Page 54 - CASA Bulletin of Anesthiology 2021, Vol 8, No. 6 (1)

CASA Bulletin of Anesthesiology

demonstrated that cannabinoids and endocannabinoids could modulate both voltage-gated ion
channels (calcium, sodium, and potassium) and ligand-gated ion channels (serotonin type 3,
nicotinic acetylcholine, and glycine receptors), as well as cell membrane proteins and
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neurotransmitter receptors. The exact mechanism of such modulation is not clear and more
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studies are warranted to provide potential treatment targets.

Although heavier cannabis users are more likely to develop CWS, some individuals develop
CWS with short term, less than daily exposure. This raised the question whether genetic
background predisposes certain individuals to withdrawal. Earlier genetic epidemiology studies
focused on CUD and concluded that it was highly heritable. For example, the San Francisco
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family study found that not only cannabis use, abuse, and dependence, but also age of first use
were all heritable. The same study also found that certain symptoms of CWS especially
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nervousness was heritable, too. More studies have been conducted since the inclusion of CWS in
DSM-5. Twin study in Australia by Verweij and colleagues found that approximately 50% of
variances in withdrawal were attributable to additive genetic factors (68% in abuse/dependence).
The remaining variances were mainly due to unshared environmental influences. The authors
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concluded that CWS is moderately heritable. More importantly, the genetic influences on
cannabis withdrawal almost completely (99%) overlapped with those on abuse/dependence. This
is reassuring for genetic informed studies that did not assess withdrawal.

Treatment

Cannabis withdrawal is considered a negative reinforcement for relapse and patients have
reported using other substances such as nicotine and alcohol as a reliever. 6, 7, 10, 37 Therefore, much
effort has been made to identify treatment options for CWS.

Despite the growing interests and positive results from small-scale trials, there is no approved
pharmacological treatment for CWS, or CUD. Current candidates for CWS are either through the
cannabinoid receptor, or other neurotransmitters. The most studied cannabinoids are THC and
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cannabidiol (CBD). While THC has psychoactive activity thus a narrow therapeutic window,
CBD lacks psychotropic property and is considered a promising candidate for CUD and CWS
treatment. Animal study showed that CBD alleviated withdrawal symptoms and reversed gene
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expression changes induced by cannabis withdrawal including opioid μ receptor (Oprm1),
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cannabinoid CB1 receptor (Cnr1) and CB2 receptor (Cnr2) in the nucleus accumbens in mice.
Further study is necessary to determine whether CBD has similar therapeutic effect in human
subjects. THC was able to decrease the intensity of withdrawal symptoms in several studies,
however, did not show efficacy in terms of abstinence maintenance in a recent metanalysis.
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Among non-cannabinoid agents, bupropion caught early attention due to its approval for
tobacco cessation. Although cannabis and nicotine withdrawal share notable overlapping
symptoms, bupropion was reported to worsen CWS symptoms. Serotonin reuptake inhibitors
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(SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) produced mixed results based
on both literature review and metanalysis. 39, 40 Some studies reported CWS symptom alleviation
with SSRIs and SNRIs, while others showed no differenced as compared to placebos. Treatment
with neither class resulted in increased likelihood of abstinence. Anticonvulsants such as
gabapentin and topiramate showed promising results with decreased cannabis use and symptom
intensity. However, studies so far are limited due to low power and poor completion rate.
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Larger scale, fully powered studies are necessary to provide more conclusive evidence for the
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