A primer on medicinal cannabis safety and potential adverse effects
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Focus | Clinical
A primer on medicinal
cannabis safety and
potential adverse effects
Jonathon C Arnold IT HAS BEEN FIVE YEARS since medicinal of recreational cannabis, whereas CBD
cannabis was legalised in Australia, and is not intoxicating.6
we are now seeing a rapid escalation in the Many products contain different
Background
Medicinal cannabis prescriptions are
use of medicinal cannabis products within ratios of CBD and THC, for example
on the rise in Australia, and general legal pathways.1 The aim of this review is 10:1, 20:1 or 50:1 (Figure 1). Some
practitioners will increasingly encounter to provide a primer on the safety issues products will contain CBD or THC alone
patients using cannabis-based products. that need to be considered with medicinal as highly purified active pharmaceutical
cannabis. Historically, the toxicology ingredient (API)–containing formulations
Objective
The aim of this review is to provide a
of cannabis has been viewed within that are often referred to as isolates.
primer on the safety issues that need the prism of its recreational use, where These formulations do not contain other
to be considered with medicinal cannabis. it was once deemed a very dangerous cannabinoids, terpenes or flavonoids.
and highly addictive drug. However, Other products contain CBD and/or
Discussion
recently the United Nations accepted THC with a ‘full-spectrum’ of cannabis
Medicinal cannabis is generally well
tolerated when dosed appropriately. recommendations of the World Health plant constituents including other
It is important for doctors to consider Organization (WHO) to remove cannabis phytocannabinoids (eg cannabichromene,
carefully the ∆9-tetrahydrocannabinol from Schedule IV of the Single Convention cannabigerol, ∆9-tetrahydrocannabinolic
(THC) and/or cannabidiol (CBD) content on Narcotic Drugs, in recognition of the acid or cannabidiolic acid) as well as
of the products. CBD is not intoxicating fact that cannabis has legitimate medicinal terpenes and flavonoids, all of which may
and has fewer safety concerns than THC.
properties and a more acceptable safety have therapeutic effects.7–10 To ascertain
When commencing a new medicinal
profile than previously thought.2–5 exactly what is contained in a given
cannabis product, the recommendation
is to prescribe relatively low doses and medicinal cannabis product, a request
slowly up-titrate the dose. This aims to can be made to the manufacturer for a
minimise dose-related toxicities and the What is medicinal cannabis? certificate of analysis. Therapeutic daily
potential for drug–drug interactions with Medicinal cannabis is not just a single doses of CBD are typically between 50 mg
concomitant medications. THC found in entity and encompasses a diversity and 1500 mg, which are greater than
medicinal cannabis may acutely impair
of products.1 Cannabis contains those for THC, which are between 5 mg
cognitive function and is best not
prescribed to children or adolescents
approximately 500 molecules, including and 20 mg.1
unless the benefits outweigh the risks. approximately 100 plant-derived cannabis When evaluating the safety profile
THC-containing cannabis products compounds (phytocannabinoids), of medicinal cannabis products, it is
should not be prescribed to individuals terpenes and flavonoids. The important to consider the relative THC
with angina or a history of myocardial best-characterised phytocannabinoids and CBD content, as CBD generally
infarction, or to those who have a are ∆9-tetrahydrocannabinol (THC) has fewer safety concerns than THC.
personal or family history of psychosis.
and cannabidiol (CBD). THC is Indeed, on the basis of CBD’s excellent
responsible for the intoxicating effects safety profile,11 the Therapeutic Goods
© The Royal Australian College of General Practitioners 2021 Reprinted from AJGP Vol. 50, No. 6, June 2021 345
Focus | Clinical A primer on medicinal cannabis safety and potential adverse effects
Administration (TGA) recently approved (Sativex) and CBD (Epidyolex). Sativex is an sesame oil and is devoid of THC. Extensive
a legal pathway for low-dose CBD oromucosal spray formulation containing preclinical and clinical toxicological data
formulations to be provided over the equal doses of both THC and CBD and is were collected on these approved cannabis-
counter as Schedule 3 pharmacist-only indicated for treating spasticity associated based medicines and were included in
medications for conditions that do not with multiple sclerosis. Sativex contains their registration dossiers. The nabiximols
require medical oversight. However, no two cannabis plant extracts in peppermint gives rise to acute adverse effects
product has yet been formally approved oil corresponding to 27 mg/mL THC and indistinguishable from THC alone.3,4
within the pathway, and the onus is on 25 mg/mL CBD. Epidyolex is indicated
companies to provide scientific data to to treat intractable childhood epilepsies Unapproved products
the TGA to support registration. and is taken orally via syringe. Epidyolex The rest of the cannabis-based
was recently listed on the Pharmaceutical medicines on the market are available
Approved products Benefits Scheme (PBS) and its cost as ‘unapproved’ products via the
The only cannabis-based medicines that subsidised by the Australian Government. Special Access or Authorised Prescriber
are registered by the TGA are nabiximols Epidyolex contains 100 mg CBD/mL of Schemes.1 As at 2 March 2021, the TGA
has approved 99,000 applications via
Special Access Scheme (SAS) category B
for patients to access unapproved
medicinal cannabis products. There are
approximately 150 unapproved medicinal
cannabis products on the market that
must abide by the Australian standard
for medicinal cannabis (TGO 93), which
aims to ensure the products have reliable
cannabinoid content and are free of toxic
contaminants. CBD-dominant products
(≥98% pure CBD) are Schedule 4,
prescription-only medications when
prescribed to patients with conditions that
require medical oversight. In contrast,
products containing THC are Schedule 8
controlled medications, meaning
prescriptions require state or territory
health department approvals as THC is
classified as a drug of dependence.1
Acute adverse effects
Cannabis containing THC
Cannabis is a relatively safe drug, and it
is not associated with fatal overdoses. On
the basis of animal lethal dosing studies,
the human lethal dose of THC has been
extrapolated to be >15,000 mg.12 This
highlights that THC has a very wide safety
margin, as this lethal dose is 750 times
greater than a typical intoxicating dose of
20 mg. Unlike the opioids, cannabis does
Figure 1. The acute and long-term adverse effects of medicinal cannabis. Medicinal not cause respiratory depression because
cannabis is generally well tolerated when appropriate doses are used. The products contain of a paucity of cannabinoid receptor
∆9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD). There are more safety concerns expression in the brainstem.
regarding THC than CBD. Medicinal cannabis containing THC is contraindicated in patients
A major issue with acute dosing
with angina or a history of myocardial infarction, or a personal or family history of schizophrenia or
psychotic-related disorders. Vigilance is required when medicinal cannabis is prescribed to patients of medicinal cannabis products that
taking conventional medications because of the potential for drug–drug interactions (DDIs). contain THC is intoxication. A typical
Figure created with Biorender.com intoxicating dose of THC in a person who
has never used cannabis previously is
346 Reprinted from AJGP Vol. 50, No. 6, June 2021 © The Royal Australian College of General Practitioners 2021A primer on medicinal cannabis safety and potential adverse effects Focus | Clinical
approximately 10 mg, although caution is warfarin, tacrolimas and methadone by with tobacco, which further complicates
warranted as some patients may be more magnifying the adverse effects of these interpretation of studies on the harms
sensitive.1 When intoxicated, patients medications.24–27 Accordingly, careful of recreational cannabis.34 It must also
may experience euphoria and anxiolysis upwards dose titration of CBD-dominant be recognised that most of the evidence
as well as enhanced sensory perceptions. products is best practice, especially on the adverse effects of recreational
Higher doses of THC are associated in patients taking other medications. cannabis use relies on observational,
with anxiety, panic and disorientation It is important that doctors carefully population-based studies, which may
in some individuals. Subtle cognitive monitor patients for any side effects of include multiple confounders and cannot
deficits such as impaired attention and their concomitant medications when unequivocally infer causation. All these
short-term memory impairment may be commencing medicinal cannabis products. limitations must be kept in mind when
experienced.13 THC-containing cannabis evaluating the existing evidence. In time
may impair driving performance.14 THC Effects on the cardiovascular system there will be better evidence for any
in medicinal cannabis may also cause the It would be prudent to advise against the long-term health impacts of medicinal
classic ‘munchies’ effect by enhancing use of medicinal cannabis containing cannabis more specifically, which is likely
appetite. Dry mouth and dizziness are THC in patients with angina or a history to be safer than recreational cannabis.
common side effects. Cannabis may also of myocardial infarction. Cannabis An excellent evaluation of the long-term
cause nausea and vomiting.15 containing THC can cause tachycardia, toxicity of THC comes from a placebo-
Cannabis may provoke a transient and there are reports of cannabis-induced controlled randomised controlled trial
psychosis in some healthy participants myocardial infarction.28 A meta-analysis (RCT) in 329 patients with multiple
because of its THC content,16,17 although of studies reported that acute THC sclerosis in which THC was administered
these reactions are rare. In a study that increases heart rate by eight beats per daily to participants for three years (up to
examined emergency hospital admissions minute, and that the effects are dose 28 mg/day).35 This trial concluded that
across 14 European countries over a dependent.29 With repeated dosing, the THC has an acceptable safety profile
six-month period, only seven cases of tachycardic effects diminish because of with low-to-moderate toxicity and a low
cannabis-induced psychosis were found tolerance. Interestingly, some studies incidence of serious adverse events;
when cannabis was the only drug used.18 in healthy participants and patients there was no difference in the total
CBD-dominant cannabis products may with hypertension showed longer-term number of adverse events in the placebo
also contain THC, and so it is important exposure to THC or cannabis reduced group versus the THC group.35 The most
that doctors consider the THC content in blood pressure.30,31 Acute or repeated common adverse effects of THC when
their dosing recommendations to avoid dosing with CBD does not appear to compared with placebo were dizziness
THC-related intoxication. affect heart rate or blood pressure.32 and light-headedness, and dissociative
thinking or perception disorders. More
Cannabis containing CBD research is needed to address the
CBD administered as a highly purified Long-term adverse effects long-term effects of CBD. Long-term
substance is very safe and not intoxicating. There is a need for more safety and adverse effects of CBD were reported
Phase 1 studies demonstrate that it is well pharmacovigilance studies with in patients with childhood epilepsy
tolerated even at very high doses (up to medicinal cannabis products. Most receiving Epidyolex under an expanded
6000 mg).19 The most common side effect evidence on the potential long-term access program for up to 144 weeks.36
of CBD is diarrhoea.20 The main area of adverse effects of cannabis derives The adverse effects were similar to those
concern related to CBD’s safety is the from its recreational use, which may not reported in shorter-term trials, with the
potential for drug–drug interactions that readily apply to medicinal cannabis use. most common adverse effects being
might occur when CBD is administered Recreational cannabis is unregulated somnolence (30%) and diarrhoea (24%).
with conventional pharmacotherapies. and contains high concentrations of
CBD is an inhibitor of cytochrome P450 THC, which is exploited for the specific Cognitive function
(CYP450) enzymes such as CYP3A4 and purpose of intoxication.33 However, Acute use of cannabis containing THC
CYP2C19, and high doses of CBD used medicinal cannabis is regulated by may impair cognitive and memory
to treat childhood epilepsies increase specific manufacturing standards and function, especially when intoxicating
plasma concentrations of anticonvulsant is prescribed under medical supervision doses of THC are administered. However,
medications, particularly clobazam, using strict dosing regimens. Further, evidence for long-term and enduring
which can lead to increased sedation.21–23 studies on the adverse effects of cognitive and memory dysfunction is
Co-administration of CBD with valproate recreational cannabis involved smoking highly contentious. A systematic review
is suspected to cause an elevation of as the dominant route of administration, and meta-analysis of 69 cross-sectional
liver transaminases. CBD has also been which is not recommended in a medicinal studies in a recreational context found
observed to cause clinically significant cannabis setting. Cannabis smoking also only a small effect size for reduced
pharmacokinetic interactions with encompasses mixing cannabis flower cognitive functioning in people who used
© The Royal Australian College of General Practitioners 2021 Reprinted from AJGP Vol. 50, No. 6, June 2021 347Focus | Clinical A primer on medicinal cannabis safety and potential adverse effects
cannabis frequently at high doses for an Individuals with dependence may also Cannabis hyperemesis syndrome
extended period.37 The study’s authors experience a cannabis withdrawal There are rare case reports of long-term,
questioned the clinical significance of syndrome when they abstain from heavy recreational cannabis use promoting
the cognitive impairments for most cannabis use, although this is mild when severe nausea and vomiting, which is
people who use cannabis. There was no compared with syndromes associated known as the cannabis hyperemesis
association between cannabis use and with alcohol, benzodiazepines or heroin. syndrome.59–61 The syndrome is associated
reduced cognitive function in studies in Cannabis withdrawal promotes symptoms with compulsive bathing behaviour and
which the participants were drug-free for of insomnia, depression, anxiety and resolves on cessation of cannabis use.
>72 hours, thus suggesting any cognitive gastrointestinal disturbance that may Cannabis hyperemesis syndrome appears
impairing effects were reversible. last 48–72 hours.50 Overall, cannabis has to be mediated by THC, and there is no
Some small-scale studies have mild-to-moderate addictive liability. The evidence of CBD causing the syndrome.
reported structural abnormalities in issue of cannabis dependence in those There have been no reports of cannabis
the brains of people who used cannabis using it purely for medicinal purposes hyperemesis occurring in patients taking
heavily over a long period of time in a has yet to be adequately studied. It medicinal cannabis, which may be due to
recreational setting.38–40 However, these may be that medicinal use of cannabis, lower doses of THC being prescribed.
effects were not replicated in larger where intoxication is not the primary
studies that controlled for confounding aim, may be less susceptible to any
variables (eg alcohol use, tobacco use).41–43 habit-forming effects of THC. CBD is Conclusion
A high-profile article reported that not habit-forming.51 Medicinal cannabis is generally well
long-term cannabis use commencing tolerated, but the science related to its
in adolescence reduced IQ.44 However, Psychosis and psychosis-related potential adverse effects is in its infancy.
there were no reductions in IQ in those disorders What has been learnt from the adverse
who commenced use in adulthood and Acute cannabis-induced psychosis effects of recreational cannabis use may
had been abstinent for a year, suggesting has been documented but is rare. not readily apply to medicinal cannabis,
adult use does not have any residual Of more concern is the link between which is administered under medical
effects on cognitive function. Notably, cannabis use and schizophrenia. Human supervision using strict dosing regimens
the same authors more recently revised population studies suggest that there and non-smoking routes of administration.
their conclusions, stating that adolescent is a dose-dependent increase in the High-quality safety studies are needed,
cannabis use was not responsible for risk of developing schizophrenia in especially of unapproved medicinal
the reductions in IQ, but rather it was those who commence cannabis use cannabis products, which are increasingly
explained by familial factors.45–47 during adolescence as a recreational being used in the community. New,
In conclusion, the prescription of drug.52,53 Some argue against the view unforeseen adverse events may arise in
medicinal cannabis for adults is unlikely that cannabis causes schizophrenia by this rapidly evolving area of medicine,
to have irreversible adverse effects on citing that the rapid increase in global and pharmacovigilance measures must
cognitive function. Patients should be cannabis use in recent decades has not be implemented to ensure patient safety.
monitored for acute impairing effects on translated into an increased incidence
cognition that might arise with medicinal of schizophrenia.54–56 Most agree
cannabis containing THC. The effects of that cannabis does not directly cause Key points
CBD products that do not contain THC schizophrenia, but rather cannabis • Medicinal cannabis is generally
would be of less concern, as CBD does may be permissive to schizophrenia in well tolerated when prescribed at
not appear to affect cognitive function.48 individuals who are already vulnerable. appropriate doses; CBD has fewer
It must be emphasised that the vast safety concerns than THC.
Drug dependence majority of people who use cannabis • It is recommended that patients are
Repeated recreational use of street will never develop a psychotic disorder. prescribed lower doses, which are
cannabis for the sole purpose of It has been estimated that 4700 young slowly up-titrated (beginning with
intoxication may lead to cannabis people would need to be dissuaded from THC dosesA primer on medicinal cannabis safety and potential adverse effects Focus | Clinical
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