Child Adolesc Psychiatr Clin N Am 2020 29 1 145-56

T h e Chang i n g L eg al
Landscape of Cannabis Use

a n d I t s R o l e i n Yo u t h - o n s e t
Psychosis
Abigail Wright, PhDa,b,*, Corinne Cather, PhDa,b,
Jodie Gilman, PhDb,c, Anne Eden Evins, MD, MPHb,c
KEYWORDS
First-episode psychosis Schizophrenia Cannabis use Tetrahydrocannabinol
THC High potency CBD
KEY POINTS
The changing landscape of cannabis (eg, availability, potency, and risk perception) has
contributed to an increase in cannabis use.
Early and frequent cannabis use, and use of high-potency cannabis, may contribute to an
increase in psychotic disorders.
Prevention and treatment, including contingency management and first-episode psycho-
sis programs, are becoming increasingly important to support youth mental health.
INCREASED AVAILABILITY, POTENCY, AND ROUTES OF ADMINISTRATION OF

CANNABIS PRODUCTS
The Cannabis sativa plant has 2 primary cannabinoids: D9-tetrahydrocannabinol

(THC), the component of cannabis that produces intoxicating effects and is known
to cause anxiety, euphoria, disrupted cognitive function, psychosislike
(eg, suspiciousness, altered perception) and negative (eg, amotivation, apathy) symp-
toms1; and cannabidiol (CBD), which is not thought to lead to dependence and has
been studied for potential antiinflammatory, anxiolytic, and antipsychotic effects.2,3
Cannabis is the most commonly used illicit drug worldwide,4 and its use has increased
Disclosure: The authors have no disclosures.

a
Massachusetts General Hospital, Center of Excellence in Psychosocial and Systemic Research,
151 Merrimac Street, 6th Floor, Boston, MA 02114, USA; b Harvard Medical School, Boston, MA
USA; c Massachusetts General Hospital, Center for Addiction Medicine, 101 Merrimac Street,
Boston, MA 02114, USA
* Corresponding author.
E-mail address: AWRIGHT24@mgh.harvard.edu
Child Adolesc Psychiatric Clin N Am 29 (2020) 145–156

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146 Wright et al
over the last few decades,5 with 18.4% of adolescents6 and 32.6% of college students
in North America7 reporting cannabis use in the past 30 days. High usage rates of
cannabis by youth could partially reflect difficulty obtaining alcohol in this age group.8
The changing legal landscape for this drug has been associated with increased usage,
availability, and potency of cannabis products, as well as with a reduced perception of
harm of cannabis use.9
In the past decade, there has been a dramatic increase in the availability of
cannabis products. Since the 1996 enactment of the first state law allowing
the medical use of cannabis, 33 US states and the District of Columbia have legal-
ized medical marijuana. More than 17 states allow products that are high in CBD
and low in THC10 and 11 states allow essentially unregulated cannabis for recrea-
tional use.11 Of note, there are no standardized definitions of medical marijuana,
high-CBD products, or low-THC products.12 It is difficult to identify the amount of
THC in commercial products in the United States now, because products vary
from batch to batch, often lack standardized testing, and have been reported to
be inaccurately labeled.13
Concomitant with increased general availability, the authors have seen both
increased THC potency of standard cannabis products as well as increased avail-
ability of novel high-potency products. Percentage THC content in illicit (street)
and commercial flower marijuana markets increased from 3.96% (1.82%) THC
content in 1995 to 11.84% (6.6%) THC content in 2014,14 with no change in
CBD levels.15 Synthetic cannabinoids (eg, spice/K2), highly potent, full CD1 (clus-
ter of differentiation 1) receptor agonists, as well as skunk or resin products have
recently become popular; these products produce more intense effects than
whole-plant cannabis.16 There has been an enormous increase in the availability
of CBD products (eg, CBD oil, gummies, edibles, vapes, or bath products), which
are generally considered safe, helpful, and homeopathic by a large segment of
users who do not elect to use products containing THC. Despite minimal, generally
low-quality evidence for medical benefits, they are touted to cause relief from pain,
anxiety, depression, insomnia, and even psychosis.2,17 (An exception is CBD for
certain forms of pediatric epilepsy, including Lennox-Gastaut syndrome18 and Dra-
vet syndrome.19) Of note, US Food and Drug Administration tests have shown that
some CBD products sold in the United States contain little to no CBD, and contain
high levels of THC.20,21 This finding suggests that individuals may be unaware that
they are consuming THC and its itinerant potential negative effects on mental
health, highlighting the need for additional regulation of CBD and commercial
cannabis products to protect consumers.19
Clinicians should be aware of novel methods of consumption; for example, so-
called vaping or dabbing, and ingestion of edibles, which may increase the appeal
of using cannabis products and be more difficult for observers to detect than smoked
cannabis. Vape pens for cannabis can be indistinguishable from electronic cigarettes,
and there are Web sites that instruct youth how to be stealthy, including using an elec-
tronic cigarette to vape cannabis products. Dabbing is accomplished by extracting
concentrated doses of cannabis into a sticky oil, which is heated on a hot surface
(typically a nail) and inhaled through a device that can resemble a bong. Because of
different pharmacokinetics of smoking versus ingesting cannabis, edibles delay the
timing and increase both the duration and intensity of intoxication. Ingesting cannabis
produces a 30-minute to 60-minute delay to peak high and up to a 3 times longer high
(2 hours vs 6 hours) than smoking cannabis,22 which, in an effort to experience intox-
ication, has resulted in accidental ingestion of too much cannabis and associated
adverse effects.23
The Changing Legal Landscape of Cannabis Use 147
EFFECTS OF CANNABIS USE IN PEOPLE WITH PSYCHOTIC DISORDERS
Cannabis use is common in people with chronic schizophrenia24 and first-episode

psychosis (FEP)25 and has been associated with a poor prognosis.26,27 Cannabis
use after FEP worsens both psychotic symptoms and psychosocial functioning, con-
trolling for other risk factors.28–30 In laboratory studies, a single dose of THC causes
transient psychotic symptoms in a greater proportion of people with schizophrenia
than healthy volunteers.1 Synthetic cannabinoids (eg, spice/K2) also trigger psychotic
symptoms, aggression, and suicidal thoughts31,32 in those with prior psychosis, sug-
gesting THC use as a risk factor for poor outcomes in those with psychosis.
Persistent cannabis use after the first episode of schizophrenia has been associated
with relapse,33 increasing the risk for relapse 2.2-fold, even after controlling for con-
founding factors, including medication adherence.34 Although some research has
suggested the association is bidirectional,35 cross-lagged analyses indicate that
cannabis use predicts risk of relapse, rather than relapse predicting cannabis use.33
Cannabis use in FEP has been associated with increased frequency of hospital admis-
sions,36 longer duration of first hospital stay, and greater odds of having more than 20
hospitalizations.37 Critically important, discontinuation of cannabis use after FEP
significantly reduces relapse risk to the level of nonusers,38 improving both symp-
toms38 and functioning.39 Cannabis discontinuation increases the probability of remis-
sion in FEP,40 supporting cannabis abstinence as one of the few modifiable clinical
targets to improve psychotic disorder outcomes. Although the negative impact of
persistent cannabis use on recovery from a psychotic disorder37 has long been recog-
nized, new research has begun to support the independent contribution of early initi-
ation, frequent use, and use of high-potency cannabis to the onset and course of new
psychotic disorders.37,41
DOES CANNABIS CAUSE PSYCHOTIC DISORDERS?
The cause of psychotic disorders is multifactorial, influenced by genes,42 environ-

ment,43 and their interaction.44 In recent years, there has been increased attention
to the role of cannabis as a potentially preventable environmental risk factor for psy-
chosis.45 Evidence in support of a causal relationship between cannabis and psycho-
sis includes several factors, such as the plausibility of cannabis use as compromising
adolescent brain structure and function, evidence of cannabis use as preceding
the onset of a psychotic disorder, and a strong dose-dependent association between
cannabis use and psychotic disorder. Alternatively, epidemiologic data have yet to
empirically show the expected increased incidence of psychotic disorders associated
with increased availability and usage of cannabis. It has also been difficult to disen-
tangle contributions of shared genetic and environmental factors and there is some
evidence for a common genetic pathway to both psychotic disorders and cannabis
use.
Late adolescence is a particularly vulnerable period, because the brain is undergo-
ing extensive changes, including the development of higher cognitive functions46 and
an increase in white matter volume enabling rapid flow of information throughout
the brain.47 Psychosis usually develops during this vulnerable period in late adoles-
cence,48 and is also associated with impaired brain function49 and reduced cognitive
performance50 (See Philip D. Harvey and Elizabeth C. Isner’s article, “Cognition, Social
Cognition, and Functional Capacity in Early Onset Schizophrenia,” in this issue).
Cannabis use during development of critical higher-order cognitive functioning may
produce long-term changes on the brain, as shown by studies with adult cannabis
users showing both immediate and long-term impacts on brain structure, connectivity,
148 Wright et al
and function,51–53 including cognitive performance,54,55 motivation,41 and emotional

processing.56 A recent literature review highlighted the strong connection between
early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psy-
chiatric outcomes in adulthood (in both clinical and preclinical studies).57 US Depart-
ment of Health and Human Services increased awareness of the effects of cannabis
use on cognitive functioning in adolescence and, as a consequence, the link to school
absences, dropouts, and even suicide attempts.58,59
Motivations for cannabis use in people with severe mental illness have been
debated. So-called self-medication has been proposed to suggest cannabis use as
a method of relieving mental health symptoms,60 which suggests the possibility that
the manifestations of a psychotic disorder could precede cannabis use and violate
the assumption of temporality required to show a causal relationship. However,
a fair amount of evidence against the self-medication theory has amassed61,62:
most importantly, findings of large temporal periods separating the onset of cannabis
use and the onset of psychosis or other apparent significant mental health symp-
toms.54 Several studies provide compelling evidence that cannabis use precedes
the onset of psychotic illness55 and psychotic symptoms,63 even in people with no re-
ported lifetime psychotic symptoms.61 In a 35-year follow-up of a large cohort study of
50,087 conscripts, frequent cannabis users had a 3.7-fold greater incidence of psy-
chotic outcomes compared with nonusers.64 Moreover, it has been found that 28%
to 45% of those initially diagnosed with a substance-induced psychosis convert to
schizophrenia or bipolar disorder,65–67 suggesting that frank psychotic symptoms in
the context of cannabis use could herald syndromal illness and warrant intervention.
Importantly, a strong dose effect for both frequency and THC potency on risk of psy-
chotic disorder has been well replicated. Greater frequency of cannabis use is asso-
ciated with increased risk of psychotic disorder,68 with studies showing a 50% to
200% increase in risk for participants who used most heavily.69 Youth who use
high-THC-potency cannabis show a 3-fold increase in risk of a psychotic disorder
compared with those who never used cannabis.70 Daily users of high-potency
cannabis show the highest risk of developing a psychotic disorder.70
Recently, a large study of 901 people with FEP and 1237 controls in Europe and
Brazil provided evidence to support a causal relationship between cannabis use
and new-onset psychosis. This study collected data on frequency of cannabis use
and potency of cannabis used, and amalgamated data on regional incidence of FEP
with expected concentration of THC in cannabis for sites (eg, London and Amsterdam
were considered high-potency sites and Italy and Spain were considered low-potency
sites). Daily cannabis use was associated with an increase in the risk for psychosis
nearly 4 times higher compared with never users and, for daily users of high-
potency THC cannabis, the risk was nearly 5 times higher (even when controlling for
risk factors).71 Importantly, the investigators estimate that, if high-potency cannabis
were no longer available, 12% to 50% of all FEP cases could be prevented across
the sites.
This study also highlighted that people who use cannabis and develop schizo-
phrenia do so at a significantly younger age than those who did not use cannabis,71
replicating a prior report.72 Men who used high-potency cannabis daily had psychotic
illness onset an average of 6 years earlier than non–cannabis users.73 Earlier age at
onset of cannabis use predicted earlier onset of psychotic symptoms,62 a marker of
poor outcome,74 particularly those who initiated cannabis before age 16 years.71
There remains controversy regarding whether the same factors increase risk of psy-
chosis and risk of cannabis use or whether this association is entirely caused by
cannabis increasing psychosis risk because studies have failed to take into account
the confounding of correlated genetic and environmental factors,75 including child-

hood trauma,76 tobacco,77 and urbanicity,43 which may interact synergistically to
increase risk of psychosis.78 In addition, epidemiologic data have not supported the
expected increased incidence of schizophrenia with increased cannabis use over 3 de-
cades in Australia, as would be predicted if increased cannabis use was directly
related to schizophrenia.63 Heritable variations in dopamine neurotransmission have
been found to moderate individual sensitivity to the psychotogenic effects of
cannabis. For example, the AKT1 pathway has been implicated in schizophrenia,79,80
is linked to dopamine signaling,81 and is activated by cannabinoids.82 The interaction
between Protein kinase B (AKT1) and cannabis use predicted a 2-fold increase of risk
of psychotic disorder with cannabis use,83,84 supporting a gene-environment interac-
tion. A meta-analysis of a large genome-wide association study of lifetime cannabis
use indicated that genetic risk factors for cannabis use and schizophrenia are posi-
tively correlated.85 Moreover, it has been suggested that a large portion of the asso-
ciation between cannabis abuse and schizophrenia derived from monozygotic twin
studies is related to familial factors.86 In contrast, meta-analyses have not supported
an interaction between the genes (COMT [catechol-O-methyltransferase] genotype)
and a cannabis-psychosis link,87,88 suggesting that, despite early, positive reports,
the genetic risk for schizophrenia at this particular locus predicts only a small amount
of the risk for using cannabis.41,89 Although a possible link with genetic variations does
not disregard a link between cannabis and psychosis, it does suggest that the asso-
ciation is far more nuanced than was previously thought.75
Although cannabis use has been associated with symptoms of psychosis and peo-
ple with a psychotic disorder are more likely to use cannabis than those without a psy-
chotic disorder, the question remains whether these associations represent a causal
relationship between cannabis use and psychosis in individuals without an underlying
risk. The relationship between cannabis and psychosis seems to fulfill many of the
standard criteria for causality, including temporality, biological gradient, plausibility,
evidence, consistency, and coherence.90 However, assessing the effect of dose
and exposure (biological gradient) has been challenging because THC content varies
considerably and, because of ethical and feasibility issues, assessing the impact of
long-term cannabis use has been difficult.
CLINICAL RECOMMENDATIONS
Given the changing landscape, continued research and attention to the relationship
between psychosis and cannabis is critical for identifying risk factors and informing
intervention. Risk factors for developing psychosis with cannabis use may include ge-
netic risk (eg, having a first-degree family member with schizophrenia spectrum or
bipolar disorder), male gender, frequent (daily) cannabis use (particularly of high-
potency cannabis), and younger age of initiation of cannabis use. Pediatricians and
other child and adolescent care providers can have an impact by monitoring cannabis
use, assessing for psychotic symptoms and changes in behavior, expressly advising
siblings of individuals with a history of psychosis against cannabis use, and educating
young people on the risks of cannabis use (eg, addiction, psychotic symptoms, and
negative effects on learning and memory91,92). For individuals with FEP and using
cannabis, coordinated specialty care programs can be beneficial because they
include an integrated substance use component.93 However, there is currently a
lack of evidence-based practice for addressing cannabis use in this population.94–96
The Recovery After an Initial Schizophrenia Episode (RAISE)-Early Treatment Program
(ETP) study randomized 404 individuals with FEP97 (See Abigail Wright and
150 Wright et al
colleagues’ article, “Evidence-Based Psychosocial Treatment for Individuals with

Early Psychosis,” in this issue) to receive usual care or coordinated specialty care, a
multicomponent intervention that included educational, motivational, and cognitive-
behavior strategies for clients and their families to address substance use disorders.
Although half the participants enrolled met criteria for a substance use disorder
(35% for a cannabis use disorder), there were no changes in substance use after
the program, highlighting the need for future enhancements to this component of
the intervention as well as clinician training.98
Studies with general-population adolescents have shown positive outcomes using
voucher-based contingency management to incentivize cannabis abstinence,99 appli-
cable to serious mental illness.100 Schuster and colleagues101 showed that 90% of
youth in such a program achieved biochemically validated sobriety from cannabis
for 30 days. A later study supported the effectiveness of contingency management
for achieving abstinence and showed improvements in memory with abstinence102;
however, 94% of individuals who stopped using cannabis resumed regular cannabis
use within 2 weeks.101 Abstaining from using cannabis for a prolonged time can be
difficult for youth who have become accustomed to using and may use cannabis for
several reasons, including facilitation of social activities, pleasure, stress reduction,
sleep, or as a way of feeling more independent. In such cases, recommending a
reduction in the frequency of cannabis use, a brief trial period of abstinence (as a
method to allow for evaluating the pros and cons of abstinence), or a switch to low-
potency cannabis could reduce harm, strengthen the treatment alliance, and poten-
tially lay a foundation for future abstinence from cannabis.
SUMMARY
If the current course of broadening commercialization of increasingly potent cannabis

products is maintained, clinicians are likely to begin to see effects that were rare in the
past, when cannabis use was not as widespread. Vulnerable populations, particularly
young people and individuals with genetic risk for psychosis, seem to be at increased
risk of psychosis, especially with exposure to products with higher THC potency. New
routes of administration, including vaped and edible products, and a culture of rapidly
changing norms and reduced perceptions of risk make it possible that the current,
limited knowledge of the effect of cannabis exposure on risk for psychotic illness
may no longer be accurate. Clinicians should routinely monitor for cannabis use,
changes in behavior or functioning, and presence of attenuated or frank psychotic
symptoms. There is a pressing and growing need to identify interventions with long-
term effectiveness for cannabis reduction and abstinence. The time is right for the
United States to follow Canada’s lead and invest in public health education and
messaging regarding cannabis as legal, but not safe, for younger users, particularly
of high-potency products.103 There is a need for science-based campaigns and pre-
vention programs to inform vulnerable groups of the risks, and these risks should
be reinforced by organizations at the local, state, and national level.59 Prevention
efforts, such as a reduction in the availability of high-potency cannabis and early iden-
tification of risk factors (eg, younger age of initiation, daily use, and use of high-potency
cannabis) have the potential to delay or even prevent the onset of a psychotic disorder.
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T h e Chang i n g L eg al

Landscape of Cannabis Use

INCREASED AVAILABILITY, POTENCY, AND ROUTES OF ADMINISTRATION OF

The Cannabis sativa plant has 2 primary cannabinoids: D9-tetrahydrocannabinol

Disclosure: The authors have no disclosures.

Child Adolesc Psychiatric Clin N Am 29 (2020) 145–156

EFFECTS OF CANNABIS USE IN PEOPLE WITH PSYCHOTIC DISORDERS

Cannabis use is common in people with chronic schizophrenia24 and first-episode

DOES CANNABIS CAUSE PSYCHOTIC DISORDERS?

The cause of psychotic disorders is multifactorial, influenced by genes,42 environ-

and function,51–53 including cognitive performance,54,55 motivation,41 and emotional

the confounding of correlated genetic and environmental factors,75 including child-

colleagues’ article, “Evidence-Based Psychosocial Treatment for Individuals with

If the current course of broadening commercialization of increasingly potent cannabis

1. D’Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intra-

22. Lemberger L, Weiss J, Watanabe A, et al. Delta-9-tetrahydrocannabinol. Tempo-

94. Barrowclough C, Marshall M, Gregg L, et al. A phase-specific psychological

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