Keywords
cannabis-based medicine - cannabinoids - psychiatry - THC - CBD
Introduction
Currently, cannabis-based medications are well established in the treatment of
chronic pain, spasticity in patients suffering from multiple sclerosis, nausea and
vomiting, and – to a lesser extent – in palliative care [1]. In contrast, physicians in many countries
rarely prescribe cannabinoids to patients suffering from mental illnesses. This is
attributed to different factors, including only limited evidence suggesting the
beneficial effects of cannabinoids in psychiatric disorders due to a tremendous lack
of well-designed studies and limited access to cannabis programs [2]
[3]
[4]
[5]. Furthermore, psychiatrists more or less
automatically associate the use of cannabis with cannabis use
disorders (CUD), which may result in special caution in using cannabinoids as a
medicine. To date, no finished cannabis-based product has been approved for
the treatment of a mental illness.
Despite these facts, for many years, a substantial number of patients have been
widely known to use cannabis as a form of self-medication for a variety of
psychological symptoms and mental illnesses or report “dual motives use,” which
means combined medical and recreational cannabis use. According to surveys
performed at different time points in different geographical regions, mental
illnesses, including attention-deficit/hyperactivity disorder (ADHD), depression,
sleep disorders, anxiety, and post-traumatic stress disorder (PTSD) are among the
most common reasons for taking cannabis as medicine [6]
[7]
[8]
[9]. However, until today, data for none of
these indications is sufficient to have confidence that cannabis-based
medicine is more likely to reduce symptoms than placebo. According to recent
systematic reviews and meta-analyses specifically investigating the effects of
cannabis-based medicines on mental illnesses, a larger number of
well-designed and sufficiently powered studies is not available [2]
[3]
[4].
Against the background that mental illnesses represent a significant global burden
and a considerable number of patients experience inadequate relief or intolerable
side effects after the use of conventional treatments, including psychotherapy and
pharmaceutical medications, cannabis-based medicines may represent a
promising new treatment approach, particularly for otherwise therapy-resistant
patients suffering from psychiatric disorders such as CUD, autism spectrum disorder
(ASD), Tourette syndrome (TS), PTSD, anxiety disorders, sleeping disorders, ADHD,
and depression. Furthermore, it has been suggested that cannabinoids and substances
that potentiate endocannabinoid neurotransmission may augment the effects of
behavioral therapy in different conditions, such as obsessive-compulsive behavior
(OCB) and traumatic stress-induced behavior [10]
[11].
Currently available cannabis-based medicines
Currently available cannabis-based medicines
The classification of cannabis-based medicines is primarily based on the
content of the two most important and best-characterized cannabinoids,
tetrahydrocannabinol (THC) and cannabidiol (CBD). Currently, only very few
cannabis-based approved medicines are available (for an overview, see
[Table 1]). The majority of products
currently used are prescription drugs. Cannabis-based medicine can be taken
orally (as oil, spray, or capsules), by inhalation, or rarely for topical use.
Except for pure CBD and the plant-derived, purified pharmaceutical-grade CBD
medication Epidiolex (in German-speaking countries: Epidyolex),
cannabis-based medicines are included in the category of narcotic drugs.
Depending on national laws and indications, in some countries, costs for
cannabis-based medicines are reimbursed by health insurance. However, in
particular, for patients with mental illnesses, health insurances often refuse to
cover the costs, resulting in (illegal) self-medication with recreational
cannabis unsupervised by a physician. This, in turn, limits the practical
experience of psychiatrists in using cannabis-based medicines for patients
with mental illnesses.
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 = tetrahydrocannabinol.
In many countries today, more than one hundred different chemotypes of
cannabis with different concentrations of THC and CBD can be prescribed.
Depending on the THC:CBD ratio, cannabis flowers and extracts can be
classified as THC dominant (THC>CBD), CBD dominant (CBD>THC), and balanced
(THC=CBD) products. However, cannabis flowers and full-spectrum extracts may
contain, in addition to the two most well-known and best-studied “major”
cannabinoids Δ9-THC and CBD, further so-called “minor” cannabinoids such as Δ8-THC,
cannabigerol, cannabichromene, and cannabinol (CBN). Altogether, in the
cannabis plant, more than 100 different cannabinoids have been
identified, as well as about 400 further non-cannabinoid constituents, including
phenols, flavonoids, terpenes, and alkaloids [12]
[13]
[14]. Up to now, it is still unclear whether the
combination of all these ingredients of cannabis is more effective in the
treatment of certain illnesses compared to the use of pure THC and CBD,
respectively. According to the so-called “entourage effect”, the combination of
different cannabinoids and non-cannabinoid ingredients of cannabis leads to
synergistic effects, boosting and complimenting those of THC and CBD [15].
There is still an ongoing debate on how to best classify cannabis. While some
researchers prefer to treat all varieties as one diverse species, others describe up
to three or four different species, including Cannabis sativa, C.
indica, C. ruderalis, and C. afghanica. Alternatively, a
classification based on the content of cannabinoids and THC is suggested describing,
respectively, three or five different chemotypes ranging from high ∆9-THC content to
fiber hemp containing no cannabinoids. However, currently, most experts believe that
cannabis is best characterized as a single species, C. sativa L.,
with three different varieties being C. sativa L. var. sativa, C.
sativa L. var. indica, and C. sativa L. var.
ruderalis
[16]
[17]. Cannabis users often describe
distinct or even opposite psychoactive effects of C. indica – as being
relaxing and calming – and C. sativa – as being uplifting and energetic –
although these effects are not based on scientific evidence. Accordingly, there is a
suggestion to abandon a nomenclature that differentiates between C. sativa
and C. indica and instead only declare cannabinoid and terpenoid profiles of
the different cannabis chemotypes [16].
Different modes of action of tetrahydrocannabinol and cannabidiol
Different modes of action of tetrahydrocannabinol and cannabidiol
Before initiating a cannabis-based treatment, treating physicians should know
that THC and CBD – although both belonging to the group of natural cannabinoids in
the cannabis plant – have very different effects on the endocannabinoid
system (ECS) and also different molecular targets. THC is a potent orthosteric
agonist for cannabinoid CB1 and CB2 receptors. However, as a partial agonist, THC
has a mixed agonist-antagonist effect depending on the cell type and receptor
expression, as well as the presence of endocannabinoids or other full agonists. In
contrast, CBD has multiple molecular targets. CBD acts as an inverse agonist at
cannabinoid receptors and, therefore, may reduce the activity of the ECS. However,
CBD also inhibits the degradation of endocannabinoids, including anandamide, through
the enzyme fatty acid amide hydrolase (FAAH), resulting in an increase in
endocannabinoid levels and thus may cause cannabinoid receptor activation. In
addition, CBD is a full agonist at 5-hydroxytryptamine 1 A serotonin receptors and
transient receptor potential vanilloid 1 (TRPV1) channels. It is believed that most
of the effects associated with CBD are mediated through these two receptors.
However, CBD has been demonstrated to also act as a partial agonist at D2 dopamine
receptors, a full agonist at adenosine A1 receptors, a negative allosteric modulator
of µ opioid receptors (MOR), an agonist of intracellular peroxisome
proliferator-activated receptor gamma, and has an overall inhibitory effect on
sodium and calcium channels [18]
[19].
It has been hypothesized that the addition of CBD to THC may not only enhance the
clinical effects of THC but also reduce adverse events. According to the “entourage
effect”, it has been speculated that not only CBD but also other cannabinoids and
non-cannabinoid components of cannabis, such as terpenoids, may attenuate the
effects of THC [15]
[20]. Assuming a synergistic activity when
combining CBD, other cannabinoids, and terpenoids with THC, some researchers
suggested the use of full-spectrum cannabis extracts or cannabis
flowers in clinical therapy instead of isolated THC [20]. However, until today, it is unclear whether such an “entourage
effect” exists and how such synergistic (or additive) effects could occur. By
inhibiting FAAH activity, the addition of CBD to THC may result in increased levels
of N-arachidonoylethanolamine (AEA), resulting in turn in increased agonistic
effects on cannabinoid receptors. Furthermore, there is evidence that some effects
of THC are biphasic depending on dose and that presumed synergistic effects are
dependent on the relative ratios between the cannabinoids. However, it is important
to note that besides possible synergistic effects, the combination of THC and CBD
may also result in antagonistic effects, since CBD binds to CB1 receptors as an
allosteric negative modulator and can influence the pharmacokinetic of THC by
inhibiting the metabolism of THC into its more potent psychoactive metabolite
11-hydroxy-THC (11-OH-THC) [21]. Accordingly,
THC and CBD may have opposite clinical effects, for example, with respect to
appetite, cognition, and behavior.
Common side effects of cannabis-based medicines and
contraindications
Common side effects of cannabis-based medicines and
contraindications
In general, cannabis-based medicines are considered well-tolerated and safe
[22]
[23]. Independent of the specific indication, the most common side effects
of THC-containing cannabis-based medicines are drowsiness, fatigue,
dizziness, and dry mouth. All side effects – and in particular psychological effects
such as anxiety as well as psychoactive and cognitive effects – are subject to
tolerance development. Accordingly, in any case, a “start low, go slow” dosing
strategy is recommended. Special caution is recommended in children and older
patients, cannabis-naïve patients, patients with clinically relevant somatic
diseases such as cardiovascular diseases, pregnant and breastfeeding women, and
patients with substance use disorder (SUD). Absolute contraindications are known
sensitivity and acute psychosis. So far, no cases of deaths due to overdose of
cannabis have been reported [23]
[24]
[25].
Pure CBD is extremely well-tolerated, causing almost no side effects after acute
administration of doses up to 900 mg. Chronic administration of high doses up to
1500 mg/d causes only mild to moderate side effects such as diarrhea, nausea,
headache, and somnolence [26]. While THC has
only a few interactions with other drugs, CBD may have clinically relevant and
serious interactions with several drugs, including ketoconazole, warfarin, clobazam,
tamoxifen, and several other substances [26]
[27].
Therapeutic doses of cannabis-based medicines
Therapeutic doses of cannabis-based medicines
Since the balanced cannabis extract nabiximols is officially licensed for the
treatment of spasticity in adults with multiple sclerosis in several countries, for
this finished medicinal product – in contrast to all prescription drugs – expert
information is available, including dosage instructions. For nabiximols, a starting
dose of 1 spray containing 2.7 mg delta-9-THC and 2.5 mg CBD from Cannabis sativa
L. is recommended. In general, up-titration should be slow to avoid side
effects, for example, by one spray every 3–5 days. The maximum approved dose of
nabiximols is 12 sprays, corresponding to 32.4 mg THC.
In line with this dosage instruction, in most indications and for all THC-containing
oral products, a starting dose of about 2.5 mg THC is recommended. On average, the
total daily dose of pure THC and THC-containing cannabis extracts is between
10 and 20 mg THC/day [22]. In the elderly,
children, patients with polypharmacy, and other vulnerable groups of patients, a
lower starting dose of about 1 mg THC/day is recommended [23].
With respect to pure CBD, in all current indications (including intractable childhood
epilepsies), high oral doses of CBD (e. g., 10–50 mg/kg in children
and>400 mg/day in adults, respectively) are recommended. So far, it is uncertain
whether lower (i. e.,<300 mg/day) oral doses of CBD have therapeutic potential
[28].
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 inhalation of cannabis flowers, the use of a vaporizer is
recommended.
Possible underlying mechanisms for beneficial effects of cannabis-based
medicine in mental illnesses
Possible underlying mechanisms for beneficial effects of cannabis-based
medicine in mental illnesses
Since there is preliminary evidence that cannabinoids might be effective in a wide
spectrum of mental illnesses with different underlying pathophysiology, different
hypotheses have been proposed on how these effects can be best explained. Since the
database is still weak, currently, it cannot be ruled out that at least some of the
beneficial effects obtained from open uncontrolled or small-scale studies are due to
placebo effects. Also, blinding in studies using THC-containing substances can be
difficult because of the psychoactive effects of THC. Finally, cannabinoids – and in
particular THC – have sedating and calming effects, which also can have positive
effects on various symptoms in patients with mental illnesses.
However, it also can be speculated that cannabinoids may improve symptoms in
different psychiatric disorders because of their effects on stress reduction since
it is well-known that several psychiatric symptoms may increase with stress, such as
anxiety, PTSD, sleeping problems, depression, and tics and at the same time it has
been shown that the ECS is the most important stress regulatory system in the body
[29]. Endocannabinoids are released “on
demand.” Accordingly, concentrations can be influenced by several different factors
that may alter the synthesis or degradation of the endocannabinoids. However, the
two most important endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol
(2-AG), as well as the activity of the FAAH enzyme and the CB1 receptor, are
regulated by stress. Thus, the ECS is highly stress-responsive, resulting in altered
synaptic activity and modulation of the sympathetic nervous system and the
hypothalamic–pituitary–adrenal (HPA) axis. This, in turn, may have beneficial
effects on clinical symptoms that are stress-responsive [29].
Furthermore, it is well established that the ECS is the most important
neuromodulatory system in the brain, influencing all important neurotransmitter
systems, including the dopaminergic, glutamatergic, GABAergic, norepinephrinergic,
acetylcholinergic, and serotoninergic systems [30]. For example, it has been demonstrated that there is a complex
interaction between the ESC and the dopaminergic system: (i) vanilloid TRPV1
receptors modulate dopaminergic transmission, (ii) stimulation of dopamine D2-like
receptors increases the levels of AEA, and (iii) endocannabinoids may counteract the
effects of dopamine D2 receptor stimulation and control directly dopaminergic
neurotransmission. The key role of the ECS in neuromodulation and its influence on
several neurotransmitter systems provides a plausible explanation for the possible
beneficial effects of cannabinoids on different conditions with different underlying
pathologies and different transmitters involved [31].
Finally, it has been suggested that different disorders, including some mental
illnesses, might be caused by a dysfunction or deficiency in the ECS [32]. Accordingly, the term “clinical
endocannabinoid deficiency” has been suggested, describing clinical features as
sequelae of a deficiency in the ECS. It has been speculated that such a deficiency
may be caused by genetic or congenital defects, or occur secondarily due to
infections, injuries, or other diseases. As described in more detail below, in some
psychiatric disorders, including ADHD, depression, PTSD, and TS, alterations in
levels of endocannabinoids or related enzymes, changes in CB1 receptor signaling,
and associations with specific cannabinoid receptor alleles have been described,
suggesting that changes in the ECS may be related to the underlying cause of the
diseases.
Cannabis-based medicines in selected psychiatric indications
Cannabis-based medicines in selected psychiatric indications
In the following, available data on cannabis-based treatment for different
mental illnesses is summarized. All those disorders were included, with at least
minimal data from small controlled or uncontrolled studies or case series available.
All data included report results in adults besides a small number of studies and
single case reports, respectively, in ASD and TS. Data is presented in alphabetical
order. For studies reporting the effects of cannabinoids in dementia and psychosis,
please refer to Dammann et al. and Broers et al. in this issue.
Anxiety disorders
In healthy subjects, it has been shown that CBD reduces anxiety symptoms [33]
[34]
[35]. Due to the prominent
role of the ECS in stress regulation [29]
and the close relationship between stress and anxiety, it has been speculated
that beneficial effects on anxiety may be related to stress reduction [36]. According to epidemiological studies,
anxiety disorders, including generalized anxiety disorder, social anxiety
disorder, and panic disorder, but also other anxiety-related conditions, are a
common reason for the use of cannabis
[[6]
[37]
[38]
[39]. Data obtained from medical cannabis registry programs in
Australia and Canada showed that cannabis is commonly prescribed for the
treatment of anxiety disorders [37]
[40]. So far, no randomized controlled
trials (RCTs) have been performed investigating the effect of THC-containing
cannabinoids on anxiety disorders.
In three small RCTs (N=10, N=24, N=37), treatment with medium to high dose CBD
(300–600 mg/day) resulted in a significant improvement in social anxiety
disorder [41]
[42]
[43]. In a recently published RCT (N=80), researchers investigated
whether additional treatment with CBD enhances the effects of exposure therapy
in treatment-refractory patients with panic disorder with agoraphobia or social
anxiety disorder. However, single doses of 300 mg CBD had been administered only
once weekly before therapist-assisted exposure in vivo sessions. This only once
weekly medium dose of CBD did not result in any difference in treatment response
compared to placebo [44].
According to a recent systematic review and meta-analysis, there is low-quality
evidence suggesting that CBD reduces anxiety. In addition, the authors found
some indication of publication bias and concluded that further clinical trials
are needed [45].
A first study investigating the effect of JNJ-42165279, a selective inhibitor of
FAAH, the enzyme responsible for the degradation of fatty acid amides (FAA)
including anandamide, palmitoylethanolamide (PEA), and N-oleoylethanolamide
(OEA), in social anxiety disorder demonstrated non-significant improvements of
this endocannabinoid modulator [46].
Attention deficit/hyperactivity disorder (ADHD)
From surveys and retrospective studies, it is well known that patients with ADHD
often self-medicate with cannabis and report an amelioration in a broad
spectrum of symptoms, including inattention, hyperactivity, impulsivity,
depression, anxiety, sleeping problems resulting in improved psychosocial
performance and quality of life [6]
[47]
[48]
[49]. According to an online
survey performed in Germany in 2020 with N=1028 participants indicating the use
of medicinal cannabis flowers prescribed by a physician, ADHD was the
diagnosis most frequently indicated as a current indication for
cannabis-based treatment [50].
According to case studies including one and three patients, respectively [51]
[52], and a case series including N=30 patients [53], THC-containing cannabis-based
medicines (pure THC, cannabis flowers) improve concentration, sleep,
impulsivity, depression, anxiety, quality of life, and enhance the driving
performance of the patient.
So far, only one small controlled study examined the efficacy of the
cannabis extract nabiximols in adults with ADHD (N=30). The mean dose
was 4.7 sprays (range, 1–13), corresponding to 12.6 mg THC. Although the primary
endpoint was not reached, several secondary endpoints showed significant
improvements in hyperactivity, impulsivity, and cognitive measure of inhibition
and a trend towards improvement in inattention and emotional lability [54].
There is some evidence for an involvement of the ECS in ADHD pathology since a
reduced activity of the enzyme FAAH was found in the serum of boys with ADHD
[55]. In addition, differences in
allele frequency and genotype distribution of the FAAH rs2295633 gene were
detected in children with ADHD [56].
Autism spectrum disorder (ASD)
Increasing evidence suggests that cannabinoids might be effective in the
treatment of behavioral problems in patients with ASD, such as rage attacks,
impulsivity, and aggression [57]. In a
case study, PEA plus the flavonoid luteolin resulted in symptom improvement,
including stereotypies, in a 10-year-old boy with ASD [58]. In a retrospective study in children
and adolescents (N=60), treatment with a full-spectrum CBD dominant
cannabis extract (CBD:THC between 20:1 to 6:1, mean daily dose:
3.8+±+2.6 mg/kg/day CBD and 0.29+±+0.22 mg/kg/day THC) improved “behavioral
outbursts.” The higher the THC dose, the stronger the effects were [59]. In a prospective uncontrolled study
(N=53), pure CBD (median daily dose=90 (45–143) mg) resulted in an improvement
of different behavioral symptoms, including angry outbursts, autoaggression,
hyperactivity, sleeping problems, and anxiety [60]. According to another open-label study, longer-term treatment
with CBD-rich cannabis (individually adjusted dose: maximum 10 mg/kg/day
or total of 400 mg/day of CBD and 0.5 mg/kg/day or total of 20 mg/day of THC)
over 6 months resulted in the majority of N=82 children and adolescents with ASD
in improvements in social communication abilities as well as restricted and
repetitive behaviors [61].
In a large controlled study, N=150 children and adolescents were included, and
the efficacy of full-spectrum cannabis extracts (CBD:THC=20:1) and
purified THC and CBD in the same ratio were compared with a placebo. The dose
depended on body weight up to a maximum of 420 mg CBD and 21 mg THC per day.
While the primary study endpoint (“change in overall behavior”) was not met,
treatment with the full-spectrum extract resulted in a significant improvement
in disruptive behavior compared to placebo or the full-spectrum extract [62]. Overall, cannabinoids were well
tolerated, with only mild adverse effects. These promising effects were
corroborated in another recent RCT, including N=60 children with ASD
demonstrating significant improvements in social interaction, anxiety,
psychomotor agitation, number of meals a day, and concentration after treatment
with a CBD-rich cannabis extract at a concentration of 0.5% (5 mg/mL) in
a 9:1 ratio of CBD:THC (daily dose ranged from 6 to 70 drops) [63].
Cannabis use disorder (CUD) and other substance use disorders (SUD)
A limited number of studies have explored the potential of cannabis-based
medicine as an adjunctive or alternative treatment for specific SUDs. Doses most
often used ranged from 5–40 mg THC/day and 400–800 mg CBD/day, respectively.
According to a small number of RTCs, including between N=16 and N=154 patients,
there is preliminary evidence suggesting that orally taken THC and, in
particular the cannabis extract nabiximols can improve symptoms
associated with CUD such as severity and time course of cannabis
withdrawal symptoms, overall health, and quality of life and may reduce
cannabis craving and use of smoked cannabis
[64]
[65]
[66]
[67]. In a randomized clinical trial (N=84),
in addition, pure CBD was more efficacious than placebo at reducing
cannabis use in patients with CUD [68]. Finally, in a single center RTC in N=70 men, the FAAH-inhibitor
PF-04457845 was superior compared to placebo in reducing symptoms of
cannabis withdrawal as well as cannabis use [69].
There is limited evidence suggesting that THC may decrease the severity of opioid
withdrawal symptoms [70]
[71] and that CBD may reduce opioid craving
[72]. It is well-known that
cannabis is frequently used as a substitute for prescription drugs,
including opioids [73]. There is no
convincing data available suggesting that cannabinoids reduce symptoms
associated with cocaine use disorder [74]
[75] or with other
substances such as tobacco [76]. Although
cannabinoids, including THC and CBD demonstrate potential for treating SUDs, the
available evidence is limited and larger well-designed studies are needed.
Depression
Data obtained from epidemiological studies and surveys including large samples
has shown that people self-medicating with cannabis and patients taking
prescribed cannabis-based medicines, respectively, often report an
improvement in mood and that depression is one of the most common reasons for
cannabinoid therapy [6]
[49]
[77]
[78]
[79]
[80]. Interestingly, in one of these studies that included N=1,819
individuals, the THC concentration of cannabis flowers was the strongest
independent positive predictor for the improvement of depressive symptoms [80].
Remarkably, until today, well-designed RTCs investigating the effect of
cannabinoids on major depression are missing. Controlled studies investigating
the efficacy of nabiximols and smoked cannabis flowers with varying THC
levels (0–9.4%), respectively, in other conditions such as multiple sclerosis,
cancer pain, CUD, and neuropathic pain failed to demonstrate a significant
improvement of depression as a secondary endpoint [2]
[81].
On the other hand, there is no evidence suggesting that recreational use of
cannabis is an independent risk factor for the onset of mood
disorders [78]. A recent genetic study
suggested that carriers of the cannabinoid receptor 1 (CNR1) A-allele are more
susceptible to developing depression [82].
Obsessive compulsive disorder (OCD)
While numerous animal studies have suggested that cannabis-based medicines
may improve obsessive-compulsive symptoms (for review, see [83]), clinical studies are limited. In a
large internet survey from the US, the majority of patients with OCD
self-reported that using cannabis medicinally resulted in an improvement
of OCD [84]. According to a small number
of single case studies, dronabinol, and cannabis flowers improve
compulsive behaviors and obsessive thoughts [83]
[85]
[86]. In a small RCT (N=11), co-medication
with nabilone (up to 2 mg/day, corresponding to 14–16 mg THC/day) augmented
exposure-based behavioral psychotherapy for OCD, while monotherapy with nabilone
had no significant effect [10]. In a small
placebo-controlled single-dose study (N=12), no acute effects of low-dose smoked
cannabis with different THC:CBD ratios (about 400 mg of
cannabis with either 7.0% THC and 0.18% CBD or 0.4% THC and 10.4%
CBD) were detected [87].
While in a small open-label study (N=14), dronabinol was effective in reducing
trichotillomania [88], in one randomized,
double-blind, placebo-controlled, parallel-group follow-up study over 10 weeks
in a mixed population with trichotillomania (N=34) or skin picking disorder
(N=16), dronabinol (5–15 mg/day) did not significantly separate from placebo on
any efficacy measure [89].
Post-traumatic stress disorder (PTSD)
The title of a recent editorial by Abizaid et al., “Cannabis: A potential
efficacious intervention for PTSD or simply snake oil?” [90] strikingly illustrates the
controversial debate about the sense or nonsense of cannabis in the
treatment of PTSD. Similar to other mental illnesses, from epidemiological
studies, it is well-known that patients with PTSD often self-medicate with
cannabis
[6]. In some
observational studies, negative effects have been reported in patients with PTSD
when using cannabis, such as overall worsening of symptoms, more violent
behavior, more alcohol use [91], an
increase in trauma-associated intrusions [92] as well as suicidal thoughts and behavior [93]. Other surveys suggested the contrary,
showing the use of cannabis resulted in more than 50% improvement in all
recorded PTSD symptoms, including intrusive thoughts, flashbacks, irritability,
anxiety [94] as well as a significantly
lower risk of a major depressive episode and the presence of suicidal ideation
[95].
From a small number of case reports and uncontrolled studies, beneficial effects
on different symptoms in patients with PTSD have been reported after use of
cannabis
[96]
[97]
[98], THC, nabilone [99]
[100]
[101], and pure CBD [102]
[103], respectively.
Up to now, there are only three small controlled studies (including between N=10
and N=33 patients) available reporting significantly improved nightmares and
overall clinical impression after treatment with 0.5 mg nabilone [104] and improved anxiety and cognitive
impairment after a single dose of 300 mg CBD [105]
[106]. In the largest RCT
published so far in this indication, treatment with three different
concentrations of smoked cannabis (THC/CBD=12%/<0.05%,
THC/CBD=0.50%/11%, and THC/CBD =7.9%/8.1%) in N=80 military veterans with PTSD
was not superior compared to placebo [107].
Limited data suggest that the ECS is involved in the pathogenesis of PTSD, as
indicated by a globally increased binding to central cannabinoid CB1 receptors
as well as decreased blood levels of the endocannabinoid anandamide [108].
Sleeping disorders
Anecdotally, it has been reported several times that patients often use
cannabis and cannabis-based medicine, respectively, to improve
sleeping problems [6]
[7]
[37]
[77]
[109]. In patients with chronic pain, the
beneficial effects of cannabis-based medicines on sleep as a secondary
outcome measure have been demonstrated [110]. In a small controlled study (N=19), it was found that nabilone
(mean dose=0.86 mg/day (corresponding to 6–7 mg THC), range, 0.25–1.75 mg/day)
improves – among other non-motor symptoms – night-time sleep problems in
patients with Parkinson’s disease [111].
However, the database supporting the use of medicinal cannabis as an
effective and safe treatment option for sleep disorders is still very weak [112]. So far, only two small RCTs have been
performed investigating the efficacy of cannabis-based treatment in
patients with sleep disorders. In the first study, N=24 patients with chronic
insomnia (symptoms+≥+3 months) received up to 1 mL of the cannabinoid extract
ZTL-101, which contains 20 mg/mL THC, 1 mg/mL CBD, 2 mg/mL CBN, and naturally
occurring terpenes or placebo for two weeks [113]. Insomnia symptoms and sleep quality significantly improved
after treatment with the cannabis extract. In the second study, including
N=29 patients with insomnia, medicinal cannabis oil containing 10 mg/mL
THC and 15 mg/mL CBD (up to a maximum dose of 15 mg THC/22.5 mg CBD per day)
over 2 weeks also resulted in an improvement of time and quality of sleep. In
addition, midnight melatonin levels improved significantly [114].
Tourette syndrome (TS)
Thirty-five years ago, in 1988, an anecdotal report suggested for the first time
that smoked cannabis may improve symptoms in patients with TS [115]. Thereafter, several similar case
reports and open-label studies have been published reporting not only a
sustained reduction of tics and premonitory urges, but also an improvement of a
broad spectrum of psychiatric comorbidities, including ADHD, sleeping problems,
self-injurious behavior, impulsivity, OCB, and depression after use of smoked
cannabis
[ [116]
[117]
[118]
[119]
[120] and oral cannabis-based
medicines such as THC, THC plus CBD, THC plus PEA, and nabiximols, respectively
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]. In addition, one case study reported an improvement in the
driving performance of the patient after the use of THC [123]. Beneficial effects of
cannabis-based treatments (THC, nabiximols, and inhaled cannabis)
were also been reported in four children and adolescents aged 7 to 16 years with
improved tics, ADHD, depression, and insomnia [120]
[126]
[129]
[130]
[131].
To date, four controlled trials have been published investigating the effects of
different cannabinoids in adults with TS. In two small-scale studies including
N=12 (single dose of THC up to 10 mg) and N=24 patients (up to 10 mg THC/day for
6 weeks), respectively, THC resulted in a significant improvement of tics [132]
[133] without causing impairment in neuropsychological performance
[134]
[135]. Another small RCT (N=12) suggested that vaporized single doses
of 0.25 g of medicinal cannabis containing 10% THC and 9%/9% THC/CBD –
but not 13% CBD – reduce tics and premonitory urges [136].
Only recently, results from the first large, well-designed RCT investigating the
efficacy and safety of the cannabis extract nabiximols have been reported
[137]
[138]. Although this study, including N=97 patients with TS, formally
failed to demonstrate superiority for nabiximols (mean dose=7.21+±+3·42
puffs/day for 13 weeks) over placebo in the primary endpoint, the results showed
clear trends for improvements in tic severity, depression, and quality of life
after treatment with nabiximols.
While in a small controlled single-dose single-center phase 1b cross-over study
(N=20), the endocannabinoid modulator Lu AG06466 (formerly known as ABX-1431)
that reduces the degradation of the endocannabinoid 2-AG by inhibiting the
monoacylglycerol lipase (MAGL) was effective in reducing tics and premonitory
urges in patients with TS [139], in a
follow-up RCT including N=49 patients, Lu AG06466 was not effective in reducing
tics or related symptoms in patients with chronic tic disorders [140].
Preliminary data suggests a dysfunction in the ESC in TS, since levels of
different endocannabinoids (anandamide, 2-AG, the endocannabinoid-like molecule
PEA, and arachidonic acid (AA)) were 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
between variants of the CNR1 gene and an increased risk for TS [142].
Summary
Future studies will show whether the ECS is pathophysiologically involved in mental
illnesses. Because of its paramount role as a neuromodulatory system in the brain,
it can be speculated that stimulation of the ECS influences symptoms of mental
illnesses, even if they are caused by alterations in other neurotransmitter systems.
Finally, agonists at central cannabinoid CB1 receptors, such as THC-containing
cannabinoids, can reduce stress, which may ameliorate a wide spectrum of
psychopathological symptoms.
Although a substantial number of patients with various mental illnesses self-medicate
with cannabis, current knowledge about the efficacy and safety of
cannabis-based medicine in psychiatry is still in its infancy. There is
limited evidence that THC-containing substances may improve tics in patients with TS
as well as different symptoms in ASD and PTSD. From a small number of studies it is
suggested that CBD improves social anxiety disorder. Although cannabinoids are often
used in these indications, based on current literature, it is still unclear whether
they may be effective in sleep disorders, depression, and ADHD. It should be noted
that all data presented refer to data in adult patients besides a small number of
studies on ASD and TS. Accordingly, in children, cannabis-based medicine
should be used with particular caution, because only very little data is available
on efficacy and safety in patients with various psychiatric disorders in this age
group.
Against the background that cannabis-based medications are safe and, in most
cases, well tolerated, this group of substances may provide a new treatment strategy
in otherwise treatment-resistant patients suffering from psychiatric disorders,
including CUD, ASD, TS, PTSD, anxiety disorders, sleeping disorders, ADHD, and
depression. Currently, different cannabinoid modulators that either inhibit the
degradation or the reuptake of endocannabinoids are under development and might be
further alternative options for the treatment of mental illnesses in the future.
