longitudinal study of 45 000+ male Swedish military conscripts, providing compelling evidence for a relationship between cannabis and schizophrenia. Over 15 years, those who had used cannabis on 50+ occasions throughout their lives were 6 times more likely than never-users to develop schizophrenia (Andréasson et al., Reference Andréasson, Engström, Allebeck and Rydberg1987). Subsequent large, general population prospective cohort studies supported this trend. A later study in New Zealand followed 1037 healthy individuals from age 11–26 and contributed two novel findings: (1) A significant increase in incidence of schizophreniform disorder among those who initiated cannabis use before age 15, but not before age 18, and (2) Initiation before either ages 15 or 18 was associated with more severe psychotic symptoms at age 26 (Arseneault, Reference Arseneault2002). Similarly, in the Netherlands 4045 healthy individuals and 59 with previously diagnosed psychotic disorder (ages 18–64, mean 41.4) were assessed annually over three years. Lifetime (pre-baseline) cannabis use predicted psychosis at follow-up better than new initiation of cannabis use between baseline and follow-up, with a greater effect among those with a prior history of psychosis (van Os, Reference van Os2002). Earlier initiation also predicted greater incidence of subthreshold symptoms in a large 10-year cohort study of healthy individuals (Kuepper et al., Reference Kuepper, van Os, Lieb, Wittchen, Hofler and Henquet2011), as well as greater severity of subthreshold psychotic symptoms in two large cross-sectional surveys of Dutch and Greek adolescents (Schubart et al., Reference Schubart, Sommer, van Gastel, Goetgebuer, Kahn and Boks2011; Stefanis et al., Reference Stefanis, Delespaul, Henquet, Bakoula, Stefanis and Van Os2004). Concerns regarding adolescents' particular susceptibility to neurodevelopmental perturbations have been raised when considering a cannabis-mediated pathway to psychotic disorder. In a cross-sectional study, adolescents who use cannabis daily to weekly reported more severe psychotic-like symptoms than both adults who use cannabis at the same frequency and adolescents with minimal cannabis exposure (Lawn et al., Reference Lawn, Mokrysz, Lees, Trinci, Petrilli, Skumlien and Curran2022). Further work is needed to explore differential susceptibility of the adolescent brain to cannabis' neuropsychiatric effects.

Moreover, meta-analyses have affirmed a dose-dependent relationship between frequency of cannabis use and later incidence of a psychotic disorder (Kiburi, Molebatsi, Ntlantsana, & Lynskey, Reference Kiburi, Molebatsi, Ntlantsana and Lynskey2021; Marconi, Di Forti, Lewis, Murray, & Vassos, Reference Marconi, Di Forti, Lewis, Murray and Vassos2016; Moore et al., Reference Moore, Zammit, Lingford-Hughes, Barnes, Jones, Burke and Lewis2007). An international case–control study including first-episode patients found daily cannabis use to be associated with 3.2-fold increased risk of developing a psychotic disorder; people who used high-potency cannabis had 4.8-fold increased risk (Di Forti et al., Reference Di Forti, Quattrone, Freeman, Tripoli, Gayer-Anderson, Quigley and van der Ven2019). A survey of 100 000+ US adults found frequent cannabis use to be associated with self-reported psychotic disorder; past-year cannabis users also self-reported psychotic disorder significantly more often than non-past-year cannabis users (Livne, Shmulewitz, Sarvet, Wall, & Hasin, Reference Livne, Shmulewitz, Sarvet, Wall and Hasin2022). Recent evidence also suggests that young males may be particularly vulnerable to these effects (Hjorthøj et al., Reference Hjorthøj, Compton, Starzer, Nordholm, Einstein, Erlangsen and Han2023).

Notably, meta-analyses indicate that among individuals with first episode psychosis, those with a history of cannabis use experienced their first episode 2.7 years younger than those who never tried cannabis (Godin & Shehata, Reference Godin and Shehata2022; Large, Sharma, Compton, Slade, & Nielssen, Reference Large, Sharma, Compton, Slade and Nielssen2011). This earlier-onset trend is exacerbated by THC concentration (Di Forti et al., Reference Di Forti, Sallis, Allegri, Trotta, Ferraro, Stilo and Murray2014), though there is mixed evidence for frequency of use moderating earlier onset (Godin & Shehata, Reference Godin and Shehata2022; Wainberg, Jacobs, di Forti, & Tripathy, Reference Wainberg, Jacobs, di Forti and Tripathy2021). Earlier psychosis onset confers worrisome prognostic factors: greater disability, more frequent relapse, increased antipsychotic nonadherence, decreased treatment efficacy, and longer hospitalizations (Compton et al., Reference Compton, Kelley, Ramsay, Pringle, Goulding, Esterberg and Walker2009). In the general population, age of initiation, frequency of use, comorbid substance use, childhood trauma, and genetic risk have been reported to moderate the relationship between adolescent cannabis use and conversion to psychosis (Kiburi et al., Reference Kiburi, Molebatsi, Ntlantsana and Lynskey2021).

In contrast, the direct impact of cannabis use on conversion to psychosis in CHR-P is less clear. Earlier initiation of cannabis use is associated with younger onset of subthreshold psychotic symptoms (Dragt et al., Reference Dragt, Nieman, Becker, van de Fliert, Dingemans, de Haan and Linszen2010, Reference Dragt, Nieman, Schultze-Lutter, Van Der Meer, Becker and De Haan2012). Two meta-analyses failed to find lifetime endorsement of cannabis use predictive of conversion in CHR-P (Carney, Cotter, Firth, Bradshaw, & Yung, Reference Carney, Cotter, Firth, Bradshaw and Yung2017; Kraan et al., Reference Kraan, Velthorst, Koenders, Zwaart, Ising, van den Berg and van der Gaag2016), though a separate comparison found increased conversion among CHR-P individuals with cannabis use disorder (CUD), suggesting a potential dose-dependent effect (Kraan et al., Reference Kraan, Velthorst, Koenders, Zwaart, Ising, van den Berg and van der Gaag2016). Shorter latency to conversion among CHR-P individuals with CUD has been observed, though adjusting for alcohol use negated a predictive relationship between CUD and long-term conversion risk (Auther et al., Reference Auther, Cadenhead, Carrión, Addington, Bearden, Cannon and Cornblatt2015). Specific aspects of cannabis use have been reported to predict conversion in CHR-P: earlier initiation of use, increased frequency of use, continued use following CHR-P diagnosis, and experiencing psychotic-like symptoms during cannabis use (Dragt et al., Reference Dragt, Nieman, Becker, van de Fliert, Dingemans, de Haan and Linszen2010; McHugh et al., Reference McHugh, McGorry, Yung, Lin, Wood, Hartmann and Nelson2017; Valmaggia et al., Reference Valmaggia, Day, Jones, Bissoli, Pugh, Hall and McGuire2014). However, other studies found no evidence for a gradient in conversion risk with increasing frequency of subclinical cannabis use in CHR-P (Auther et al., Reference Auther, McLaughlin, Carrión, Nagachandran, Correll and Cornblatt2012; Phillips et al., Reference Phillips, Curry, Yung, Pan Yuen, Adlard and Mcgorry2002; Yung, Phillips, Yuen, & McGorry, Reference Yung, Phillips, Yuen and McGorry2004). To explain the absence of a clear association, some researchers have speculated that cannabis use may predict the emergence of CHR-P symptoms without contributing to psychosis conversion (Addington et al., Reference Addington, Case, Saleem, Auther, Cornblatt and Cadenhead2014). Although plausible, prior CHR-P cannabis use research lacks the nuance to support the specificity of the hypothesis. For example, comparisons of lifetime cannabis use are often binary, binning single-time through daily users together as compared to never-users. Prior studies have also been limited by the exclusion of CHR-P individuals with CUD (to avoid confounding), small sample size of participants who use cannabis, ascertainment bias toward help-seeking individuals, aggregation of all non-medicinal psychoactive substances into ‘substance use’, and minimal longitudinal data (Addington et al., Reference Addington, Case, Saleem, Auther, Cornblatt and Cadenhead2014; Auther et al., Reference Auther, Cadenhead, Carrión, Addington, Bearden, Cannon and Cornblatt2015; Yung et al., Reference Yung, Phillips, Yuen and McGorry2004). Moreover, as the CHR-P population is inherently heterogeneous, consideration of subgroups predisposed to distinct cannabis use patterns may shed light on prior discordant findings.

Causation or spurious correlation?

It remains unclear whether the relationship between adolescent cannabis use and increased incidence of psychotic disorder is causative or correlative. Two main hypotheses have been proposed: one suggesting a causal role (adolescent THC use directly contributes to elevated risk of developing a psychotic disorder), while the other emphasizes shared vulnerability, whereby other factor(s) predispose the individuals to both use THC and to develop a psychotic disorder – independently of each other (Gillespie & Kendler, Reference Gillespie and Kendler2021).

The causal hypothesis has garnered more attention within the existing literature. However, consideration of the shared vulnerability hypothesis is warranted, as mechanisms remain unclear. Coincidental correlation (or bidirectional causation) suggests the existence of shared risk genes for both cannabis use and psychotic spectrum experiences found in Genome-Wide Association Studies (Gillespie & Kendler, Reference Gillespie and Kendler2021; Karcher et al., Reference Karcher, Barch, Demers, Baranger, Heath, Lynskey and Agrawal2019; Pasman et al., Reference Pasman, Verweij, Gerring, Stringer, Sanchez-Roige, Treur and Vink2018; Power et al., Reference Power, Verweij, Zuhair, Montgomery, Henders, Heath and Martin2014; Vaissiere, Thorp, Ong, Ortega-Alonzo, & Derks, Reference Vaissiere, Thorp, Ong, Ortega-Alonzo and Derks2020). This hypothesis is based, in part, by variation in the CADM2 gene, which correlates with both schizophrenia and lifetime cannabis use (Pasman et al., Reference Pasman, Verweij, Gerring, Stringer, Sanchez-Roige, Treur and Vink2018). Mendelian Randomization, a method which uses genotypes as variables to reduce confounding and aid causal inference, provided assumptions are met, has been used to define the relationship between cannabis use and genes underlying increased risk for schizophrenia. Two Mendelian Randomization analyses found a causal influence of schizophrenia risk genes on lifetime cannabis use (Gage et al., Reference Gage, Jones, Burgess, Bowden, Davey Smith, Zammit and Munafò2017; Pasman et al., Reference Pasman, Verweij, Gerring, Stringer, Sanchez-Roige, Treur and Vink2018), while another reported the opposite (Vaucher et al., Reference Vaucher, Keating, Lasserre, Gan, Lyall, Ward and Holmes2018). However, authors conceded that binary binning of all cannabis users under ‘lifetime use’ as previously described may too have introduced confounding (Gage et al., Reference Gage, Jones, Burgess, Bowden, Davey Smith, Zammit and Munafò2017). Studies of co-twins and other relatives have demonstrated modest causal impact of CUD on psychotic-like experiences and disorders, with notable contributions of personal, shared genetic, and environmental factors (Giordano, Ohlsson, Sundquist, Sundquist, & Kendler, Reference Giordano, Ohlsson, Sundquist, Sundquist and Kendler2015; Karcher et al., Reference Karcher, Barch, Demers, Baranger, Heath, Lynskey and Agrawal2019; Nesvåg et al., Reference Nesvåg, Reichborn-Kjennerud, Gillespie, Knudsen, Bramness, Kendler and Ystrom2016). Lifetime cannabis use, but not CUD, has been shown to moderate the effect of schizophrenia polygenic risk score on frequency of psychotic-like experiences (Schaefer et al., Reference Schaefer, Jang, Vrieze, Iacono, McGue and Wilson2021; Wainberg et al., Reference Wainberg, Jacobs, di Forti and Tripathy2021). A longitudinal study of Danish national registry data (3 000 000+ individuals) found that while cannabis abuse increased risk of later schizophrenia by 5.4-fold, risk was also significantly increased–albeit more modestly–by alcohol, hallucinogen, sedative, and other substance use (Nielsen, Toftdahl, Nordentoft, & Hjorthøj, Reference Nielsen, Toftdahl, Nordentoft and Hjorthøj2017). If individuals are predisposed to both use cannabis and develop psychosis, the possibility of an illusory relationship cannot be fully discounted.

Skeptics of a causal hypothesis point out the dissociation between recent decades' significant increases in cannabis use and relatively stable global rates of schizophrenia diagnoses (Degenhardt, Hall, & Lynskey, Reference Degenhardt, Hall and Lynskey2003). However, recent work indicates elevated rates of first-episode psychosis in regions with predominantly high-potency cannabis (Di Forti et al., Reference Di Forti, Marconi, Carra, Fraietta, Trotta, Bonomo and Murray2015, Reference Di Forti, Quattrone, Freeman, Tripoli, Gayer-Anderson, Quigley and van der Ven2019). Moreover, limitations have been identified within existing prediction models, including gaps and lags in incidence data (Hickman, Vickerman, Macleod, Kirkbride, & Jones, Reference Hickman, Vickerman, Macleod, Kirkbride and Jones2007).

A reverse causality (i.e., self-medication of psychotic symptoms) relationship is poorly supported by the scientific literature. Longitudinal and experience sampling studies found a temporal sequence of cannabis use preceding psychotic-like experiences, but psychotic symptoms did not predict subsequent cannabis use (Kuepper et al., Reference Kuepper, van Os, Lieb, Wittchen, Hofler and Henquet2011; Verdoux, Gindre, Sorbara, Tournier, & Swendsen, Reference Verdoux, Gindre, Sorbara, Tournier and Swendsen2003). CHR-P individuals do not significantly endorse using cannabis to relieve positive symptoms as a motive for their use (Gill et al., Reference Gill, Poe, Azimov, Ben-David, Vadhan, Girgis and Corcoran2015). Further, the most common reason for cessation of cannabis use in a longitudinal study of 182 CHR-P individuals was exacerbation of positive symptoms (Valmaggia et al., Reference Valmaggia, Day, Jones, Bissoli, Pugh, Hall and McGuire2014). Additional research to clarify factors driving continued cannabis use in CHR-P is warranted.

Minimize THC and substitute CBD in cannabis use

Given the mounting evidence that THC can cause transient psychotic-like symptoms and may contribute to chronic psychotic disorders – both in a dose-dependent manner – CHR-P individuals are recommended to minimize their THC intake. Meanwhile, high doses of CBD (much greater than found in retail cannabis or cannabis-derived products) have been shown to attenuate THC's psychotomimetic effects (Bhattacharyya et al., Reference Bhattacharyya, Morrison, Fusar-Poli, Martin-Santos, Borgwardt, Winton-Brown and McGuire2010; Englund et al., Reference Englund, Morrison, Nottage, Hague, Kane, Bonaccorso and Kapur2013; Schubart et al., Reference Schubart, Sommer, van Gastel, Goetgebuer, Kahn and Boks2011), though low doses of CBD may be ineffective (Englund et al., Reference Englund, Oliver, Chesney, Chester, Wilson, Sovi and McGuire2022; Lawn et al., Reference Lawn, Trinci, Mokrysz, Borissova, Ofori, Petrilli and Curran2023). CHR-P individuals who do not want to entirely stop using cannabis should consider switching to cannabis products with minimal THC and high CBD concentrations. Although thresholds of psychoactive effect have yet to be rigorously determined, the US Department of Agriculture currently restricts content of THC in hemp (a non-controlled substance) to 0.3% (Hemp and the 2018 Farm Bill, 2019). This could serve as a conservative benchmark for harm reduction purposes. See online Supplemental Materials for further consideration of potential advantages and disadvantages to this approach.

Avoid high potency THC concentrate products

Experimental evidence supports a dose-dependent effect of THC on acute psychotic-like experiences (D'Souza et al., Reference D'Souza, Perry, MacDougall, Ammerman, Cooper, Wu and Krystal2004). High doses of THC can also transiently worsen anxiety in healthy individuals despite reducing it at low doses (Childs et al., Reference Childs, Lutz and de Wit2017), and anxiety reduction is a top motive for cannabis use in the CHR-P population (Gill et al., Reference Gill, Poe, Azimov, Ben-David, Vadhan, Girgis and Corcoran2015). Cannabis concentrates are steadily growing in popularity, containing approximately 52% THC on average and up to 95% (Bidwell, Martin-Willett, & Karoly, Reference Bidwell, Martin-Willett and Karoly2021). Their high potency makes regulating dosage difficult if one sought to avoid inducing psychotic-like symptoms and anxiety (or exacerbating chronic psychosis risk). Use of cannabis concentrates can be viewed as akin to rapidly drinking liquor and should be targeted for intervention.

Use caution with infused oral products like edibles

Consumption of cannabis-infused foods (‘edibles’) carries unique risks. Unlike inhaled cannabis, edibles can take hours before effects are realized, with latency and potency varying between consumers of the same batch based on biological factors like metabolism, weight, and sex (Reboussin et al., Reference Reboussin, Wagoner, Sutfin, Suerken, Ross, Egan and Johnson2019). Edibles, relative to inhaled cannabis, produce a longer lasting psychotropic effect due to liver metabolism of Δ-9-THC to 11-hydroxy-Δ-9-THC, a psychoactive metabolite of THC that is also a CB1 receptor agonist (Wiley, Barrus, Farquhar, Lefever, & Gamage, Reference Wiley, Barrus, Farquhar, Lefever and Gamage2021). Homemade edibles are prone to variation in concentration within and between batches. Though edibles are increasingly perceived as a healthier alternative to smoking, they may pose a greater risk for both over-intoxication and induction of psychotic-like experiences than inhaled cannabis (Reboussin et al., Reference Reboussin, Wagoner, Sutfin, Suerken, Ross, Egan and Johnson2019). Thus, providers should educate CHR-P cannabis users about oral cannabis use and its unique psychotomimetic risks.

Reduce frequency of cannabis use

Reducing frequency of cannabis use may also lower risk of developing chronic psychotic disorder. In the general population, more frequent use is associated with increased incidence of both psychotic disorders and transient symptoms (Kiburi et al., Reference Kiburi, Molebatsi, Ntlantsana and Lynskey2021; Marconi et al., Reference Marconi, Di Forti, Lewis, Murray and Vassos2016; Moore et al., Reference Moore, Zammit, Lingford-Hughes, Barnes, Jones, Burke and Lewis2007; Wainberg et al., Reference Wainberg, Jacobs, di Forti and Tripathy2021). There is mixed evidence available for CHR-P regarding lower conversion risk with decreasing frequency of use (Auther et al., Reference Auther, McLaughlin, Carrión, Nagachandran, Correll and Cornblatt2012; Kraan et al., Reference Kraan, Velthorst, Koenders, Zwaart, Ising, van den Berg and van der Gaag2016; Phillips et al., Reference Phillips, Curry, Yung, Pan Yuen, Adlard and Mcgorry2002; Valmaggia et al., Reference Valmaggia, Day, Jones, Bissoli, Pugh, Hall and McGuire2014; Yung et al., Reference Yung, Phillips, Yuen and McGorry2004). It is unclear whether decreasing usage will change long-term clinical outcomes. Regardless, reducing frequency of use would lessen the likelihood of acute symptom exacerbation and decrease the brain's cumulative THC exposure.