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Clinical Management of Sleep and Sleep Disorders With
Cannabis and Cannabinoids: Implications to
Practicing Psychiatrists
Jaime M. Monti, MD* and Seithikurippu R. Pandi-Perumal, MSc†‡
Abstract: Phytocannabinoid derivatives are among the several com-
pounds found in the cannabis plant. The phytocannabinoid chemicals
Δ9-tetrahydrocannabinol (THC) and cannabidiol are mostly responsible
for the drug's behavioral effects. Chronic cannabis administration has been
shown to disrupt circadian rhythms and reduce the duration of the deepest
phase (stage N3) of nonrapid eye movement sleep. Cannabidiol is thought
to be responsible for the disruption of the circadian rhythm, whereas THC
is thought to be accountable for the changes in sleep architecture. The qual-
ity of one's sleep has a sign ificant impact on cannabis abstinence or relapse.
As a result, the diminished sleep-promoting efficiency of cannabis in
chronic users, as well as the resulting sleep difficulties once cannabis use
is stopped, may sabotage attempts to quit and raise the risk of relapse. In
individuals with obstructive sleep apnea who do not complain about the
treatment process known as continuous positive airway pressure, cannabi-
noids are one of the treatments being considered. In this regard, preclinical
investigations have demonstrated that combining the agent oleamide and
THC aids in the stabilization of respiration in all stages of sleep as well as
the maintenance of autonomic stability during sleep. The synthetic THC
dronabinol was found to lower the apnea-hypopnea index in a clinical inves-
tigation and is regarded safe for the short-term treatment of obstructive sleep
apnea. Patients experiencing nightmares who had been diagnosed with post-
traumatic stress disorder were given the synthetic endocannabinoid receptor
agonist nabilone. When compared with a placebo, the chemical proved help-
ful in reducing the frequency of nightmares. It is worth noting that a single
study that looked at the effects of cannabidiol on REM behavior disorder
found that symptoms improved. Based on the available findings, cannabi-
noids can be used as an alternate treatment for various sleep disorders. How-
ever, additional research is needed to corroborate the conclusions of these in-
vestigations.
Key Words: Δ9-tetrahydrocannabinol, cannabidiol, cannabis, dronabinol,
oleamide, sleep
(Clin Neuropharm 2022;45: 27–31)
Cannabis isone of the most frequently used drugs in the world.
Recent usage surveys indicate that it is used by approximately
4.5% of the population for therapeutic as well as recreational
purposes.
1
Cannabis use has been linked to a syndrome character-
ized by reduced motivation, difficulty initiating new thoughts, and
impairment of memory. Moreover, in certain predisposed individ-
uals, it can produce schizophrenia.
2,3
However, there is evidence
that cannabis may be of benefit, among others, for the treatment
of certain pain syndromes,
4,5
as an anxiolytic,
6
and for alleviating
sleep disorders.
7,8
Among the medicinal uses of cannabis, sleep
issues are one of the main indications for which it is prescribed
in countries where the drug has legal status as a medicinal agent.
9
The cannabis plant has been shown to contain more than 538
chemicals that belong to different classes, among which are ter-
penes, phytocannabinoids, and phenolic compounds (Fig. 1).
The compounds Δ9-tetrahydrocannabinol (THC) and cannabidiol
(CBD) are the 2 major phytocannabinoids included in cannabis
and are largely responsible for the rangeof cellular and behavioral
effects, which are associated commonly with the drug. These ef-
fects are mediated by the actions of 2 G protein–coupled cannabi-
noid receptors, CB1 and CB2, along with 2 endogenous ligands,
2-arachidonylglycerol, and arachidonoyl ethanolamine (ananda-
mide). The use of cannabis, either orally or by smoking, has been
shown to have a sedative effect if THC is present at low doses,
whereas at higher concentration levels, activating actions occur.
10
Taken together, these studies support the conclusion that infer-
ences regarding the sleep-enhancing or sleep-inducing effects of
cannabis need to consider the ratio of phytocannabinoids that
are present in the sample being administered, as well as the dos-
age, timing, and administration route, which collectively or indi-
vidually can influence cannabis' sleep-related effects.
CANNABINOIDS
Although the term cannabis is usually interpreted to mean a
single entity, it has a collective meaning
11
and refers to approxi-
mately 100 compounds that are called cannabinoids.
12
Among
this diverse range of compounds, THC and CBD have received
the most research attention. The receptors activated by THC pro-
duce biphasic effects, depending on the strength of the dosage that
is administered. Studies have demonstrated that low doses of THC
can have anxiolytic effects while high dosages can lead to panic
symptoms.
13
Compared with THC, the other major cannabinoid,
CBD, does not have these psychoactive effects and has been under
study as an alternative treatment for psychosis.
13,14
SLEEP AND CANNABIS
Studies of the sleep-related effects of cannabis have shown
mixed results on sleep architecture and circadian rhythms. In this
respect, it has been established that chronic administration of can-
nabis can shorten the duration of the deepest phase of nonrapid
eye movement sleep and can impair circadian rhythms.
15
Some
evidence has suggested that microglia BV-2 cells, which are pres-
ent in the central nervous system, may at least partially mediate
these effects. However, this mediation is differentially affected
*Department of Pharmacology and Therapeutics, School of Medicine Clinics
Hospital, University of the Republic, Montevideo, Uruguay; †Somnogen
Canada, Inc, Toronto, Canada; and ‡Saveetha Medical College and Hospitals,
Saveetha Institute of Medical and Technical Sciences, Saveetha University,
Chennai, India.
Address correspondence and reprint requests to Seithikurippu R. Pandi-
Perumal, MSc, Somnogen Canada, Inc, College St, Toronto, Canada;
E‐mail: pandiperumal2022@gmail.com
https://orcid.org/0000-0002-8686-7259
S.R.P. is a stockholder and the president and chief executive officer of Somnogen
Canada, Inc, a Canadian Corporation. He declares that he has no competing
interests that might be perceived to influence the content of this article. This
does not alter the authors' adherence to all the journal policies. He receives
occasional royalty for the volumes that he edited for other publishers.
No data sets were generated or analyzed during the current study.
The authors contributed equally to this study.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/WNF.0000000000000494
REVIEW ARTIC LE
Clinical Neuropharmacology •Volume 45, Number 2, March/April 2022 www.clinicalneuropharm.com 27
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
by the presence of CBD or THC. In related in vitro studies, mi-
croglia BV-2 cells from mice were treated with either CBD or
THC, and 2 hours later were left without further treatment or were
treated with lipopolysaccharides (LPS) for another 4 hours. Tran-
scriptome analysiswas then performed on the microglial cells that
had been pretreated with THC or CBD, either with or without
LPS. The investigators found that with or without stimulation by
LPS, CBD produced significant effects on circadian genes, includ-
ing upregulation of the clock genes Arntl, CRY2, and PER1. In ad-
dition, deregulation of clock genes, including effects on RevErbα,
RORA, CREBBP, RORB, AFT4, NFIL3, and AFT5, was also ob-
served within BV-2 microglial cells. Similar effects, however,
were not shown in cells that were treated with THC, thus implicat-
ing CBD as the primary cannabinoid responsible for the disrup-
tion of circadian regulation, while THC would be accountable
for the changes in sleep architecture.
16
This evidence thus indi-
cates that via the actions of CBD, cannabis disrupts circadian
rhythms and, by extension, the sleep/wake cycle. Consistent with
these findings are clinical studies showing that chronic cannabis
use is associated with poor sleep quality, disrupted sleep, and
sleep-related disorders.
17
Of note, cannabis usage disrupts the sleep cycle and other
brain functions. The sleep disruption caused by cannabinoids, par-
ticularly THC, interferes with both memory and information pro-
cessing. Disturbed sleep and other withdrawal symptoms have
been reported by adolescent and adult cannabis users, even after
45 days ofhaving ceased the use of the substance.
18
Moreover, ob-
jective measures have shown direct effects of cannabis use on
sleep quality. Accordingly, Mondino et al
10
found that when ad-
ministered to nonusers of cannabis, vaporized THC produced dis-
ruptions to polysomnographic measures of sleep spindle coher-
ence, one of the signs of normal cognitive processing. An added
layer of complexity that influences predictions of cannabis effects,
especially among individuals who acquire the substance in its un-
processed form and use it without medical supervision, is that can-
nabinoid concentration differs in various parts of the plant. In gen-
eral, the leaves/flowers of cannabis contain more cannabinoids
than the stems. These variations may differ further depending on
the species of cannabis, of which there are 3: hybrid, indicia,
and sativa. The effects of these different species of cannabis on
sleep continue to remain underresearched. To address the limita-
tions of knowledge in this area, Belendiuk et al
18
studied the ef-
fects of the different cannabis species on sleep. The investigators
recruited 81 study hospital patients who described themselves as
cannabis users, reported that they had experienced insomnia or
nightmares, and had used cannabis for self-treatment of these con-
ditions in the year preceding the study's inception. Sleep quality
measures were based on before/after comparisons of results from
overnight polysomnography/sleep diaries. The investigators com-
pared the effects on nightmare reduction of the indica and sativa va-
rieties of cannabis, which were administered for 3 weeks to 6 months.
For the control of insomnia symptoms, the cannabinoid agents, CBD
or THC, were administered in separate conditions, and their ef-
fects were compared. The study results revealed that the indica
and sativa varieties of cannabis were equally effective for reducing
nightmares in some patients but exacerbated symptoms in others.
Lower doses of THC were found to enhance sleep quality,
whereas increases in THC concentrations were associated with
less enhancement or actual increases in insomnia symptoms.
18
SLEEP AND CANNABIS RELAPSE
Sleep quality is considered to be a major factor affecting us-
age cessation or relapse in the use of cannabis. In approximately
FIGURE 1. A, Cannabis indica plant. B, Cannabis sativa plant. C, Cannabis bud. D, Chemical structure of cannabidiol and
tetrahydrocannabinol. E, Chemical structure of dronabinol. F, Chemical structure of anandamide and oleamide.
Monti and Pandi-Perumal Clinical Neuropharmacology •Volume 45, Number 2, March/April 2022
28 www.clinicalneuropharm.com © 2022 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
65% of users, low-quality sleep is identified as the primary reason
for relapse. As compared with nonusers or those who only use
cannabis occasionally, cannabis users who have developed toler-
ance need higher dosages of the drug to overcome, for example,
abnormal sleep latency problems. The diminishing sleep-
promoting effectiveness of cannabis among long-term users, as
well as the ensuing sleep difficulties after cannabis use is termi-
nated, may therefore interfere with cessation attempts and increase
the likelihood of relapse.
19
In 1 study, the effects of cannabis on
sleep were determined among psychiatric outpatients who were
being treated for problems with sleep and anxiety. The study par-
ticipants received a 25-mg dose per day of CBD in capsule form
over 30 days. The Pittsburg Sleep Quality Index was used to mea-
sure sleep quality and the Hamilton Anxiety Rating Scale was
used for measuring anxiety amount. The investigation showed that
CBD was more effective for producing sustained anxiety reduc-
tion than it was for improving sleep, although sleep quality did im-
prove mildly.
20
CANNABIS AND SLEEP-RELATED DISORDERS
Insomnia and Cannabis
Some recent studies have focused on which dosages of CBD
have optimal sleep-inducing effects. In 1 study, middle-range to
high dosages of CBD were found to increase the total percentage
of sleep. In addition, the middle-range doses of the compound de-
creased the latency of REMS, whereas the higher doses induced
the opposite effect. Recent findings have suggested that CBD exerts
its effect on sleep quality via its anxiolytic properties. It is also evident
from the studies that the concentration and amount of dose of the ad-
ministered cannabinoids, as well as the route of administration, have
differential effects on the separate components of insomnia.
21
In 1 study of “protective behavioral strategies”(PBS), the
frequency of cannabis use among college students who also had
insomnia symptoms was investigated. Low-dose cannabis PBS re-
ports indicated higher symptoms of insomnia (Wong et al,
22
2019). It was found that some study respondents increased their
use of cannabis as a means for dealing with sleep problems. In ad-
dition, students who used lower doses of cannabis as a PBS re-
ported having symptoms of insomnia that were greater than
among other groups.
22
Cannabis and Sleep Apnea Treatment
Sleep apnea is a sleep-related breathing difficulty for which
the criterion standard of treatment is a procedure known as contin-
uous positive airway pressure (CPAP). The method involves wear-
ing a facialmask throughout the night. The mask is connected to a
pump that forces air into the patient's upper or lower airway pas-
sages. A difficulty with the treatment is that it is uncomfortable
for many patients and often results in noncompliance with the
treatment. Several alternative therapies have been sought for this
sleep condition. In this respect, the prescription of cannabinoids
is one of the options that are under consideration. Initial animal
model studies, as well as those among humans, suggested that
THC administration could produce short-term relief for sleep ap-
nea. Carley et al
23
studied the effects ofTHC in rats and found that
it helped stabilize the respiratory pattern at all stages in a dose-
dependent pattern. Although the expression of central sleep apnea
in rats is somewhat similar to that of humans, the symptom severity
is more pronounced during REMS in central and obstructive apnea
patients. The compound oleamide (cis-9,10-octadecenoamide) has
been considered for the treatment of sleep apnea. It is a derivative
of oleic acid with a nitrogen group and seems to be naturally asso-
ciated with sleep. Its injection induces sleep and activates the same
receptors as THC. When combined with the agent oleamide, THC
was found to help in respiration stabilization in all sleep stages and
to maintain autonomic stability during sleep in the preclinical study.
Oleamide and THC were also found to help in the blockade of
serotonin-induced sleep apnea exacerbation. The investigators
concluded that both endogenous and exogenous cannabinoids
can help in reducing symptoms of sleep-related apnea.
23
Another
study focused on regulated cannabinoid use for treating sleep ap-
nea. The agent dronabinol was investigated in phase II, fully
blinded, randomized placebo-controlled clinical trials for the treat-
ment of moderate or severe obstructive sleep apnea (OSA) and
was found to be well tolerated and safe. Dronabinol was also
found to reduce the apneic-hypopnea index in a dose-dependent
manner, with patients who received higher doses showing more
satisfactory results. One single adverse effect at a serious level
was vomiting and diarrhea. The investigators concluded that
dronabinol at 2.5 to 10 mg daily doses can be used safely for
the short-term treatment of OSA and for improving the apneic-
hypopnea index.
24
It should be mentioned that in 1 American ju-
risdiction, cannabis is now recognized as an acceptable alternative
for treating OSA. The Minnesota Department of Health has issued
a position statement that medical cannabis can be prescribed for
patients who do not qualify for or who cannot tolerate CPAP ther-
apy.
25
At the time of thiswriting, the American state of Minnesota
is the first state to have officially recognized cannabis as a non-
CPAP treatment alternative for OSA. Different concentrations of
the liquid extract are available in the state and may be taken ad
libitum.
HARMFUL EFFECTS OF CANNABIS AND
DRONABIDOL IN SLEEP APNEA PATIENTS
Several adverse effects have been observed after the use of
dronabinol as a treatment for OSA or other sleep problems. In this
respect, increases in the rate of motor vehicle crashes have been
reported after the use of dronabinol, and thus, treatment regimens
based on the sole use of this agent for, for example, OSA, or its
use in combination with CPAP, must be implemented with due
recognition of its risk potential. In this respect, patients should
be advised to refrain from driving during treatment. It has also
been observed that increases in daily food and caloric intake occur
after the use ofcannabis by healthy volunteers. In addition, weight
gain has also been observed in patients with cancer and HIV/
AIDS who have been taking dronabinol.
25
Cannabis and REM Behavior Disorder
There is only a single study available that has measured the
effect of cannabinoids on REM behavior disorder. Chagas et al
26
(2014) investigated the effect of CBD on REM behavior disorder
and reportedthat a reduction of symptoms occurred. Nevertheless,
more controlled research and clinical trials need to be conducted
to validate this treatment method.
Cannabis and Other Sleep-Related Conditions
Nightmares, which occur as an associated symptom of post-
traumatic stress disorder (PTSD), have been the focus of research
on the potential ameliorative effect of cannabinoids on this sleep
disorder. Initial clinical trials suggested that cannabis reduced
the frequency of nightmares and increased sleep quality.
21
How-
ever, several adverse effects were also reported by the research
participants, including dryness of the mouth, headache, and
lightheadedness. The occurrence of these adverse effects requires
further investigation with controlled studies.
Jetly et al
27
(2015) conducted a double-blind, placebo-
controlled trial on the effectiveness of nabilone, a synthetic
Clinical Neuropharmacology •Volume 45, Number 2, March/April 2022 Management of Sleep and Sleep Disorders
© 2022 Wolters Kluwer Health, Inc. All rights reserved. www.clinicalneuropharm.com 29
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
endocannabinoid receptor agonist, on nightmares among soldiers
who had been diagnosed as having PTSD. The investigation con-
cluded that the drug was effective for reducing the frequency of
nightmares when compared with placebo. In another study of
the effects of nabilone, the drug was evaluated in an open-label
clinical trial for its ability to reduce treatment-resistant nightmares
among subjects who were experiencing PTSD. The investigators
found that most patients experienced either nightmare cessation
or nightmare intensity reduction. Some patients also showed im-
provements in total sleep time, sleep quality or night sweats, or a
reduction in daytime flashbacks.
28
In a further study of the impact of cannabis extracts on sleep-
related effects, combinations of THC and CBD were evaluated for
their influence on nocturnal sleep, memory, early-morning perfor-
mance, and daytime sleepiness. A 4-way crossover design was
used that included tests of a placebo, 5-mg THC combined with
5-mg CBD, 15-mg THC (solo use), and 15-mg THC combined
with 15-mg CBD. The study showed that 15-mg THC (solo use)
reduced sleep latency but increased daytime sleepiness and mood
lability. In addition, next-morning memory was impaired. Con-
cerning sleep architecture, the administration of combinations of
THC and CBD (5-mg THC plus 5-mg CBD, and 15-mg THC plus
15-mg CBD) were associated with decreases in stage 3 sleep and
increases in wakefulness.
29
Cannabis Withdrawal and Sleep
Disturbed sleep and lucid dreaming are one of the main
symptoms of cannabis withdrawal, which is reported in 67% to
73% of adults and 33% to 43% of adolescents. It has been estab-
lished that sudden cannabis use cessation leads to a decrease in
sleep time, sleep quality, and REM sleep duration. Also waking
up from sleep during the night and other sleep-related disturbances
have been observed after cannabis cessation. Thus, the overall re-
sults from different studies demonstrated that terminating cannabis
use is associated with poor sleep and other sleep-related distur-
bances in users.
12
Some reports have suggested that these distur-
bances can be reduced after the adjunctive use of hypnotic medi-
cations such as zolpidem.
30
Lithium and nitrazepam have shown
some limited effectiveness for treating sleep disturbances after
cannabis cessation.
31
In cases of sustained abstinence, conflicting reports have
been provided about the effects on REM sleep. It has been ob-
served that REM sleep time increases/rebounds during the early
stages of abstinence, but as abstinence progresses, REM sleep de-
creases. The main reason for this continued worsening of sleep
with decreasing in REM sleep is not clear and will require clarifi-
cation with further studies.
32
CONCLUSIONS
Many unsolved concerns remain, as noted throughout this re-
view, presenting significant potential for both scientific and clini-
cal research in sleep and neuropsychiatry. This narrative review
lays out a practical framework for the level of care required for
safe and responsible prescribing and close monitoring of this ther-
apeutic class of medications, including an understanding of its
abuse potential as well as therapeutic potentials, risk mitigation
strategies, tailored intervention, dosing and tapering, and with-
drawal adverse effects. There is a need for a more in-depth and nu-
anced grasp of concepts, accurate diagnosis, mechanisms, modal-
ities of treatment, and practicality. This overview will help practitioners
understand the benefits and drawbacks of using cannabinoid-
based therapeutics for sleep management, as well as the indica-
tions and data derived from diverse research findings, to ensure
optimal adoption in clinical practice. Finally, further clinical trials
evaluating the long-term efficacy and safety of cannabinoid-based
pharmaceuticals approved for adults are needed to successfully treat
complex insomnia, OSA, and REM behavior disorder.
ACKNOWLEDGMENTS
The authors thank Prof. Raphael Mechoulam, Lionel
Jacobson Professor of Medicinal Chemistry at the Hebrew Uni-
versity in Jerusalem, Israel, for providing critical feedback on an
earlier version of this article and for his insightful comments that
added to the publication's overall quality.
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