Article published online: 2024-03-01

Review Thieme

Cannabinoids in the Treatment of Selected Mental Illnesses:

Practical Approach and Overview of the Literature

Authors
Kirsten R. Müller-Vahl

Affiliations Abs trac t

Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Although an increasing number of patients suffering from men-
Hannover Medical School, Hannover, Germany tal illnesses self-medicate with cannabis, current knowledge
about the efficacy and safety of cannabis-based medicine in
Keywords psychiatry is still extremely limited. So far, no cannabis-based
cannabis-based medicine, cannabinoids, psychiatry, THC, finished product has been approved for the treatment of a
CBD mental illness. There is increasing evidence that cannabinoids
may improve symptoms in autism spectrum disorder (ASD),
received 17.09.2023 Tourette syndrome (TS), anxiety disorders, and post-traumat-
revised 12.01.2024 ic stress disorder (PTSD). According to surveys, patients often
accepted 17.01.2024 use cannabinoids to improve mood, sleep, and symptoms of
published online 01.03.2024 attention deficit/hyperactivity disorder (ADHD). There is evi-
dence suggesting that tetrahydrocannabinol (THC) and THC-
Bibliography containing cannabis extracts, such as nabiximols, can be used
Pharmacopsychiatry 2024; 57: 104–114 as substitutes in patients with cannabis use disorder.
DOI 10.1055/a-2256-0098 Preliminary evidence also suggests an involvement of the en-
ISSN 0176-3679 docannabinoid system (ECS) in the pathophysiology of TS,
© 2024. The Author(s). ADHD, and PTSD. Since the ECS is the most important neuro-
This is an open access article published by Thieme under the terms of the modulatory system in the brain, it possibly induces beneficial
Creative Commons Attribution-NonDerivative-NonCommercial-License,
permitting copying and reproduction so long as the original work is given effects of cannabinoids by alterations in other neurotransmit-
appropriate credit. Contents may not be used for commercial purposes, or ter systems. Finally, the ECS is an important stress management
adapted, remixed, transformed or built upon. (https://creativecommons.
org/licenses/by-nc-nd/4.0/). system. Thus, cannabinoids may improve symptoms in patients
Georg Thieme Verlag KG, Rüdigerstraße 14, with mental illnesses by reducing stress.
70469 Stuttgart, Germany Practically, cannabis-based treatment in patients with psychi-
atric disorders does not differ from other indications. The start-
Correspondence ing dose of THC-containing products should be low (1–2.5 mg
Prof. Kirsten R. Müller-Vahl THC/day), and the dose should be up-titrated slowly (by
Clinic of Psychiatry, Social Psychiatry and Psychotherapy 1–2.5 mg every 3–5 days). The average daily dose is 10–20 mg
Hannover Medical School THC. In contrast, cannabidiol (CBD) is mainly used in high
Carl-Neuberg-Straße 1 doses > 400 mg/day.
30625 Hannover
Germany
[email protected]

Introduction and limited access to cannabis programs [2–5]. Furthermore, psy-

Currently, cannabis-based medications are well established in the chiatrists more or less automatically associate the use of cannabis
treatment of chronic pain, spasticity in patients suffering from mul- with cannabis use disorders (CUD), which may result in special cau-
tiple sclerosis, nausea and vomiting, and – to a lesser extent – in tion in using cannabinoids as a medicine. To date, no finished can-
palliative care [1]. In contrast, physicians in many countries rarely nabis-based product has been approved for the treatment of a men-
prescribe cannabinoids to patients suffering from mental illnesses. tal illness.
This is attributed to different factors, including only limited evi- Despite these facts, for many years, a substantial number of pa-
dence suggesting the beneficial effects of cannabinoids in psychi- tients have been widely known to use cannabis as a form of self-
atric disorders due to a tremendous lack of well-designed studies medication for a variety of psychological symptoms and mental ill-

104 Müller-Vahl KR. Cannabis in Psychiatry… Pharmacopsychiatry 2024; 57: 104–114 | © 2024. The Author(s).
nesses or report “dual motives use,” which means combined med- ticular, for patients with mental illnesses, health insurances often
ical and recreational cannabis use. According to surveys performed refuse to cover the costs, resulting in (illegal) self-medication with
at different time points in different geographical regions, mental recreational cannabis unsupervised by a physician. This, in turn,
illnesses, including attention-deficit/hyperactivity disorder limits the practical experience of psychiatrists in using cannabis-
(ADHD), depression, sleep disorders, anxiety, and post-traumatic based medicines for patients with mental illnesses.
stress disorder (PTSD) are among the most common reasons for In many countries today, more than one hundred different
taking cannabis as medicine [6–9]. However, until today, data for chemotypes of cannabis with different concentrations of THC and
none of these indications is sufficient to have confidence that can- CBD can be prescribed. Depending on the THC:CBD ratio, cannabis
nabis-based medicine is more likely to reduce symptoms than pla- flowers and extracts can be classified as THC dominant (THC > CBD),
cebo. According to recent systematic reviews and meta-analyses CBD dominant (CBD > THC), and balanced (THC = CBD) products.
specifically investigating the effects of cannabis-based medicines However, cannabis flowers and full-spectrum extracts may contain,
on mental illnesses, a larger number of well-designed and suffi- in addition to the two most well-known and best-studied “major”
ciently powered studies is not available [2–4]. cannabinoids Δ9-THC and CBD, further so-called “minor” canna­
Against the background that mental illnesses represent a sig- binoids such as Δ8-THC, cannabigerol, cannabichromene, and can-
nificant global burden and a considerable number of patients ex- nabinol (CBN). Altogether, in the cannabis plant, more than 100
perience inadequate relief or intolerable side effects after the use different cannabinoids have been identified, as well as about 400
of conventional treatments, including psychotherapy and pharma- further non-cannabinoid constituents, including phenols, flavo-
ceutical medications, cannabis-based medicines may represent a noids, terpenes, and alkaloids [12–14]. Up to now, it is still unclear
promising new treatment approach, particularly for otherwise ther- whether the combination of all these ingredients of cannabis is
apy-resistant patients suffering from psychiatric disorders such as more effective in the treatment of certain illnesses compared to
CUD, autism spectrum disorder (ASD), Tourette syndrome (TS), the use of pure THC and CBD, respectively. According to the so-
PTSD, anxiety disorders, sleeping disorders, ADHD, and depres- called “entourage effect”, the combination of different cannabi-
sion. Furthermore, it has been suggested that cannabinoids and noids and non-cannabinoid ingredients of cannabis leads to syner-
substances that potentiate endocannabinoid neurotransmission gistic effects, boosting and complimenting those of THC and CBD
may augment the effects of behavioral therapy in different condi- [15].
tions, such as obsessive-compulsive behavior (OCB) and traumatic There is still an ongoing debate on how to best classify canna-
stress-induced behavior [10, 11]. bis. While some researchers prefer to treat all varieties as one di-
verse species, others describe up to three or four different species,
including Cannabis sativa, C. indica, C. ruderalis, and C. afghanica.
Currently available cannabis-based medicines Alternatively, a classification based on the content of cannabinoids
The classification of cannabis-based medicines is primarily based and THC is suggested describing, respectively, three or five differ-
on the content of the two most important and best-characterized ent chemotypes ranging from high ∆9-THC content to fiber hemp
cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). containing no cannabinoids. However, currently, most experts be-
Currently, only very few cannabis-based approved medicines are lieve that cannabis is best characterized as a single species, C. sativa
available (for an overview, see ▶Table 1). The majority of products L., with three different varieties being C. sativa L. var. sativa, C. sa-
currently used are prescription drugs. Cannabis-based medicine tiva L. var. indica, and C. sativa L. var. ruderalis[16, 17]. Cannabis users
can be taken orally (as oil, spray, or capsules), by inhalation, or rare- often describe distinct or even opposite psychoactive effects of C.
ly for topical use. Except for pure CBD and the plant-derived, puri- indica – as being relaxing and calming – and C. sativa – as being up-
fied pharmaceutical-grade CBD medication Epidiolex (in German- lifting and energetic – although these effects are not based on sci-
speaking countries: Epidyolex), cannabis-based medicines are in- entific evidence. Accordingly, there is a suggestion to abandon a
cluded in the category of narcotic drugs. Depending on national nomenclature that differentiates between C. sativa and C. indica and
laws and indications, in some countries, costs for cannabis-based instead only declare cannabinoid and terpenoid profiles of the dif-
medicines are reimbursed by health insurance. However, in par- ferent cannabis chemotypes [16].

▶Table 1 Currently available cannabis-based medicines.

Drug Ingredients Finished medicinal product* Prescription drug

Pure substance Dronabinol THC Marinol, Syndros dronabinol
Nabilone Nabilon Canemes#, Cesamet# –
CBD CBD Epidyolex#, Epidiolex# CBD
Cannabis flowers Standardized for THC and CBD - > 100 strains*
Cannabis extracts Nabiximols Standardized for THC:CBD (1:1) Sativex –
Standardized for THC and CBD - > 50 full spectrum extracts*
#spelling
and trade name, respectively, differ from country to country, *availability differs from county to country, CBD = cannabidiol, THC = tetrahydro-
cannabinol.

Müller-Vahl KR. Cannabis in Psychiatry … Pharmacopsychiatry 2024; 57: 104–114 | © 2024. The Author(s). 105
 Review Thieme

Different modes of action of Common side effects of cannabis-based

tetrahydrocannabinol and cannabidiol medicines and contraindications
Before initiating a cannabis-based treatment, treating physicians In general, cannabis-based medicines are considered well-tolerat-
should know that THC and CBD – although both belonging to the ed and safe [22, 23]. Independent of the specific indication, the
group of natural cannabinoids in the cannabis plant – have very dif- most common side effects of THC-containing cannabis-based med-
ferent effects on the endocannabinoid system (ECS) and also dif- icines are drowsiness, fatigue, dizziness, and dry mouth. All side ef-
ferent molecular targets. THC is a potent orthosteric agonist for fects – and in particular psychological effects such as anxiety as well
cannabinoid CB1 and CB2 receptors. However, as a partial agonist, as psychoactive and cognitive effects – are subject to tolerance de-
THC has a mixed agonist-antagonist effect depending on the cell velopment. Accordingly, in any case, a “start low, go slow” dosing
type and receptor expression, as well as the presence of endocan- strategy is recommended. Special caution is recommended in chil-
nabinoids or other full agonists. In contrast, CBD has multiple mo- dren and older patients, cannabis-naïve patients, patients with clin-
lecular targets. CBD acts as an inverse agonist at cannabinoid re- ically relevant somatic diseases such as cardiovascular diseases,
ceptors and, therefore, may reduce the activity of the ECS. How- pregnant and breastfeeding women, and patients with substance
ever, CBD also inhibits the degradation of endocannabinoids, use disorder (SUD). Absolute contraindications are known sensitiv-
including anandamide, through the enzyme fatty acid amide hy- ity and acute psychosis. So far, no cases of deaths due to overdose
drolase (FAAH), resulting in an increase in endocannabinoid levels of cannabis have been reported [23–25].
and thus may cause cannabinoid receptor activation. In addition, Pure CBD is extremely well-tolerated, causing almost no side ef-
CBD is a full agonist at 5-hydroxytryptamine 1 A serotonin recep- fects after acute administration of doses up to 900 mg. Chronic ad-
tors and transient receptor potential vanilloid 1 (TRPV1) channels. ministration of high doses up to 1500 mg/d causes only mild to
It is believed that most of the effects associated with CBD are me- moderate side effects such as diarrhea, nausea, headache, and som-
diated through these two receptors. However, CBD has been dem- nolence [26]. While THC has only a few interactions with other
onstrated to also act as a partial agonist at D2 dopamine receptors, drugs, CBD may have clinically relevant and serious interactions
a full agonist at adenosine A1 receptors, a negative allosteric mod- with several drugs, including ketoconazole, warfarin, clobazam, ta-
ulator of µ opioid receptors (MOR), an agonist of intracellular per- moxifen, and several other substances [26, 27].
oxisome proliferator-activated receptor gamma, and has an over-
all inhibitory effect on sodium and calcium channels [18, 19]. Therapeutic doses of cannabis-based
It has been hypothesized that the addition of CBD to THC may
not only enhance the clinical effects of THC but also reduce adverse medicines
events. According to the “entourage effect”, it has been speculat- Since the balanced cannabis extract nabiximols is officially licensed
ed that not only CBD but also other cannabinoids and non-cannab- for the treatment of spasticity in adults with multiple sclerosis in
inoid components of cannabis, such as terpenoids, may attenuate several countries, for this finished medicinal product – in contrast
the effects of THC [15, 20]. Assuming a synergistic activity when to all prescription drugs – expert information is available, includ-
combining CBD, other cannabinoids, and terpenoids with THC, ing dosage instructions. For nabiximols, a starting dose of 1 spray
some researchers suggested the use of full-spectrum cannabis ex- containing 2.7 mg delta-9-THC and 2.5 mg CBD from Cannabis sa-
tracts or cannabis flowers in clinical therapy instead of isolated THC tiva L. is recommended. In general, up-titration should be slow to
[20]. However, until today, it is unclear whether such an “entourage avoid side effects, for example, by one spray every 3–5 days. The
effect” exists and how such synergistic (or additive) effects could maximum approved dose of nabiximols is 12 sprays, correspond-
occur. By inhibiting FAAH activity, the addition of CBD to THC may ing to 32.4 mg THC.
result in increased levels of N-arachidonoylethanolamine (AEA), re- In line with this dosage instruction, in most indications and for
sulting in turn in increased agonistic effects on cannabinoid recep- all THC-containing oral products, a starting dose of about 2.5 mg
tors. Furthermore, there is evidence that some effects of THC are THC is recommended. On average, the total daily dose of pure THC
biphasic depending on dose and that presumed synergistic effects and THC-containing cannabis extracts is between 10 and 20 mg
are dependent on the relative ratios between the cannabinoids. THC/day [22]. In the elderly, children, patients with polypharmacy,
However, it is important to note that besides possible synergistic and other vulnerable groups of patients, a lower starting dose of
effects, the combination of THC and CBD may also result in antag- about 1 mg THC/day is recommended [23].
onistic effects, since CBD binds to CB1 receptors as an allosteric With respect to pure CBD, in all current indications (including in-
negative modulator and can influence the pharmacokinetic of THC tractable childhood epilepsies), high oral doses of CBD (e. g.,
by inhibiting the metabolism of THC into its more potent psycho- 10–50 mg/kg in children and > 400 mg/day in adults, respectively) are
active metabolite 11-hydroxy-THC (11-OH-THC) [21]. Accordingly, recommended. So far, it is uncertain whether lower (i. e., < 300 mg/
THC and CBD may have opposite clinical effects, for example, with day) oral doses of CBD have therapeutic potential [28].
respect to appetite, cognition, and behavior. In cannabis-naïve patients, treatment with cannabis flowers
should also be up-titrated slowly, for example, starting with
10–25 mg/day. On average, daily doses of cannabis flowers range
between 0.5 and 1.0 g/day. However, in individual cases, doses may
be lower than 0.05 g/day but also higher than 4 g/day. For inhala-
tion of cannabis flowers, the use of a vaporizer is recommended.

106 Müller-Vahl KR. Cannabis in Psychiatry… Pharmacopsychiatry 2024; 57: 104–114 | © 2024. The Author(s).
Possible underlying mechanisms for tions with specific cannabinoid receptor alleles have been described,
suggesting that changes in the ECS may be related to the underlying
beneficial effects of cannabis-based medicine cause of the diseases.
in mental illnesses
Since there is preliminary evidence that cannabinoids might be ef- Cannabis-based medicines in selected
fective in a wide spectrum of mental illnesses with different under-
lying pathophysiology, different hypotheses have been proposed psychiatric indications
on how these effects can be best explained. Since the database is In the following, available data on cannabis-based treatment for
still weak, currently, it cannot be ruled out that at least some of the different mental illnesses is summarized. All those disorders were
beneficial effects obtained from open uncontrolled or small-scale included, with at least minimal data from small controlled or un-
studies are due to placebo effects. Also, blinding in studies using controlled studies or case series available. All data included report
THC-containing substances can be difficult because of the psycho- results in adults besides a small number of studies and single case
active effects of THC. Finally, cannabinoids – and in particular THC reports, respectively, in ASD and TS. Data is presented in alphabet-
– have sedating and calming effects, which also can have positive ical order. For studies reporting the effects of cannabinoids in de-
effects on various symptoms in patients with mental illnesses. mentia and psychosis, please refer to Dammann et al. and Broers
However, it also can be speculated that cannabinoids may im- et al. in this issue.
prove symptoms in different psychiatric disorders because of their
effects on stress reduction since it is well-known that several psy- Anxiety disorders
chiatric symptoms may increase with stress, such as anxiety, PTSD, In healthy subjects, it has been shown that CBD reduces anxiety
sleeping problems, depression, and tics and at the same time it has symptoms [33–35]. Due to the prominent role of the ECS in stress
been shown that the ECS is the most important stress regulatory regulation [29] and the close relationship between stress and anx-
system in the body [29]. Endocannabinoids are released “on de- iety, it has been speculated that beneficial effects on anxiety may
mand.” Accordingly, concentrations can be influenced by several be related to stress reduction [36]. According to epidemiological
different factors that may alter the synthesis or degradation of the studies, anxiety disorders, including generalized anxiety disorder,
endocannabinoids. However, the two most important endocan- social anxiety disorder, and panic disorder, but also other anxiety-
nabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), related conditions, are a common reason for the use of cannabis
as well as the activity of the FAAH enzyme and the CB1 receptor, [6, 37–39]. Data obtained from medical cannabis registry programs
are regulated by stress. Thus, the ECS is highly stress-responsive, in Australia and Canada showed that cannabis is commonly pre-
resulting in altered synaptic activity and modulation of the sympa- scribed for the treatment of anxiety disorders [37, 40]. So far, no
thetic nervous system and the hypothalamic–pituitary–adrenal randomized controlled trials (RCTs) have been performed investi-
(HPA) axis. This, in turn, may have beneficial effects on clinical gating the effect of THC-containing cannabinoids on anxiety dis-
symptoms that are stress-responsive [29]. orders.
Furthermore, it is well established that the ECS is the most impor- In three small RCTs (N = 10, N = 24, N = 37), treatment with me-
tant neuromodulatory system in the brain, influencing all important dium to high dose CBD (300–600 mg/day) resulted in a significant
neurotransmitter systems, including the dopaminergic, glutamater- improvement in social anxiety disorder [41–43]. In a recently pub-
gic, GABAergic, norepinephrinergic, acetylcholinergic, and seroto- lished RCT (N = 80), researchers investigated whether additional
ninergic systems [30]. For example, it has been demonstrated that treatment with CBD enhances the effects of exposure therapy in
there is a complex interaction between the ESC and the dopaminer- treatment-refractory patients with panic disorder with agorapho-
gic system: (i) vanilloid TRPV1 receptors modulate dopaminergic bia or social anxiety disorder. However, single doses of 300 mg CBD
transmission, (ii) stimulation of dopamine D2-like receptors increas- had been administered only once weekly before therapist-assisted
es the levels of AEA, and (iii) endocannabinoids may counteract the exposure in vivo sessions. This only once weekly medium dose of
effects of dopamine D2 receptor stimulation and control directly do- CBD did not result in any difference in treatment response com-
paminergic neurotransmission. The key role of the ECS in neuromod- pared to placebo [44].
ulation and its influence on several neurotransmitter systems pro- According to a recent systematic review and meta-analysis,
vides a plausible explanation for the possible beneficial effects of there is low-quality evidence suggesting that CBD reduces anxiety.
cannabinoids on different conditions with different underlying pa- In addition, the authors found some indication of publication bias
thologies and different transmitters involved [31]. and concluded that further clinical trials are needed [45].
Finally, it has been suggested that different disorders, including A first study investigating the effect of JNJ-42165279, a selec-
some mental illnesses, might be caused by a dysfunction or deficien- tive inhibitor of FAAH, the enzyme responsible for the degradation
cy in the ECS [32]. Accordingly, the term “clinical endocannabinoid of fatty acid amides (FAA) including anandamide, palmitoylethan-
deficiency” has been suggested, describing clinical features as se- olamide (PEA), and N-oleoylethanolamide (OEA), in social anxiety
quelae of a deficiency in the ECS. It has been speculated that such a disorder demonstrated non-significant improvements of this en-
deficiency may be caused by genetic or congenital defects, or occur docannabinoid modulator [46].
secondarily due to infections, injuries, or other diseases. As described
in more detail below, in some psychiatric disorders, including ADHD, Attention deficit/hyperactivity disorder (ADHD)
depression, PTSD, and TS, alterations in levels of endocannabinoids From surveys and retrospective studies, it is well known that pa-
or related enzymes, changes in CB1 receptor signaling, and associa- tients with ADHD often self-medicate with cannabis and report an

Müller-Vahl KR. Cannabis in Psychiatry … Pharmacopsychiatry 2024; 57: 104–114 | © 2024. The Author(s). 107
 Review Thieme

amelioration in a broad spectrum of symptoms, including inatten- corroborated in another recent RCT, including N = 60 children with
tion, hyperactivity, impulsivity, depression, anxiety, sleeping prob- ASD demonstrating significant improvements in social interaction,
lems resulting in improved psychosocial performance and quality anxiety, psychomotor agitation, number of meals a day, and con-
of life [6, 47–49]. According to an online survey performed in Ger- centration after treatment with a CBD-rich cannabis extract at a
many in 2020 with N = 1028 participants indicating the use of me- concentration of 0.5 % (5 mg/mL) in a 9:1 ratio of CBD:THC (daily
dicinal cannabis flowers prescribed by a physician, ADHD was the dose ranged from 6 to 70 drops) [63].
diagnosis most frequently indicated as a current indication for can-
nabis-based treatment [50]. According to case studies including Cannabis use disorder (CUD) and other substance
one and three patients, respectively [51, 52], and a case series in- use disorders (SUD)
cluding N = 30 patients [53], THC-containing cannabis-based med- A limited number of studies have explored the potential of canna-
icines (pure THC, cannabis flowers) improve concentration, sleep, bis-based medicine as an adjunctive or alternative treatment for
impulsivity, depression, anxiety, quality of life, and enhance the specific SUDs. Doses most often used ranged from 5–40 mg THC/
driving performance of the patient. day and 400–800 mg CBD/day, respectively. According to a small
So far, only one small controlled study examined the efficacy of number of RTCs, including between N = 16 and N = 154 patients,
the cannabis extract nabiximols in adults with ADHD (N = 30). The there is preliminary evidence suggesting that orally taken THC and,
mean dose was 4.7 sprays (range, 1–13), corresponding to 12.6 mg in particular the cannabis extract nabiximols can improve symp-
THC. Although the primary endpoint was not reached, several sec- toms associated with CUD such as severity and time course of can-
ondary endpoints showed significant improvements in hyperactiv- nabis withdrawal symptoms, overall health, and quality of life and
ity, impulsivity, and cognitive measure of inhibition and a trend to- may reduce cannabis craving and use of smoked cannabis [64–67].
wards improvement in inattention and emotional lability [54]. In a randomized clinical trial (N = 84), in addition, pure CBD was
There is some evidence for an involvement of the ECS in ADHD more efficacious than placebo at reducing cannabis use in patients
pathology since a reduced activity of the enzyme FAAH was found with CUD [68]. Finally, in a single center RTC in N = 70 men, the
in the serum of boys with ADHD [55]. In addition, differences in al- FAAH-inhibitor PF-04457845 was superior compared to placebo in
lele frequency and genotype distribution of the FAAH rs2295633 reducing symptoms of cannabis withdrawal as well as cannabis use
gene were detected in children with ADHD [56]. [69].
There is limited evidence suggesting that THC may decrease the
Autism spectrum disorder (ASD) severity of opioid withdrawal symptoms [70, 71] and that CBD may
Increasing evidence suggests that cannabinoids might be effective reduce opioid craving [72]. It is well-known that cannabis is fre-
in the treatment of behavioral problems in patients with ASD, such quently used as a substitute for prescription drugs, including opi-
as rage attacks, impulsivity, and aggression [57]. In a case study, oids [73]. There is no convincing data available suggesting that can-
PEA plus the flavonoid luteolin resulted in symptom improvement, nabinoids reduce symptoms associated with cocaine use disorder
including stereotypies, in a 10-year-old boy with ASD [58]. In a ret- [74, 75] or with other substances such as tobacco [76]. Although
rospective study in children and adolescents (N = 60), treatment cannabinoids, including THC and CBD demonstrate potential for
with a full-spectrum CBD dominant cannabis extract (CBD:THC be- treating SUDs, the available evidence is limited and larger well-de-
tween 20:1 to 6:1, mean daily dose: 3.8  ±  2.6 mg/kg/day CBD and signed studies are needed.
0.29  ±  0.22 mg/kg/day THC) improved “behavioral outbursts.” The
higher the THC dose, the stronger the effects were [59]. In a pro- Depression
spective uncontrolled study (N = 53), pure CBD (median daily Data obtained from epidemiological studies and surveys including
dose = 90 (45–143) mg) resulted in an improvement of different large samples has shown that people self-medicating with canna-
behavioral symptoms, including angry outbursts, autoaggression, bis and patients taking prescribed cannabis-based medicines, re-
hyperactivity, sleeping problems, and anxiety [60]. According to spectively, often report an improvement in mood and that depres-
another open-label study, longer-term treatment with CBD-rich sion is one of the most common reasons for cannabinoid therapy
cannabis (individually adjusted dose: maximum 10 mg/kg/day or [6, 49, 77–80]. Interestingly, in one of these studies that included
total of 400 mg/day of CBD and 0.5 mg/kg/day or total of 20 mg/ N = 1,819 individuals, the THC concentration of cannabis flowers
day of THC) over 6 months resulted in the majority of N = 82 chil- was the strongest independent positive predictor for the improve-
dren and adolescents with ASD in improvements in social commu- ment of depressive symptoms [80].
nication abilities as well as restricted and repetitive behaviors [61]. Remarkably, until today, well-designed RTCs investigating the
In a large controlled study, N = 150 children and adolescents effect of cannabinoids on major depression are missing. Controlled
were included, and the efficacy of full-spectrum cannabis extracts studies investigating the efficacy of nabiximols and smoked canna-
(CBD:THC = 20:1) and purified THC and CBD in the same ratio were bis flowers with varying THC levels (0–9.4 %), respectively, in other
compared with a placebo. The dose depended on body weight up conditions such as multiple sclerosis, cancer pain, CUD, and neu-
to a maximum of 420 mg CBD and 21 mg THC per day. While the ropathic pain failed to demonstrate a significant improvement of
primary study endpoint (“change in overall behavior”) was not met, depression as a secondary endpoint [2, 81].
treatment with the full-spectrum extract resulted in a significant On the other hand, there is no evidence suggesting that recre-
improvement in disruptive behavior compared to placebo or the ational use of cannabis is an independent risk factor for the onset
full-spectrum extract [62]. Overall, cannabinoids were well toler- of mood disorders [78]. A recent genetic study suggested that car-
ated, with only mild adverse effects. These promising effects were

108 Müller-Vahl KR. Cannabis in Psychiatry… Pharmacopsychiatry 2024; 57: 104–114 | © 2024. The Author(s).
riers of the cannabinoid receptor 1 (CNR1) A-allele are more sus- Limited data suggest that the ECS is involved in the pathogen-
ceptible to developing depression [82]. esis of PTSD, as indicated by a globally increased binding to central
cannabinoid CB1 receptors as well as decreased blood levels of the
Obsessive compulsive disorder (OCD) endocannabinoid anandamide [108].
While numerous animal studies have suggested that cannabis-
based medicines may improve obsessive-compulsive symptoms Sleeping disorders
(for review, see [83]), clinical studies are limited. In a large internet Anecdotally, it has been reported several times that patients often
survey from the US, the majority of patients with OCD self-report- use cannabis and cannabis-based medicine, respectively, to improve
ed that using cannabis medicinally resulted in an improvement of sleeping problems [6, 7, 37, 77, 109]. In patients with chronic pain,
OCD [84]. According to a small number of single case studies, dron- the beneficial effects of cannabis-based medicines on sleep as a sec-
abinol, and cannabis flowers improve compulsive behaviors and ob- ondary outcome measure have been demonstrated [110]. In a small
sessive thoughts [83, 85, 86]. In a small RCT (N = 11), co-medica- controlled study (N = 19), it was found that nabilone (mean
tion with nabilone (up to 2 mg/day, corresponding to 14–16 mg dose = 0.86 mg/day (corresponding to 6–7 mg THC), range, 0.25–
THC/day) augmented exposure-based behavioral psychotherapy 1.75 mg/day) improves – among other non-motor symptoms –
for OCD, while monotherapy with nabilone had no significant ef- night-time sleep problems in patients with Parkinson’s disease
fect [10]. In a small placebo-controlled single-dose study (N = 12), [111].
no acute effects of low-dose smoked cannabis with different However, the database supporting the use of medicinal canna-
THC:CBD ratios (about 400 mg of cannabis with either 7.0 % THC bis as an effective and safe treatment option for sleep disorders is
and 0.18 % CBD or 0.4 % THC and 10.4 % CBD) were detected [87]. still very weak [112]. So far, only two small RCTs have been per-
While in a small open-label study (N = 14), dronabinol was effec- formed investigating the efficacy of cannabis-based treatment in
tive in reducing trichotillomania [88], in one randomized, double- patients with sleep disorders. In the first study, N = 24 patients with
blind, placebo-controlled, parallel-group follow-up study over 10 chronic insomnia (symptoms  ≥  3 months) received up to 1 mL of
weeks in a mixed population with trichotillomania (N = 34) or skin the cannabinoid extract ZTL-101, which contains 20 mg/mL THC,
picking disorder (N = 16), dronabinol (5–15 mg/day) did not signif- 1 mg/mL CBD, 2 mg/mL CBN, and naturally occurring terpenes or
icantly separate from placebo on any efficacy measure [89]. placebo for two weeks [113]. Insomnia symptoms and sleep qual-
ity significantly improved after treatment with the cannabis extract.
Post-traumatic stress disorder (PTSD) In the second study, including N = 29 patients with insomnia, me-
The title of a recent editorial by Abizaid et al., “Cannabis: A poten- dicinal cannabis oil containing 10 mg/mL THC and 15 mg/mL CBD
tial efficacious intervention for PTSD or simply snake oil?” [90] strik- (up to a maximum dose of 15 mg THC/22.5 mg CBD per day) over
ingly illustrates the controversial debate about the sense or non- 2 weeks also resulted in an improvement of time and quality of
sense of cannabis in the treatment of PTSD. Similar to other mental sleep. In addition, midnight melatonin levels improved significant-
illnesses, from epidemiological studies, it is well-known that pa- ly [114].
tients with PTSD often self-medicate with cannabis [6]. In some ob-
servational studies, negative effects have been reported in patients Tourette syndrome (TS)
with PTSD when using cannabis, such as overall worsening of symp- Thirty-five years ago, in 1988, an anecdotal report suggested for
toms, more violent behavior, more alcohol use [91], an increase in the first time that smoked cannabis may improve symptoms in pa-
trauma-associated intrusions [92] as well as suicidal thoughts and tients with TS [115]. Thereafter, several similar case reports and
behavior [93]. Other surveys suggested the contrary, showing the open-label studies have been published reporting not only a sus-
use of cannabis resulted in more than 50 % improvement in all re- tained reduction of tics and premonitory urges, but also an im-
corded PTSD symptoms, including intrusive thoughts, flashbacks, provement of a broad spectrum of psychiatric comorbidities, in-
irritability, anxiety [94] as well as a significantly lower risk of a major cluding ADHD, sleeping problems, self-injurious behavior, impul-
depressive episode and the presence of suicidal ideation [95]. sivity, OCB, and depression after use of smoked cannabis [116–120]
From a small number of case reports and uncontrolled studies, and oral cannabis-based medicines such as THC, THC plus CBD, THC
beneficial effects on different symptoms in patients with PTSD have plus PEA, and nabiximols, respectively [121–128]. In addition, one
been reported after use of cannabis [96–98], THC, nabilone [99– case study reported an improvement in the driving performance
101], and pure CBD [102, 103], respectively. of the patient after the use of THC [123]. Beneficial effects of can-
Up to now, there are only three small controlled studies (includ- nabis-based treatments (THC, nabiximols, and inhaled cannabis)
ing between N = 10 and N = 33 patients) available reporting signif- were also been reported in four children and adolescents aged 7 to
icantly improved nightmares and overall clinical impression after 16 years with improved tics, ADHD, depression, and insomnia
treatment with 0.5 mg nabilone [104] and improved anxiety and [120, 126, 129–131].
cognitive impairment after a single dose of 300 mg CBD [105, 106]. To date, four controlled trials have been published investigating
In the largest RCT published so far in this indication, treatment with the effects of different cannabinoids in adults with TS. In two small-
three different concentrations of smoked cannabis (THC/ scale studies including N = 12 (single dose of THC up to 10 mg) and
CBD = 12 %/ < 0.05 %, THC/CBD = 0.50 %/11 %, and THC/CBD = N = 24 patients (up to 10 mg THC/day for 6 weeks), respectively,
7.9 %/8.1 %) in N = 80 military veterans with PTSD was not superior THC resulted in a significant improvement of tics [132, 133] with-
compared to placebo [107]. out causing impairment in neuropsychological performance
[134, 135]. Another small RCT (N = 12) suggested that vaporized

Müller-Vahl KR. Cannabis in Psychiatry … Pharmacopsychiatry 2024; 57: 104–114 | © 2024. The Author(s). 109
 Review Thieme

single doses of 0.25 g of medicinal cannabis containing 10 % THC depression. Currently, different cannabinoid modulators that ei-
and 9 %/9 % THC/CBD – but not 13 % CBD – reduce tics and premon- ther inhibit the degradation or the reuptake of endocannabinoids
itory urges [136]. are under development and might be further alternative options
Only recently, results from the first large, well-designed RCT in- for the treatment of mental illnesses in the future.
vestigating the efficacy and safety of the cannabis extract nabixi-
mols have been reported [137, 138]. Although this study, includ-
ing N = 97 patients with TS, formally failed to demonstrate superi- Conflict of Interest
ority for nabiximols (mean dose = 7.21  ±  3 · 42 puffs/day for 13
weeks) over placebo in the primary endpoint, the results showed Kirsten Müller-Vahl has received financial or material research support
from DFG: GZ MU 1527/3–1 and GZ MU 1527/3–2 and Almirall Hermal
clear trends for improvements in tic severity, depression, and qual-
GmbH. She has received consultant's and other honoraria from
ity of life after treatment with nabiximols. Canymed, Emalex, Eurox Group, Sanity Group, Stadapharm GmbH,
While in a small controlled single-dose single-center phase 1b Swiss alpinapharm, Synendos Therapeutics AG, Tetrapharm, and
cross-over study (N = 20), the endocannabinoid modulator Lu Triaspharm. She is an advisory/scientific board member for Branchen-
AG06466 (formerly known as ABX-1431) that reduces the degra- verband Cannabiswirtschaft e.V. (BvCW), Sanity Group, Synendos
Therapeutics AG, Syqe Medical Ltd., and Therapix Biosciences Ltd.. She
dation of the endocannabinoid 2-AG by inhibiting the monoacylg-
has received speaker's fees from Almirall, Bundesverband der
lycerol lipase (MAGL) was effective in reducing tics and premoni- pharmazeutischen Cannabinoidunternehmen (BPC), Cogitando GmbH,
tory urges in patients with TS [139], in a follow-up RCT including Emalex, Grow, Medizinischer Dienst Westfalen Lippe, Noema,
N = 49 patients, Lu AG06466 was not effective in reducing tics or streamedup! GmbH, and Vidal. She has received royalties from
related symptoms in patients with chronic tic disorders [140]. Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and
Kohlhammer. She is an associate editor for “Cannabis and Cannabinoid
Preliminary data suggests a dysfunction in the ESC in TS, since
Research” and an Editorial Board Member of “Medical Cannabis and
levels of different endocannabinoids (anandamide, 2-AG, the en- Cannabinoids” und “MDPI-Reports” and a Scientific board member for
docannabinoid-like molecule PEA, and arachidonic acid (AA)) were “Zeitschrift für Allgemeinmedizin.”
found elevated in cerebrospinal fluid (CSF) [31]. Results of genetic
studies were inconsistent and showed either no genetic variations
of the CNR1 gene in patients with TS [141] or a relationship be-
tween variants of the CNR1 gene and an increased risk for TS [142]. References

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