Psychopharmacology (2022) 239:2713–2734

https://doi.org/10.1007/s00213-022-06196-4

REVIEW

Cannabidiol for the treatment of autism spectrum disorder: hope

or hype?
João F. C. Pedrazzi1 · Frederico R. Ferreira2 · Danyelle Silva‑Amaral3 · Daniel A. Lima1 · Jaime E. C. Hallak1 ·
Antônio W. Zuardi1 · Elaine A. Del‑Bel1,4 · Francisco S. Guimarães5 · Karla C. M. Costa5 · Alline C. Campos5 ·
Ana C. S. Crippa6 · José A. S. Crippa1

Received: 15 November 2021 / Accepted: 18 July 2022 / Published online: 29 July 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022

Abstract
Rationale Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include
impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellec‑
tual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence,
morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression,
sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its
neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available
that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder.
These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence.
Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotrans‑
mitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a
possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system
and shows promising results in studies related to disorders in the central nervous system.
Objectives Review the preclinical and clinical data supporting CBD’s potential as a treatment for the symptoms and comor‑
bidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this
drug.

Keywords Cannabidiol · Autism spectrum disorder · Treatment autism spectrum disorder · Endocannabinoid system ·
Pharmacological targets · Animal models · Clinical trials · Medical Cannabis

Introduction and stereotyped, repetitive, and restrictive behavior pat‑

terns (American Psychiatric Association 2013). Although
Autism spectrum disorder (ASD) is a set of heterogene‑ defined by these significant symptoms, the phenotype in
ous disorders of early neurodevelopment characterized ASD patients may vary, ranging from individuals with
by impaired social interaction, deficits in communication, severe intellectual disability and poor performance in

4
* João F. C. Pedrazzi Department of Morphology, Physiology, and Basic
joaofranciscopedrazzi@usp.br Pathology, School of Dentistry of Ribeirão Preto, University
of São Paulo, Ribeirão Preto, São Paulo, Brazil
1
Department of Neurosciences and Behavioral Sciences, 5
Department of Pharmacology, School of Medicine
School of Medicine of Ribeirão Preto, University of São
of Ribeirão Preto, University of São Paulo,
Paulo, Ribeirão Preto, São Paulo, Brazil
Ribeirão Preto, São Paulo, Brazil
2
Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 6
Graduate Program in Child and Adolescent Health,
Rio de Janeiro 21040‑900, Brazil
Neuropediatric Center of the Hospital of Clinics (CENEP),
3
Department of Physiology, School of Medicine of Ribeirão Federal University of Paraná, Curitiba, Paraná, Brazil
Preto, University of São Paulo, Ribeirão Preto, São Paulo,
Brazil

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Vol.:(0123456789)
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adaptive behavioral skills to individuals with normal intel‑
ligence quotient (IQ) who lead independent lives. Patients
with this disorder may also have other comorbidities that
can cause a delay in diagnosis (Lai et al. 2014), such as
hyperactivity, gastrointestinal and sleep disorders, epilepsy,
psychosis, aggressiveness, self-injury, and social anxiety
(South and Rodgers 2017). The emergence of ASD symp‑
toms appears in the first three years of life, with a higher
prevalence in males (4:1) (Brugha et al. 2011; Levy et al.
2011). In a recent study conducted in the USA based on
the 5th edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5), among 8-year-old children, 1
in 59 was shown to have ASD (Baio et al. 2018). Therefore,
the incidence of ASD has significantly increased worldwide,
ranking third among developmental disorders, ahead of con‑
genital malformations and Down syndrome (Volkmar et al.
2004; Schroeder et al. 2010). Several central nervous sys‑
tem (CNS) areas have been associated with ASD neurobiol‑
ogy, including the hippocampus, prefrontal cortex, ventral
striatum, amygdala, and cerebellum (Bugalho et al. 2006;
Rossignol and Bradstreet 2008; Luna et al. 2015). Brain
structures involved in ASD tend to develop more slowly
(Ashwood et al. 2006). Although several genetic and envi‑
ronmental factors have been identified and associated with
this disorder, the etiology of ASD remains unknown (Bölte
et al. 2019). Over the past few years, the understanding of
the genetic changes, including de novo mutations, in ASD
has expanded (Ramaswami and Geschwind 2018). Several
genes associated with ASD susceptibility have been identi‑
fied in approximately 10–20% of the cases (Brugha et al.
2011).
Furthermore, epigenetic mechanisms and specific gene-
environment interactions are likely involved in the etiology
of ASD (Lai et al. 2014). Environmental influences include
pathophysiological changes in the CNS caused by oxidative
stress, neuroinflammation, mitochondrial dysfunction, and
biochemical disorders (Herbert 2010). Clinical and experi‑
mental evidence indicates that prenatal bacterial and viral
infections, such as rubella and cytomegalovirus, interfere
in the intrauterine environment (Yamashita et al. 2003;
Libbey et al. 2005; Atladóttir et al. 2010). These factors
may promote behavioral abnormalities with similarities to
autism, including inadequate activation of proinflammatory
cytokines and abnormal immune response (Dalton et al.
2003; Kirsten et al. 2010). In several studies, the immune
system was associated with neuropsychiatric disorders (for
review, see Nutma et al. 2019).
Specific compounds to treat the core symptoms of ASD
or its progression are not yet available. Several conventional
drugs, such as atypical antipsychotics, anxiolytics, stimu‑
lants, and selective serotonin reuptake inhibitors (SSRIs),
have been used to alleviate some symptoms and commonly
related comorbidities of ASD. These non-specific beneficial
13
Psychopharmacology (2022) 239:2713–2734
effects must be balanced against the common adverse effects
and low compliance caused by these drugs. It is essential
to emphasize that early intervention could improve the
clinical outcome of children with ASD (Warren et al. 2012;
Zwaigenbaum et al. 2015). Since there is an increase in
prevalence and high economic and social costs of ASD,
new pharmacological approaches and molecular targets are
needed to elucidate and optimize the treatment of ASD,
which is often limited. Consequently, there is an increasing
interest in investigating CBD for the vast symptomatology
of ASD since this compound may present a therapeutic pro‑
file for psychiatric conditions that are associated with this
disorder (for review, see Poleg et al. 2019). Additionally,
the probable involvement of the endocannabinoid system
in the pathophysiology of ASD is the subject of extensive
investigation. Consistent results from endocannabinoid dys‑
function in animal models of ASD and clinical studies have
been shown (Qin et al. 2015; Servadio et al. 2016; Melancia
et al. 2018). Moreover, retrospective and uncontrolled trials
of CBD- enriched Cannabis in subjects under this condition
have been published (Aran et al. 2019a, b; Kuester et al.
2017; Mostafavi and Gaitanis 2020). Despite promising
results from the use of CBD in patients with ASD, there are
few discussions regarding its interactions with other drugs,
the side effects and the selection of patients who could ben‑
efit from its use.
Meanwhile, anecdotal evidence emerges concomitantly
with the search for CBD formulations, which often do not
undergo scientific rigor. Given the complexity of ASD, the
urgency of developing effective and safe treatments is evi‑
dent while simultaneously conducting responsible and criti‑
cal approaches to drugs that can have therapeutic effects, as
is the case with CBD.
The current review will present preclinical and clinical
studies that motivate the use of CBD and how the modula‑
tion of the endocannabinoid system can benefit the range
of symptoms present in ASD and adequately discuss the
challenges of its use from the perspective of its intense
dissemination.
The endocannabinoid system and its involvement
in the pathophysiology of ASD
The Cannabis plant contains many chemical compounds,
including flavonoids, terpenes, fatty acids, and phytocan‑
nabinoids. There are more than 100 phytocannabinoids in
Cannabis, including delta-9-tetrahydrocannabinol (THC),
the main psychotomimetic constituent, and CBD, which
lacks the subjective effects caused by THC (for review,
see Carlini 2010). In the early 1990s, the discovery of
the cannabinoid receptors type 1 (CB1) and type 2 (CB2)
significantly advanced the understanding of the effects of
chemical compounds in Cannabis (Matsuda et al. 1990;
Psychopharmacology (2022) 239:2713–2734
Kaminski et al. 1992; Munro et al. 1993). THC is a partial
agonist of CB1 receptors. The activation of these receptors
plays a critical role in the acute anxiogenic and psychotic
experiences associated with the use of Cannabis (Huestis
et al. 2001). The receptors are mainly located presynapti‑
cally, with high densities in the cerebral cortex, olfactory
bulb, hippocampus, lateral caudate-putamen, substantia
nigra, globus pallidus, and cerebellum. In contrast, a low
density of these receptors is observed in the thalamus and
peripheral organs and tissue (Pertwee, 2008; Russo et al.
2005; Munro et al. 1993). The CB1 receptors are located in
areas associated with motor control, learning and memory,
emotional response and cognitive functions, and structures
related to ASD neurobiology (Zamberletti et al. 2017). The
CB2 receptor is mainly expressed in the immune system.
However, the receptor is also present in microglia and some
postsynaptic locations in the CNS (Sagar et al. 2009). CB2
receptors may also be expressed in neural cells involved in
the perception/modulation of pain (Zhang et al. 2003; Elmes
et al. 2004; Clayton et al. 2002; Nackley et al. 2003). CB1
and CB2 receptors are coupled to inhibitory protein G that,
when activated, inhibits the enzyme adenylate cyclase, lead‑
ing to a decrease in cyclic AMP levels and inhibition of
calcium channels (Breivogel et al. 1997; Piomelli, 2003).
The activation of CB1 receptors inhibits the release of
other neurotransmitters, such as GABA and glutamate. The
main endogenous agonists of CB1 and CB2 receptors are
derived from arachidonic acid and, similar to the phytocan‑
nabinoids in Cannabis sativa, are lipid. The most studied
endocannabinoids are 2-arachidonoyl glycerol (2-AG) and
anandamide (arachidonoyl ethanolamine, ananda, from the
Sanskrit meaning “joy, bliss, delight.” (Devane et al. 1992;
Mechoulam et al. 1995; Sugiura et al. 1995). Unlike classic
neurotransmitters, endocannabinoids are not synthesized at
presynaptic terminals or stored in vesicles but are formed
based on demand at postsynaptic terminals (Devane 1994;
Iversen 1994). After calcium influx, activation of phospho‑
lipases converts the phospholipids into endocannabinoids
(phospholipase D in the case of anandamide and diacylg‑
lycerol lipase in the case of 2-AG). These substances act
on presynaptic CB1 receptors inhibiting neurotransmitter
release (Beltramo et al. 1997, Egertová et al. 1998, Piomelli
2003). The availability of endocannabinoids is regulated by
enzymatic uptake/degradation. The fatty acid amide hydro‑
lase (FAAH) and monoacylglycerol lipase (MGL) enzymes
efficiently hydrolyze anandamide and 2-AG, respectively
(Cravatt et al. 1996; Dinh et al. 2002). The concept of the
endocannabinoid system has been recently revised to include
other receptors that have an affinity for anandamide, such as
the G protein-coupled receptor 55 (GPR55), the transient
receptor potential vanilloid-1 (TRPV1) cation channel,
and peroxisome proliferator-activated receptors (PPARs).
N-acylethanolamines and N-acyldopamines, another class
2715
of lipids, have properties similar to endocannabinoids, act‑
ing in many cases on CB1 and CB2 receptors in addition
to GPR55, TRPV1, and PPARs (Di Marzo 2020; Cristino
et al. 2020). The number of receptors, enzymes, proteins, ion
channels, and transporters involved in the spectrum of the
endocannabinoid system has been updated and increased,
including a more expanded system termed the endocan‑
nabinoidome. Due to their wide distribution in the CNS,
the endocannabinoidome has been suggested to participate
in the modulation of various brain functions, including
memory and learning, executive functions, and motivational
processes relevant to neurodevelopmental disorders such as
ASD (Di Marzo and Maccarrone 2008).
More than 100 genes and genomic regions are currently
associated with autism. The earliest successes in gene discov‑
ery revealed important general properties, such as most pro‑
teins encoded by autism risk genes participate in either synap‑
tic structure and function or chromatin modification and
regulation of gene expression. Furthermore, in a large-scale
exome sequencing study, both developmental and functional
changes were implicated in the neurobiology of autism (Sat‑
terstrom et al. 2019). Rare genetic variants have been found in
genes closely linked to the endocannabinoid system, such as
cannabinoid receptor 1 (CNR1), CNR2, GPR55, diacylglyc‑
erol lipase alpha (DAGLA), MGL, and FAAH (Smith et al.
2017). In that study, molecular trials were conducted on 6032
patients with a broad spectrum of neurological disorders and
rare genetic variants observed. The variants were evaluated for
association with phenotypes similar to those observed in the
knockout orthologous genes in mice. Rare heterozygous cod‑
ing variants in CNR1, which encode CB1 receptors, are sig‑
nificantly associated with sensitivity to pain (especially
migraine), sleep, and memory disorders alone or in combina‑
tion with anxiety when compared with a set of controls without
these variants in the CNR1 gene. Similarly, rare heterozygous
variants in DAGLA, which encode DAGLA, have been found
significantly associated with seizures and neurodevelopmental
disorders, including ASD and abnormalities of brain morphol‑
ogy, compared with healthy controls. As mentioned earlier,
DAGLA synthesizes the endocannabinoid 2-AG in the brain,
interacting with CB1 receptors (Howlett et al. 2010). The phe‑
notypes associated with rare variants of CNR1 are similar to
the phenotypes thought to be involved in the clinical syndrome
of endocannabinoid deficiency. The several phenotypes associ‑
ated with rare variants of DAGLA emphasize the critical role
of rapid synthesis of 2-AG and the endocannabinoid system in
regulating neurological function and development, events
associated with the neurobiology of ASD (Smith et al. 2017).
It is worth mentioning that genetic variations associated with
the endocannabinoid system may be why ASD patients using
CBD-enriched Cannabis do not benefit equally from treating
their symptoms, while others may be more susceptible to side
effects. Indeed, it is suggested these patients may be more
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prone to the broadside effect profile relative to other patient
populations (Mostafavi and Gaitanis 2020). Thus, preclinical
studies, pharmacogenetics, pharmacogenomics, and double-
blind, randomized placebo-controlled clinical trials to evaluate
gene expression and post-translational mechanisms are critical
to elucidate this challenge. To date, clinical studies suggest that
CBD-enriched Cannabis may benefit epilepsy, aggression,
improved mood, anxiety, and social interaction in ASD
patients. These approaches will be discussed throughout the
review. Changes in the functioning of the immune system have
been associated with the etiology of ASD (Lyall et al. 2014;
Siniscalco et al. 2012). In agreement with these findings, based
on an analysis of mononuclear cells extracted from peripheral
blood, patients with ASD have excessive production of IL-1β,
which can result in long-term immunological changes
(Enstrom et al. 2010). As already discussed, CB2 receptors are
closely associated with the immune response. In a pioneering
study, the mononuclear cells in the peripheral blood of patients
with ASD were compared with healthy controls (Siniscalco
et al. 2013). The authors reported significantly high mRNA
and protein levels in CB2 receptors in the ASD group, indicat‑
ing modulation of the endocannabinoid system through these
receptors could be a therapeutic target in the search for drugs
that can treat the various symptoms present in ASD (Sinis‑
calco et al. 2013). Furthermore, reduced concentration of the
endocannabinoid anandamide (Karhson et al. 2018; Aran et al.
2019a, b) and lower levels of oleoyl ethanolamide and palmi‑
toylethanolamide (Aran et al. 2019a, b) have been described
in ASD patients. In addition, reduced plasma anandamide lev‑
els (Karhson et al. 2018) and associations between polymor‑
phisms in the gene encoding CB1 receptor and emotional
processing (Chakrabarti et al. 2006; 2011; Domschke et al.
2008) have been reported in children with ASD. A better
understanding of neurochemical mechanisms that mediate
emotional processing like the social reward is essential for
developing novel treatments, especially for disorders in which
these processes are impaired. Social reward applies to a variety
of positive stimuli and experiences. Humans and animals have
a strong motivation to seek social relationships. The need to
be part of a group causes us to act prosocially, evidencing the
satisfactory nature of sociability (Rademacher et al. 2017).
These events are critical to maintaining health and survival.
Several approaches suggest that adequate social stimuli early
in life are fundamental for developing socio-emotional and
cognitive skills, while adverse social experiences negatively
affect neurodevelopment and behavior, culminating in
increased susceptibility to neuropsychiatric conditions (Man‑
duca et al. 2021). It is proposed that impairments in social
reward in patients with ASD may result from early deficits in
social motivation (Chevallier et al. 2012). There is evidence
that endocannabinoid neurotransmission has a critical role in
mediating social reward in different animal groups. Moreover,
CB1 receptors are widely expressed in areas implicated with
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Psychopharmacology (2022) 239:2713–2734
this behavior, such as the prefrontal cortex, basolateral amyg‑
dala, hippocampus and ventral striatum (Wei et al. 2017; Man‑
duca et al. 2021). In two widely used mouse models of ASD,
the BTBR and fmr1−/− (model of fragile X syndrome), the
FAAH blockade by URB597 completely reversed the social
impairment in mice (Wei et al. 2016). Furthermore, the CB1
receptor blockade, by AM251, prevented the prosocial effect
of FAAH inhibition in BTBR mice, indicating that increasing
anandamide activity at these receptors improves ASD-related
social impairment (Qin et al. 2015). 2-AG also seems to play
an important role in the regulation of social reward in rodents,
as its selective decrease in the forebrain of male transgenic
mice (MGL-Tg mice) impaired their performance in the
socially induced place conditioning (Wei et al. 2016). Further‑
more, CB1 receptor knockout mice exhibit more aggressive
behaviors, as well as active and passive defensive coping
behaviors such as avoidance, freezing, and risk assessment,
suggesting these receptors play an essential role in decreasing
social stress and consequently in the regulation of social
reward (Rodriguez-Arias et al. 2013; Litvin et al. 2013). Dur‑
ing development, CB1 receptors drive axon guidance and are
associated with synaptogenesis (Harkany et al. 2008; Watson
et al. 2008; Fride et al. 2009). Children with ASD have abnor‑
mal brain connectivity, which could be due to a lack of CB1
axon guidance (McFadden and Minshew, 2013). In addition,
reduced expression of CB1 receptors was found in the post‑
mortem brains of individuals with ASD (Purcell et al. 2001).
In preclinical models of ASD induced by valproic acid (VPA),
CB1 receptors displayed altered phosphorylation in different
brain areas associated with anandamide metabolism changes
in a sex-dependent manner (Servadio et al. 2016; Melancia
et al. 2018). In addition, the increased anandamide caused by
inhibition of its degradation enzyme (FAAH) with the com‑
pound URB597 corrected social and emotional impairments
induced by VPA exposure during the neurodevelopmental
period in both studies. Furthermore, in a recent study, the
in vivo optogenetics technique showed that activating the baso‑
lateral amygdala-nucleus accumbens (BLA-NAc) glutamater‑
gic circuit reduced interaction and increased social avoidance
in mice (Folkes et al. 2020). The increased endocannabinoid
2-AG signaling caused by inhibiting its degradation enzyme
(MGL) with the compound JZL184 reduced the glutamatergic
activity of the BLA-NAc. It prevented the impairment in social
interaction associated with the stimulation of this pathway
­ hank3B−/− mice, an ASD model
in vivo. In addition, in the S
which displays significant impairment in social interaction, the
optogenetic inhibition of the BLA-NAc circuit markedly
increased social interaction in the mice. Thus, systemic injec‑
tion of JZL184 or direct microinjection into the NAc also nor‑
­ hank3B−/− mice.
malized deficits in the social interaction of S
However, ex vivo administration of JZL184 corrected aberrant
excitatory and inhibitory neurotransmission in the NAc and
reduced feed-forward inhibition induced by BLA-NAc in NAc
Psychopharmacology (2022) 239:2713–2734
neurons in Shank3B −/− mice. These data reveal neuromodula‑
tory mechanisms at the level of neuronal circuitry, which regu‑
lates the social function relevant to ASD, indicating that
increased signaling by 2-AG can reduce social deficits by
modulating excitatory and inhibitory neurotransmission in the
NAc (Folkes et al. 2020). Evidence also shows the endocan‑
nabinoid system interacts with oxytocin-mediated social
reward. Oxytocin mobilizes anandamide in the NAc, which
may be associated with social impairment in ASD (Wei et al.
2015). The involvement of oxytocin in the pathophysiology of
ASD has been previously investigated (Young and Barrett
2015). Intranasal administration of the ‘‘prosocial” neuropep‑
tide oxytocin was shown to have potential therapeutic effects
on ASD (Anagnostou et al. 2012; Bernaerts et al. 2020). Fur‑
thermore, the involvement of oxytocin in the pathophysiology
of ASD has been confirmed (Young and Barrett 2015). Oxy‑
tocin is produced in the paraventricular and supraoptic nuclei
of the hypothalamus (Swanson and Sawchenko 1983) released
by magnocellular neurons in the bloodstream and is crucial for
stimulating the contraction of the smooth muscle of the uterus,
facilitating labor, induction of lactation, and mechanisms
involved with the reproduction and care of offspring, in addi‑
tion to intimate participation in social and reward behavior
(Carter 2014). Notably, in several studies, an interaction
between the endocannabinoid system and oxytocin mediating
social reward has been reported. Oxytocin induces mobiliza‑
tion of anandamide to the NAc, which may be associated the
social impairment in ASD (Wei et al. 2015). Endocannabi‑
noids could modify the inflammatory process associated with
ASD (Knuesel et al. 2014). In the maternal immune activation
(MIA) model, intense production of the proinflammatory
cytokine interleukin (IL)-17 is associated with abnormal corti‑
cal development and social deficits in the offspring occurs
(Choi et al. 2016). In a mouse model of immune hypersensitiv‑
ity, anandamide decreased IL-17 production and increased the
expression of the anti-inflammatory cytokine IL-10 (Jackson
et al. 2014). Treatment with the innate immunostimulant
lipopolysaccharide (LPS) during adolescence increased anan‑
damide level and FAAH activity in the amygdala and
decreased social behavior. These alterations are attenuated by
the FAAH inhibitor PF-04457845 (Doenni et al. 2016).
CBD structure, pharmacological targets, and studies
with therapeutic potential relevant to ASD
CBD is the main non-psychotomimetic phytocannabinoid
present in the Cannabis plant and was isolated in the early
1940s by Adams et al. 1940. However, the chemical struc‑
ture was elucidated only in 1963 by Mechoulam and Shvo
(1963). The observation that CBD antagonized some of the
main pharmacological effects of THC led to the hypothesis
that CBD could have anxiolytic and antipsychotic properties
(Zuardi et al. 1982; 1993; Guimarães et al. 1990;
2717
Bhattacharyya et al. 2010; Englund et al. 2013). This
hypothesis was further investigated in several laboratory
animal and clinical studies. More than 65 potential pharma‑
cological targets associated with several promising thera‑
peutic applications of CBD are described. Unlike THC,
in vitro assay results indicated CBD has a low affinity or can
even function as an antagonist or inverse agonist of CB1
receptors (Thomas et al. 2007; Laprairie et al. 2015). How‑
ever, CBD can also block the metabolism and/or uptake of
anandamide (Bisogno et al. 2001; Schubart et al. 2014). This
last action is the primary effect of CBD on the CB1- or CB2-
mediated neurotransmission complex. CBD does not cause
the cannabinoid tetrad (hypolocomotion, catalepsy, hypo‑
thermia, and antinociception) that is considered a good pre‑
dictor of THC-like pharmacological activity, thus confirm‑
ing that CBD lacks direct CB1 agonist properties (Martin
et al. 1991). However, some of the CBD effects (e.g.,
increased hippocampal neurogenesis) are prevented by CB1
or CB2 receptor antagonists, indicating they depend on the
facilitation of endocannabinoid signaling (Campos et al.
2013; Fogaça et al. 2018). Regarding the endocannabinoi‑
dome, CBD presents pharmacological targets that may be
relevant to ASD. CBD can activate TRPV1 receptors
(Bisogno et al. 2001), facilitating glutamate release (Musella
et al. 2010; Ho et al. 2012). This compound can facilitate
5-HT1A-mediated neurotransmission causing anxiolytic,
antidepressant, and pro-cognitive effects. Moreover, consid‑
erable evidence in animal models that address fear memory
processing indicates that CBD can decrease learned fear in
parameters relevant to the translational study of phobias and
post-traumatic stress disorder (Campos and Guimarães
2008; Linge et al. 2016; Russo et al. 2005; Lee et al. 2017).
In addition, the receptors in glycinergic signaling are altered
in subjects with ASD (Pilorge et al. 2016). Therefore, CBD
can directly or indirectly act on spinal glycine receptors,
especially in the a1 and a3 subunits, causing an analgesic
effect on inflammatory pain (Lu et al. 2018). Due to its poly‑
phenolic structure, CBD displays important antioxidant
properties. In addition, CBD has anti-inflammatory effects,
which may be associated with its neuroprotective activities,
increasing the therapeutic properties of CBD in ASD patho‑
physiology (Chadwick et al. 2013; Franco and Perucca
2019). Furthermore, CBD blocks the orphan GPR55, a
mechanism associated with its anticonvulsant and antitu‑
moral effects (Morales et al. 2017; Laezza et al. 2020). The
GPRs are widely expressed in the brain. In studies with mice
subjected to acute stress, activation of these receptors report‑
edly produced an anxiolytic and antidepressant effect. How‑
ever, whether CBD exerts similar actions on GPR55 remains
unclear (Sawzdargo et al. 1999; Shi et al. 2017). The endo‑
cannabinoid system with phytocannabinoids can modulate
mesocorticolimbic dopaminergic signaling, a pathway asso‑
ciated with the emergence of psychosis (Hudson et al. 2018).
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2718
Previous in vitro binding assay results indicated CBD
mighty function as a partial agonist of D2-type dopaminer‑
gic receptors in the rat striatum, reinforcing its antipsychotic
properties shared with clinically used drugs such as aripipra‑
zole (Seeman 2016). Furthermore, in a neurodevelopment
model in which methylazoxymethanol acetate (MAM) is
used in pregnant rats to generate offspring that mimic symp‑
toms of schizophrenia in adulthood, such as cognitive defi‑
cits, dopaminergic dysfunction, and physical and behavioral
abnormalities, the action of CBD via partial agonism of D3
receptors was suggested to improve these disruptions (Stark
et al. 2020). Finally, CBD could interact with many other
signaling systems such as the opioid, adenosine, transient
channel, and PPARs (Carrier et al. 2006; Linge et al. 2016;
Sonego et al. 2018). PPARs are a family of nuclear receptors
widely distributed in various organs and tissues (O’Sullivan
2016) and may contribute to the pathophysiology of ASD.
In several studies, PPAR expression and their endogenous
modulators are downregulated in ASD because the admin‑
istration of these endogenous or synthetic ligands can
improve behaviors associated with mood and cognition
(Capano et al. 2018; Mirza and Sharma 2019). As already
mentioned, ASD may have a strong neuroinflammatory
activity, supporting the hypothesis that CBD actions via
PPARs could reduce behaviors associated with the ASD
phenotype, as well as reduce inflammation and oxidative
stress. ASD patients present several clinical manifestations
observed in other psychiatric disorders, such as psychosis,
anxiety, stereotypical behavior, hyperactivity, aggressive‑
ness, sleep disorders, epilepsy, allergies, and autoimmune
and gastrointestinal conditions (for review, see Crippa et al.
2018). The therapeutic potential of CBD in several of these
disorders has been described since the early 1970s. In a pio‑
neering study, Carlini and coworkers (1975) demonstrated
the protective role of CBD derivatives against agents that
promote seizures in rodents. Later, Cunha and coworkers
(1980) showed this anticonvulsant property in humans. In
normal subjects, CBD reduces the anxiety provoked by high
doses of delta 9-THC (Zuardi et al. 1982). The anxiolytic
effects of CBD have been described in several preclinical
and clinical studies (Guimarães et al. 1990; Batalla et al.
2021) and shown associated with regional cerebral blood
flow (rCBF) changes in limbic and paralimbic areas of the
brain (Crippa et al. 2011). In individuals with social anxiety
disorder, CBD reduced anxiety, cognitive impairment, and
discomfort in a simulated public speaking test (Bergamaschi
et al. 2011). CBD also showed antipsychotic properties in
preclinical and clinical studies. The increased serum anan‑
damide levels in patients with schizophrenia who used CBD
correlated with a reduction in psychotic symptoms (Leweke
et al. 2012), which is encouraging in the context of ASD
because, in several aforementioned trials, patients with ASD
had decreased anandamide levels (Karhson et al. 2018; Aran
13
Psychopharmacology (2022) 239:2713–2734
et al. 2019a, b). CBD administration in rodents prevented
apomorphine-induced stereotypes (Zuardi et al. 1991) and
amphetamine-induced hyperlocomotion (Moreira and Gui‑
marães 2005; Valvassori et al. 2011). When CBD was
directly injected into the NAc, CBD prevented prepulse inhi‑
bition impairment caused by amphetamine (Pedrazzi et al.
2015). In a rodent model of schizophrenia based on chronic
blockade of glutamate N-methyl-D-aspartate (NMDA)
receptors, CBD increased social interaction, improved rec‑
ognition of a new object, improved social withdrawal, pre‑
vented information processing impairment, and decreased
glial reactivity (Gururajan et al. 2011; Gomes et al. 2015a,
b; Silva et al. 2020). In addition, beneficial effects of CBD
have been demonstrated against repetitive behaviors in the
marble-burying test (Casarotto et al. 2010; Nardo et al.
2014) and social isolation-induced aggression in rodents
(Hartmann et al. 2019). Furthermore, CBD could induce
rapid and sustained antidepressant-like effects in animal
models of stress through increased brain-derived neuro‑
trophic factor signaling and synaptogenesis (Sales et al.
2019). Notably, CBD can act on signaling cascades associ‑
ated with the mechanistic target of rapamycin (mTOR) in
animal models that may be associated with symptoms pre‑
sent in ASD (Renard et al. 2016; Sales et al. 2019). It has
been shown that CBD can contain amphetamine-induced
neuronal and behavioral sensitization of the mesolimbic
dopamine pathway, controlling downstream phosphorylation
of the mTOR/p70S6kinasee signaling pathways directly
within the NAc shell. Blocking the mTOR pathway with
rapamycin can prevent the antidepressant effect of CBD in
an animal model of stress. Dysregulation of the mTOR and
protein kinase B cascade has been identified in multiple dis‑
orders, indicating a potential mechanism associated with
neurodevelopmental disorders such as ASD (Sahin and Sur
2015). The mTOR pathway is a conserved serine/threonine
kinase in the phosphoinositide-3-kinase (PI3K) family that
integrates multiple intracellular and extracellular signals and
coordinates multiple cellular responses, including protein
synthesis, growth, and proliferation (Winden et al. 2018).
An imbalance may exist between excitatory and inhibi‑
tory neurotransmissions in ASD, mainly represented by
glutamate and γ-aminobutyric acid (GABA), respectively
(Rubenstein and Merzenich 2003; Gogolla et al. 2009;
Coghlan et al. 2012). The isoforms of glutamic acid decar‑
boxylase (GAD65 and GAD67), a rate-limiting step in con‑
verting glutamate to GABA, are altered in brain structures
associated with ASD (Erlander and Tobin, 1991; Fatemi
et al. 2002). In addition, the expression of parvalbumin
(PV), a calcium-binding protein expressed in a subclass of
rapidly increasing GABAergic interneurons, which partici‑
pates in the regulation of excitatory and inhibitory stimuli in
the brain, is increased after chronic treatment with NMDA
receptor antagonists in rodents (Abdul-Monim et al. 2007).
Psychopharmacology (2022) 239:2713–2734
This finding was confirmed by Gomes et al. (2015a). They
showed that CBD protects interneurons positively labeled for
PV protein in the medial prefrontal cortex in mice chroni‑
cally treated with dizocilpine, also known as MK-801, a
noncompetitive antagonist of NMDA. Any damage to PV-
positive interneurons results in loss of control of neurons
that release the excitatory neurotransmitter glutamate,
with a consequent increase in the activity of neurons that
release dopamine, culminating in psychosis-like conditions
(Schwartz et al. 2012).
Furthermore, gestational injection of poly I: C in rodents
decreased GAD67 expression in the hippocampus of male
but not female offspring. Long-term treatment with CBD
increased hippocampal GAD67 expression regardless of sex
or gestational manipulation, reestablishing the control levels
in male offspring and increasing GAD67 expression above
control levels in females (Osborne et al. 2019a, 2019b). Fur‑
thermore, CBD can increase GABAergic neurotransmission
by antagonizing GPR55, mainly in the basal ganglia nuclei
(Kaplan et al. 2017). Conversely, CBD facilitates 5-HT1A-
mediated neurotransmission in the prefrontal cortex, modu‑
lating glutamate and GABA function (Santana et al. 2004;
Russo et al. 2005). Corroborating a possible association of
this effect with the potential therapeutic effect of CBD in
ASD subjects, proton magnetic resonance (MRS) assays
of postmortem brains of patients with ASD as well as liv‑
ing ASD patients showed abnormalities in GABAergic and
glutamatergic pathways (Ajram et al. 2017; Horder et al.
2014; Cochran et al. 2015). In addition, CBD inhibits the
balanced nucleoside transporter (ENT1) responsible for
synaptic adenosine uptake, thus increasing extracellular
adenosine levels. Therefore, extracellular adenosine posi‑
tively regulated by CBD can trigger a decrease in neuronal
hyperexcitability (Carrier et al. 2006).
As described above, CBD is a multitarget drug (Fig. 1).
Regarding ASD, in addition to the anti-epileptic properties
of CBD, several other mechanisms could be associated with
its potential therapeutic effects. Recently, researchers have
hypothesized a link between the onset of the main behavio‑
ral symptoms of ASD and the chronic neuroinflammatory
condition of the autistic brain. Cannabinoids might represent
a promising pharmacological tool for treating ASD neuro‑
inflammation. Specifically, CBD, which lacks psychotomi‑
metic side effects, could be an effective and safe medication
for treating ASD (Carbone et al. 2021). Microglia are the
primary cells responsible for the immune responses in the
CNS and maintain homeostasis and neuronal functions in the
brain, constantly surveying against infectious agents and inju‑
ries (Araujo et al. 2019). Children born from mothers who
had infections or autoimmune diseases during pregnancy
are more likely to develop ASD (Jiang et al. 2016; Careaga
et al. 2017). Furthermore, postmortem brains of ASD patients
studied using positron-emission tomography (PET) showed
2719
an increase in neuroinflammation and the number of acti‑
vated microglial cells (Vargas et al. 2005; Morgan et al. 2010;
Suzuki et al. 2013). These results indicate that microglia and
neuroinflammation could play a significant role in the patho‑
physiology of ASD (Lenz and Nelson 2018). Also, clinical
trials have shown increased pro-inflammatory cytokines in
the brain and peripheral immune cells of autistic patients
at different ages (Baranova et al. 2021; Toscano et al. 2021;
Carbone et al. 2021). However, it is still unclear if neuroin‑
flammation triggers ASD or whether this event is part of it
(Matta et al. 2019). Furthermore, in cell culture, CBD can
prevent microglial activation induced by LPSs, inhibiting the
release of proinflammatory cytokines (tumor necrosis fac‑
tor-alpha (TNF-α) and IL-1β) and glutamate, a noncytokine
mediator of inflammation, ultimately decreasing neuroin‑
flammation and subsequent glial activation both in vitro and
in vivo (Kozela et al. 2017; Dos-Santos-Pereira et al. 2020).
In a previous review regarding the use of CBD in psychia‑
try for psychosis, anxiety, addictive behavior, mood, cogni‑
tive disorders, sleep disorders, attention-deficit/hyperactiv‑
ity disorder (ADHD), and aggressiveness, the role of the
endocannabinoid system in social behavior, neurodevelop‑
ment, mental disorders, and ASD, the authors concluded
that CBD is a potential candidate for the treatment of ASD
(Poleg et al. 2019). In addition to the various comorbidi‑
ties present in ASD, 20–30% of patients may have epilepsy
(Besag 2018). The US Food and Drug Administration (FDA)
has recently approved the commercialization of an oral CBD
extract (Epidiolex, GW Pharmaceuticals) for the treatment
of drug-resistant epilepsy (Sekar and Pack 2019), especially
for two rare and severe forms, Lennox-Gastaut and Dravet
syndromes. In addition, in a genetic animal model of Dravet
syndrome, CBD effectively reduced spontaneous seizures
and social deficits in mice. This effect may be associated
with restoring neuronal excitability of inhibitory interneu‑
rons in the hippocampal dentate gyrus (Kaplan et al. 2017).
In a recent study, CBD administered in the S ­ cn1a+/− mouse
model of Dravet syndrome prevented premature mortality
and improved several behavioral comorbidities, including
impaired cognition and social interaction, without trigger‑
ing adverse motor effects associated with current pharmaco‑
therapy (Patra et al. 2020). Furthermore, approximately two-
thirds of the patients with Dravet syndrome show decreased
function in the neuronal voltage-gated sodium channel α1
subunit gene (SCN1A) due to mutations in 80% of Dravet
syndrome patients (Nabbout et al. 2003).
In a review of clinical trials designed to study the effects
of CBD treatment on different forms of epilepsy in infants,
children, and teenagers affected by epilepsy resistant to
common antiseizure drugs, the authors concluded that CBD
should be effective and safe for Lennox-Gastaut syndrome,
Dravet syndrome, and drug-resistant epilepsy (Silvestro
et al. 2019).
13
2720
Fig. 1  Chemical structure of CBD and potential targets for its
therapeutic effect on ASD. CBD acts as an agonist of the receptors
TRPV1, PPARγ, and 5-HT1A and as an antagonist of the receptor
GPR55. CBD acts as an inverse agonist of the D2 and D3 receptors.
CBD is suggested to act as an inverse agonist and a negative allos‑
teric modulator of CB1 and CB2 receptors. CBD inhibits the enzyme
FAAH, with a consequent increase in anandamide (AEA) levels. This
endocannabinoid ligand can activate CB1, CB2, and TRPV1 recep‑
tors. CBD increases the activity of mitochondrial complexes and
displays antioxidant and anti-inflammatory effects that are partially
mediated by its actions on TRPV1, mitochondria, and PPARγ. CBD
Trials with CBD‑enriched Cannabis extract
in patients with ASD
The first study was a retrospective assessment of the tolera‑
bility and efficacy of CBD-rich Cannabis in 60 children with
ASD and severe behavioral problems (Aran et al. 2019a, b).
The children were between 5 and 18 years of age, and 83%
of the sample consisted of males. In this trial, the patients
13
Psychopharmacology (2022) 239:2713–2734
inhibits the balanced nucleoside transporter (ENT1) responsible for
synaptic adenosine uptake, increasing extracellular adenosine levels.
CBD can directly or indirectly activate Gly receptors. CBD is also
capable of inhibiting sodium channels. TRPV1, transient receptor
potential vanilloid type 1; PPARγ, peroxisome proliferator-activated
receptor gamma; 5-HT1A, serotonin receptor 1A; GPR55, G-protein-
coupled receptor 55; D2, dopaminergic receptor type 2; D3, dopa‑
minergic receptor type 3; CB1, cannabinoid receptor type 1; CB2,
cannabinoid receptor type 2; FAAH, fatty acid amide hydrolase; A1,
adenosine type 1 receptor; Gly, glycine receptors
attended special education programs for children with ASD
and met the DSM-5 criteria for this disorder at the time of
the treatment. All the children had severe behavioral prob‑
lems based on a Clinical Global Impression Scale-Severity
score of 6 or 7. Initially, the ratio of CBD to THC was 20:1;
however, in 29 patients who presented insufficient responses
based on CGI-S scores ≥ 5, a new strain was attempted. This
strain consisted of a 6:1 ratio of CBD/THC, with a maximum
Psychopharmacology (2022) 239:2713–2734
dose of 5 mg/kg of CBD daily. In addition, 49 children were
treated with other drugs concomitant with Cannabis oil,
including antipsychotics, mood stabilizers, benzodiazepines,
SSRIs, and stimulants. According to their parent’s reports,
twenty children in this group showed some improvement, six
did not improve, and three showed worsening the condition.
At the end of the study, 73% of the children continued using
Cannabis oil. The other children stopped the treatment due
to marked irritability, unsuccessful attempts to administer
the oil, low effectiveness, and adverse effects combined with
low efficacy. Although the results could be considered prom‑
ising, several limitations include a low number of patients,
lack of a placebo group, the use of several different Can-
nabis strains, and the wide variation in the CBD/THC dose
ratio (Table 1).
In another study, oral CBD was evaluated in 53 children
diagnosed with ASD (Barchel et al. 2019). The study group
had a median age of 11 years, and the average duration of
treatment was 66 days. In addition, quality control of CBD
was performed by measuring CBD plasma concentrations.
Information regarding symptoms and treatment safety was
assessed twice a week through interviews with parents.
Adverse effects, such as drowsiness and appetite changes,
were moderate. Overall improvement occurred in 74.5% of
the patients when all comorbidities were evaluated. The dif‑
ference was not reported in 21.6% of cases, and symptom
worsening occurred in 3.9% of the children. The lack of
information on the history of patient ASD symptoms and
the absence of an assessment tool and a control group limit
the interpretation of the findings. In an observational study
conducted in Brazil, 18 patients with ASD ranging in age
from 6 to 17 years received 4.6 mg/kg CBD with 0.06 mg/
kg THC (Fleury-Teixeira et al. 2019). Among the remaining
15 patients, 5 were epileptic patients. The parents or caregiv‑
ers were responsible for monthly evaluating and answering
questionnaires related to the symptoms of ADHD, behav‑
ioral disorders, motor deficits, autonomy deficits, commu‑
nication, social interaction deficits, cognitive deficits, sleep
disorders, and seizures. Some improvement was reported in
motor development, communication and social interaction,
and cognitive performance. However, the small cohort size
and the critical adverse effects (e.g., irritability, increased
appetite, conjunctival hyperemia) limit the generalization
of the findings.
Schleider and coworkers (2019) conducted a prospec‑
tive cohort study in Israel between 2015 and 2017 to evalu‑
ate the effects of CBD-enriched Cannabis in 188 patients
diagnosed with ASD. The initial treatment for 94.7% of
patients was Cannabis oil given sublingually, seven patients
(3.7%) were allowed to buy oil and inflorescence, and three
patients (1.5%) were allowed to buy only inflorescence.
Most patients consumed oil consisting of 30% CBD and
1.5% THC (average 79.5 ± 61.5 mg CBD and 4.0 ± 3.0 mg
2721
THC), three times a day. The THC:CBD ratio was 1:20 and
individually titrated. Symptom assessment and structured
questionnaires assessed side effects after 6 months of CBD-
enriched Cannabis use. After this period of the 155 patients
on active treatment, 93 were evaluated. Within this sam‑
ple, 28 patients (30.1%) reported significant improvement,
50 (53.7%) moderate, 6 (6.4%) mild, and 8 (8.6%) with‑
out change in the condition. Twenty-three patients (25.2%)
reported at least one side effect, with restlessness being the
most prevalent (6.6%). Therefore, CBD-enriched Cannabis
treatment in ASD patients was safe and well-tolerated. The
results presented in this approach are encouraging. However,
similar to the other trials, a control group was not included
in this study, and the Cannabis dose was not adjusted to the
patient´s weight. Symptoms such as sleep disorders and/or
seizures, sensory difficulties, and food acceptance showed
significant improvement. However, two patients showed
increased agitation and irritability, which were resolved by
changing the strain.
A study conducted in Chile showed promising effects
of using Cannabis oil in patients with ASD (Kuester et al.
2017). Clinical changes were estimated using the CGI
Improvement scale and the Autism Parenting Stress Index.
At the end of the treatment, 66.7% of patients showed sig‑
nificant improvement in ASD symptoms, including social
communication, language, or repetitive behaviors. In gen‑
eral, symptoms such as sleep disorders and/or seizures, sen‑
sory difficulties, and food acceptance showed significant
improvement, and the tolerability was good when using oral
Cannabis extracts.
In a recently published case report, the use of CBD-
enriched Cannabis extract was described in a 15-year-old
patient with ASD, selective mutism, anxiety, and controlled
epilepsy. After 3 months of using CBD-enriched Canna-
bis, a mild improvement in anxiety symptoms was noticed.
After 9 months of this treatment, social anxiety, irritability,
aggressiveness, focus, and eloquence improved. Surpris‑
ingly, when the dose of Cannabis extract was decreased, his
aggressiveness increased.
Recently, a retrospective analysis of patients with ASD
who have used Cannabis to treat related symptoms was con‑
ducted (Mostafavi and Gaitanis 2020). The study sample
consisted of 32 patients diagnosed with ASD who used med‑
ical marijuana or hemp-based products taken orally to treat
aggression and co-morbid epilepsy. Among the study, eight
patients used Cannabis mainly for epilepsy, nine patients for
aggressive behavior, and 15 patients for aggressive behav‑
ior and epilepsy. Overall, 20 of 22 patients with epilepsy
reported some improvement in seizure control. In addition,
12 of 20 patients treated for aggressive behavior reported
improvement. Adverse treatment effects were observed in
4 patients, including increased obsessive–compulsive and
repetitive behavior and insomnia. Core symptoms of ASD,
13
 Table 1  A summary of clinical studies examining effects of CBD in patients with ASD
References
13
Aran et al. 2019a, b
Barchel et al. 2019
Fleury-Teixeira et al. 2019
Schleider et al. 2019
Kuester et al. 2017
Study sample
Children with ASD and severe
behavioral problems
N = 60 (83% M)
Mean age = 11.8 ± 3.5 years
Age range = 5–18 years
Children with ASD-related comor‑
bidities
N = 53 (85% M)
Mean age = 11 years
Age range = 4–22 years
Cohort of patients with ASD
N = 18 (72% M)
Mean age = 10 years
Age range = 6–17 years
Children with ASD
N = 188 (81.9% M)
Mean age = 12.9 ± 7.0 years
Age range = younger than the age of
5 to18 years
Children with ASD
N = 20 (15 M)
Mean age = 9 years and 10 months
Age range = 2–22 years
Treatment schedule/dosages
Cannabidiol-Rich Cannabis
20:1 or 6:1 ratio CBD/THC
Mean total daily dose: 3.8 ± 2.6 mg/
kg/day CBD and 0.29 ± 0.22 mg/
kg/day THC for children who
received three daily doses (n = 44)
and 1.8 ± 1.6 mg/kg/day CBD and
0.22 ± 0.14 mg/kg/day THC for
children who received two daily
doses (n = 16)
Mean treatment duration:
10.9 ± 2.3 months
Cannabidiol-rich Cannabis
20:1 ratio CBD/THC
CBD mean total daily dose: 16 mg/
kg (maximal daily dose 600 mg)
THC mean total daily dose: 0.8 mg/
kg
Mean treatment duration: 66 days
(30–588 days)
Cannabidiol-Rich Cannabis
75:1 ratio CBD/THC
CBD mean total daily dose:
4.6 mg/kg
THC mean total daily dose:
0.06 mg/kg
Children received two daily doses
Mean treatment duration:
6–9 months
Cannabis oil 20:1 CBD/THC
Mean total daily dose: 30% CBD
and 1.5% THC, on aver‑
age 79.5 ± 61.5 mg CBD and
4.0 ± 3.0 mg THC, three daily
doses. In case of insomnia addi‑
tional 5.0 ± 4.5 mg THC daily was
prescribed
Mean treatment duration: 6 months
Balanced CBD: THC extracts in
71.5% of patients; high-CBD in
19% of patients; and high-THC
extracts in 9.5% of patients. Daily
dose was not reported
Mean treatment duration: 7.6 months
Study design
Retrospective feasibility study
Case reports
Observational study
Prospective cohort study
Retrospective case series (abstract
only)
2722
Results Adverse events
Behavioral outbreaks improvement Sleep disturbances, irritability, loss
in 61% of patients of appetite, and a serious psychotic
event in a patient girl
CBD improved: Moderate somnolence and changes in
Self-injury in 67.6% of cases appetite
Hyperactivity in 68.4% of cases
Sleep problems in 71.4% of cases
Anxiety in 47.1% of cases
Overall improvement in 74.5% of
cases
Improvement in multiple autistic Mild and/or transient like sleepiness,
symptoms like sleep disorders, moderate irritability, diarrhea,
seizures and behavioral crisis, increased appetite, conjunctival
social interaction and cognitive hyperemia, and increased body
performance temperature
Hyperactivity: Improvement: 68.4% Sleepiness, moderate irritability, diar‑
of cases rhea, increased appetite, conjunctival
Self-injury: improvement: 67.6% hyperemia, increased body tempera‑
of cases ture, and restlessness
Sleep Problems: Improvement:
71.4% of cases
Anxiety: improvement: 47.1% of
cases
Overall: improvement: 74.5% of
cases
From the CGI-I and APSI rating One patient had greater irritability and
scales, 66.7% of patients had sig‑ two patients more agitation; these
nificant improvement. At least one effects were solved with the change
of the core symptoms improved of the strain
In most cases, sensory difficulties,
food acceptance, feeding and sleep
disorders, and/or seizures have
improved
Psychopharmacology (2022) 239:2713–2734
 Table 1  (continued)
References
Ponton et al. 2020
Mostafavi and Gaitanis 2020
Aran et al. 2021
Bilge and Ekici, 2021
13
Study sample
15-year-old boy
32 patients with ASD diagnosis
Children and adolescents with ASD
N = 150 (80% M)
Mean age = 11.8 ± 4.1 years
Age range = 5–21 years
Children with ASD
N = 33 (82% M)
Mean age = 7.7 ± 5.5 years
Treatment schedule/dosages
Cannabidiol-rich Cannabis 20:1 ratio Case report
CBD/THC. First 3 months: 2 mg/
kg of CBD and 0.1 mg/kg of THC,
two times a day in the volume of
0.1 ml. After this period, the dose
was increased to 0.2 ml twice a
day (4 mg/kg CBD and 0.2 mg/kg
THC). Mean treatment duration:
9 months
No mentioned
The study was divided into 3
groups:—whole-plant Cannabis
extract containing cannabidiol and
Δ9-tetrahydrocannabinol in a 20:
1 ratio,—purified cannabidiol, and
Δ9-tetrahydrocannabinol in the
same proportion and the placebo
group. To assess the effectiveness
of treatments, patients received
placebo or cannabinoids for
4 months followed by a 4-week
washout and cross-over designed
and predetermined for an addi‑
tional 12 weeks to better assess
patients' tolerability to treatment.
Initially, patients received 1 mg/kg
of CBD and 0.05 mg/kg of THC
daily. On alternate days the doses
were increased by 1 mg/kg for
CBD and 0.05 mg for THC until
reaching 10 mg/kg of body weight
per day of CBD and 0.5 mg/kg of
THC for children with a weight
between 20 and 40 kg or 7.5 mg/
kg of CBD per day and 0.375 mg/
kg per day of THC for patients
weighing more than 40 kg. The
treatments were administered
orally divided into 3 daily doses
Cannabidiol-rich Cannabis
Full-spectrum CBD and trace THC
CBD mean total daily dose: 0.7 mg/
kg
Children received one sublingual
drop twice a day and one drop
every 3 days
Mean treatment duration: 6.5 months
Study design Results Adverse events
Improvement in social anxiety, No significant adverse effects
irritability, aggressiveness, focus,
eloquence and social interaction
Retrospective analyses 20 of 22 patients with epilepsy (91%) Increased obsessive–compulsive and
showed some improvement in sei‑ repetitive behavior, mania, and
zure control. 12 out of 20 patients insomnia
Psychopharmacology (2022) 239:2713–2734
treated for aggressive behavior
(60%) exhibited improvement
Placebo-controlled trial The changes in the total scores of the Mild or moderate drowsiness,
HSQ-ASD (primary outcome) and decreased appetite, weight loss,
APSI (secondary outcome) did not tiredness, euphoria, and anxiety
differ between groups. Disruptive
behavior in CGI-I (co-primary
outcome) improved or greatly
improved in 49% of patients who
received the whole plant extract
(n = 45) when compared to the
placebo group (21% of patients,
n = 47). The SRS mean (secondary
result) improved by 14.9 points in
the group that received the extract
of the whole plant (n = 34) com‑
pared to the placebo group that had
a score of 3.6 points (n = 36)
Observational Study Decrease in behavioral problems in No significant side effects
10 patients (32.2%). Iincrease in
expressive language in 7 patients
(22.5%). Improvement in cognition
in 4 patients (12.9%). Increase
in social interaction in 3 patients
(9.6%). Decrease in stereotypes in
1 patient (3.2%)
2723
 2724 Psychopharmacology (2022) 239:2713–2734

such as language and social development impairments, have

Dizziness, insomnia, colic and weight

not been evaluated in patients.
Aran and coworkers (2021) conducted a placebo-con‑
trolled trial of whole-plant extract and pure cannabinoids in
150 children and adolescents diagnosed with ASD according
to DSM-5 criteria, which was confirmed using the Autism
Adverse events

Diagnostic Observation Schedule (ADOS-2), and moder‑

ate or more significant behavioral problems (rating ≥ 4) on
gain

the CGI-S scale. The participants were 5–21 years of age,

and 20% of the patients were females. The patients were
randomly assigned (1:1:1 ratio) to 1 of 3 treatments for
Improvement in social interaction,

number of meals a day and con‑

anxiety psychomotor agitation

12 weeks. Treatments included oral placebo, whole-plant

Cannabis extract containing CBD and THC at a 20:1 ratio,
and pure CBD and pure THC at the same ratio and concen‑
tration. Two objectives were assessed in the study. First, it
investigated whether whole-plant Cannabis extract signifi‑
centration

cantly improved behavioral assessments compared to pla‑

Results

cebo. The identical CBD:THC ratio was used in the previous

open-label case series. The treatments were administered
Randomized, double-blind and con‑

orally, mostly sublingually. The study started with 50 partici‑

pants randomly chosen with three different treatments. In the
trolled placebo clinical trial

first phase of the study, which lasted 12 weeks, preliminary

results were assessed using the CGI-I scale with disruptive
behavior anchor poibehaviorHome Situation Questionnaire
Study design

for e ASD (HSQ-ASD). After 4 weeks of washout followed

by the second treatment period lasting 12 weeks, the results
obtained were evaluated using the Social Responsiveness
Scale (SRS-2) and APSI (Autism Parenting Stress Index),
CBD-rich Cannabis extract at a con‑

and adverse events were assessed. At the end of the first

centration of 0.5% (5 mg/mL)

Treatment duration: 12 months

period, 45 patients who received whole-plant and pure can‑

Treatment schedule/dosages

nabinoids and 47 subjects in the placebo group completed

the study. At the end of the second study period, 44 subjects
CBD-Rich Cannabis
9:1 ratio CBD/THC

N, number of subjects; CBD, cannabidiol; THC, tetrahydrocannabinol; M, male

6–70 drops daily

th the experiment and placebo groups completed the study.

Cannabinoid treatment for behavioral problems was assessed
using the HSQ-ASD and CGI-I scores (co-primary outcome
measures). The APSI was used to measure the second study
period results and evaluate the child’s behavior. The HSQ-
ASD and APSI total scores were not significantly different
Control group (N = 29; 27 M)

between the patients who received cannabinoids and those

Mean age = 7.68 ± 1.74 years
CBD group (N = 31; 29 M)

who received placebo. The CGI-I scores of 45 participants

Age range = 5–11 years

(49%) who received whole-plant cannabinoids and answered

Children with ASD

the questionnaire were equal to or higher than 21% of the

N = 60 (52 M)
Study sample

47 subjects who received a placebo. Among the 45 partici‑

pants who received pure cannabinoids, 38% of the respond‑
ent CGI-I scores were not significantly higher than subjects
who received a placebo. The HSQ-ASD, CGI-I, and APSI
scores were not significantly different between participants
who received whole-plant extract versus pure cannabinoids.
Table 1  (continued)

Furthermore, the ASD symptoms in the second study period

were assessed using SRS-2. The total SRS-2 scores signifi‑
Silva et al. 2022

cantly improved after treatment with whole-plant extract

References

compared with placebo. In addition, treatment with the

whole plant extract was significantly associated with CGI-I

13
Psychopharmacology (2022) 239:2713–2734
and SRS-2 scores after controlling for sleepiness with the
concomitant use of medications during treatment. The most
common side effects, when they occurred, were drowsi‑
ness, decreased appetite, weight loss, tiredness, euphoria,
and anxiety. Although the initial study was designed to be
a crossover assay, the first analyses revealed the treatment
results would affect the data from the second treatment
period. Thus, the sample size was limited. The question‑
naires showed several items were inapplicable to some low-
functioning participants, which resulted in invalid scores and
a decrease in the statistical power of these measures. The
study did not conduct genetic or intelligence quotient assess‑
ments, and the effects of gene history or cognitive level on
treatment response could not be assessed. Collected data
about the use of concomitant medications were collected.
However, the authors did not mention methods to detect
factors that may affect the treatment response or adverse
events. In addition, pharmacokinetics and interventions were
not performed, and information regarding other drugs, liver
enzyme tests, and complete blood count were not collected.
The authors stated they detected no clinical evidence of
hepatic or hematological dysfunction.
In a 2-year observational study conducted in Turkey,
33 children with a mean age of 7.7 years diagnosed with
ASD received CBD-enriched Cannabis daily. According to
reports from parents and caregivers, there was considerable
improvement in the behavior of patients. Unlike other tri‑
als, this study used lower doses of CBD and traces of THC,
which could explain the lack of side effects in the sample
evaluated.
Recently, a randomized, double-blind, placebo-controlled
clinical trial conducted in Brazil evaluated the efficacy and
safety of a CBD-enriched Cannabis extract in autistic chil‑
dren. Sixty children, aged between 5 and 11 years, were
selected and divided into two groups: the treatment group,
which received the CBD-rich cannabis extract, and the con‑
trol group, which received the placebo for 12 weeks. The
Sociodemographic Questionnaire and Childhood Autism
Rating Scale (CARS) was used. In this study, a wide
improvement in social interaction was observed; the side
effects, when present, were dizziness, insomnia, colic, and
weight gain.
In addition to these papers in which the effects of CBD
on ASD symptomatology are described, the effects of a
single oral dose of CBD in ASD patients on brain excita‑
tion and inhibition systems and functional connectivity in
structures associated with this disorder are addressed in
two papers. In a randomized placebo-controlled single-
dose trial using MRS, the CBD effects on excitatory and
inhibitory systems were investigated in male adults with
and without ASD (Pretzsch et al. 2019a, b). The sample
consisted of 34 males (17 controls and 17 with ASD). MRS
measured glutamate (Glx = glutamate + glutamine) and
2725
GABA + (GABA + macromolecules) levels after receiving
a single oral dose of CBD (600 mg/kg) or placebo. CBD
altered the main excitatory and inhibitory neurotransmitters
in adults with and without ASD. CBD increased Glx in the
basal ganglia in both groups and decreased Glx in the dor‑
somedial prefrontal cortex. Conversely, CBD had opposite
effects on GABA + levels in each group. Specifically, both
in the prefrontal and subcortical regions, CBD increased
GABA + levels in controls but decreased the levels in ASD
patients.
In another study published in 2019 by Pretzcsh et al. using
the same study cohort and similar methodology, the effects
of CBD on low-frequency activity and functional connectiv‑
ity in the brain were evaluated. This approach measured the
fractional amplitude of low-frequency fluctuations (fALFF)
in the whole brain. CBD significantly increased fALFF in
cerebellar vermis VI and the right fusiform gyrus of patients
with ASD. Furthermore, the change in fALFF in the cerebel‑
lum (but not in the fusiform gyrus) was accompanied by
generalized differences in the functional vermal connectivity
with several of its subcortical and cortical targets in ASD
patients but not in controls.
Discussion
CBD has several potential neuropsychiatric therapeutic
effects on important manifestations of ASD (Fig. 2). Fur‑
thermore, several of its multiple molecular mechanisms tar‑
get brain changes involved in the pathophysiology of ASD.
Because CBD is generally well-tolerated, with no abuse
potential and low toxicity in humans and other species, it
could be a practical single or add-on alternative therapy for
ASD (Scuderi et al. 2009). Some preclinical study results
support this possibility. However, the clinical investigations
of CBD effects on ASD are limited. Positive results have
been reported in open-label trials and case reports, often
accompanied by decreased dosage and medication with‑
drawal. Side effects are mild or moderate when they appear.
They are usually diarrhea, sleep and appetite disturbances,
drowsiness, and restlessness, which generally disappear with
decreasing dosages or treatment discontinuation. However,
proper double-blind, placebo-controlled trials are needed to
explore this possibility further. The results obtained with
CBD-enriched Cannabis in patients with ASD are encourag‑
ing for patients with and without epileptic conditions. How‑
ever, some concerns should be highlighted.
The gender disparity in the samples evaluated is apparent
in clinical trials previously discussed. Although the preva‑
lence of ASD is higher in males, it is essential to note that
persistent impairments in communication and social interac‑
tion are very relevant features in ASD. It is suggested that
late or missed diagnosis in females may be related to marked
13
2726 Psychopharmacology (2022) 239:2713–2734

Fig. 2  The following image

suggests the therapeutic profile
of CBD in treating the core
symptoms of ASD, such as
improving social interaction and
communication, and decreas‑
ing stereotyped behaviors, in
addition to its neuroprotective
profile. CBD may also have
therapeutic effects on ASD-
associated comorbidities such as
psychosis, aggression, epilepsy,
conditions related to anxiety
and depression, and obsessive–
compulsive disorder (OCD).
CBD may offer a promising
treatment for the range of symp‑
toms of ASD. However, due to
the complexity of ASD, it is still
a challenge to select patients
who would benefit from the
therapeutic effects of CBD and
individuals who are more prone
to side effects

sex differences in the phenotypic presentation of these symp‑
toms (Rivet and Matson 2011; Lai and Baron-Cohen 2015;
Bargiela et al. 2016). Thus, sexual dimorphism in the expres‑
sion of genes is related to ASD, where boys, in general, are
more susceptible than girls to genetic alterations involved
in synaptic plasticity and brain development, where the
endocannabinoid system plays a crucial role (Maccarrone
et al. 2014). It is important to note that sexually dimorphic
neural pathways are intimately involved in synaptic struc‑
ture, function, and plasticity. Moreover, sex hormones can
modulate brain endocannabinoid activity (Fattore and Fratta
2010). A higher male-to-female ratio in autism may arise
because males have a lower threshold than females for aber‑
rant changes in synaptic dynamics during neurodevelopment
following genetic or environmental insults (Mottron et al.
2015).
The great popularity of CBD-enriched Cannabis-based
drugs available on the market, combined with the fact that
patients with ASD use a range of drugs to treat the vari‑
ety of symptoms present, makes it imperative to expand
the knowledge of drug-drug interactions (Balachandran
et al. 2021). CBD is extensively metabolized by liver
enzymes such as Cytochrome P450, highlighting the iso‑
forms CYP3A4 and CYP2C19 (Jiang et al. 2011). CBD
can inhibit members of the CYP3 family, where 60% of
clinically prescribed medications are also metabolized
through it (Jiang et al. 2013; Zendulka et al. 2016). In addi‑
tion, this compound inhibits the liver enzyme CYP2D6
and may increase serum concentrations of SSRIs, tricy‑
clic antidepressants, antipsychotics, beta-blockers, and
opioids. CBD can interact with various antiepileptics by
inhibiting CYP2C19 and CYP3A4, which catalyze the
metabolism of N-desmethylclobazam (nCLB), an active
metabolite of clobazam (Giraud et al. 2004; Walzer et al.
2012). The inhibition of these enzymes by CBD leads to
the accumulation of nCBL, which is about 20–100% as
potent as clobazam. A study by Gaston and Szaflarski
(2018) showed that the effectiveness of antiepileptics can
be modulated by CBD; however, its antiepileptic profile
is not affected by this class of drugs. Great attention is
recommended in the interactions of CBD with Warfarin
and with acetaminophen since, respectively, the interac‑
tions can culminate in increased bleeding (Damkier et al.
2019) and liver damage (Brown and Winterstein 2019).

13
Psychopharmacology (2022) 239:2713–2734
Therefore, in these cases, it is recommended to reduce the
dose of CBD. Besides, CBD can interact with alcohol, but
these effects are still poorly understood. However, this
drug can decrease alcohol consumption and blood levels.
In addition, CBD promotes protection against the harm‑
ful effects of alcohol on the liver and brain and reduces
oxidative stress (Nona et al. 2019; Yang et al. 2014; Con‑
sroe et al. 1979). On the other hand, this interaction pro‑
moted motor and psychomotor disruptions (Robinson and
Berridge 1993). Thus, as discussed, further double-blind,
controlled, randomized studies are essential to assess the
interactions of CBD with other drugs, as well as bioavail‑
ability, pharmacokinetics, and pharmacodynamics assess‑
ments in these contexts.
The endocannabinoid system is widely involved in
embryonic and adult neurogenesis (Jiang et al. 2005; Trazzi
et al. 2010). During neurodevelopment, synapse formation,
cell migration, axonal orientation, and cell survival are
modulated. In addition, changes in these processes during
development are primarily involved with the emergence of
psychiatric disorders (Maccarrone et al. 2014). The manipu‑
lation of the endocannabinoid system, especially during the
CNS maturation period, should be approached with caution,
especially with the use of THC, which at the molecular level
acts as a partial CB1 receptor agonist and produces its psy‑
choactive effects through the receptors. Furthermore, the
recreational use of Cannabis is associated with an increased
risk of developing psychosis in a dose-dependent manner
(De Souza Crippa et al. 2004). Clinical trial results have
shown that for patients with psychosis, as in the general
population, the use of this drug is associated with a higher
incidence of psychotic disorders and cognitive impairment
(Meier et al. 2012). In addition, the use of Cannabis is asso‑
ciated with an earlier onset of psychosis and severe cognitive
impairment (Bagot et al. 2015). A strong relationship exists
between patients who have psychosis and individuals who
routinely use Cannabis showing a higher risk of relapse due
to the disorder, exacerbation of symptoms, and longer-term
hospitalization (for review, see Koskinen et al. 2010; Large
et al. 2011; Marconi et al. 2016; Schoeler et al. 2016; Bogaty
et al. 2018; Hunt et al. 2018; Murrie et al. 2020).
In a pioneering meta-analysis study, evidence of the
relationship between episodes of psychosis and ASD was
observed (Kiyono et al. 2020). The study results indicated
the prevalence of psychotic episodes in ASD could reach
24%, 2–fivefold higher than in the general population. Cor‑
roborating the findings of this study, in a recent review by
Zheng et al. (2018), the authors reported that individuals
with ASD are 3.55 times more likely to have schizophre‑
nia than healthy people and a high incidence of episodes
of psychosis. Based on this evidence, patients with ASD
have a higher prevalence of schizophrenia and episodes of
psychosis than the general population.
2727
Ethical and legal concerns
Most of the trials evaluated in the present review raise vari‑
ous legal and ethical concerns because the children with
ASD received non-pure-grade CBD and even a mixture of
CBD and THC. To date, THC:CBD combinations are not
acceptable in any dose range for non-compassionate use
in children. ASD children were chronically exposed (up
to 6 months) to THC (up to 21 mg/day). For comparison,
in previous studies, an oral dose of 10 mg of THC acutely
induced psychosis in healthy adults (Martin-Santos et al.
2012; Bhattacharyya et al. 2009). The THC exposure dur‑
ing the neurodevelopmental phase may increase the risk of
later behavioral sequelae, including cognition, motivation,
impulsivity, mood, anxiety, psychosis, intelligence, and psy‑
chosocial functioning (Sorkhou et al. 2021). The evidence
shows that frequency and amount of THC content, early
age of use, and cumulative exposure can contribute to these
adverse outcomes even in people without past medical con‑
ditions or psychiatric disorders (Sorkhou et al. 2021). The
adverse outcomes may even be worse in the ASD population
because they are more prone to these comorbidities. Because
the plasma level of the different cannabinoids varies widely,
especially in ASD children taking other drugs that cause
drug-drug interactions, dosing both the cannabinoids and the
other medicines is strongly recommended. General medical
examinations should be given and include measurements
of hepatic enzymes and sexual hormones. Non-GMP/GLP
drugs were given to ASD children in studies without the
ideal aging down, block study design. Therefore, it is crucial
that in clinical studies involving children, the CBD adminis‑
tered should be a pure and pharmaceutical-grade compound,
and the study population should be advised regarding the
possible hazards of consuming unregulated products labeled
as CBD to minimize possible risks.
Conclusions
ASD is generally a debilitating condition, and available
treatments have limited efficacy and are associated with
significant adverse reactions. The endocannabinoid system
is involved in the pathophysiology of ASD, indicating that
CBD could have therapeutic effects on the main and associ‑
ated symptoms. However, only a few randomized controlled
trials involved the administration of CBD to ASD patients,
and highly purified GMP/GLP compounds were not used in
any of the studies. The main concerns with the use of CBD
as a therapeutic for ASD include the potential for long-term
adverse effects, drug-drug interactions, and lack of regula‑
tory oversight of retail CBD-enriched products. Therefore,
an adequate therapeutic window for CBD should be deter‑
mined to achieve satisfactory effects. In all the studies in
13
2728
which CBD use was evaluated for the treatment of ASD,
erratic CBD-enriched Cannabis extract oils with other phy‑
tocannabinoid molecules (such as THC) were used. Thus,
CBD safety requires further investigation, and an adequate
therapeutic window must be determined for the main ASD
symptoms and comorbid conditions. Finally, further clinical
long-term, placebo-controlled trials using pharmaceutical-
grade CBD, involving different doses and neurodevelop‑
mental treatment periods, are necessary to prove the effec‑
tiveness, safety, and absence of acute and severe long-term
adverse effects in ASD patients.
Acknowledgements The authors thank Lucas Prota Crippa for prepar‑
ing the art in Fig. 2
Author contribution All authors have contributed to the writing of
this review.
Funding This work was supported by the Fundação de Amparo à Pes‑
quisa do Estado de São Paulo (FAPESP) and by the Instituto Nacional
de Ciência e Tecnologia Translacional em Medicina (INCT-TM; CNPq/
FAPESP; 2008/09009–2). JAC received a grant from the University
Global Partnership Network (UGPN) – Global Priorities in Cannabi‑
noid Research Excellence Program. ACC, FSG, EADB, JAC, JEH, and
AWZ are recipients of CNPq research fellowships. The authors appreci‑
ate the financial support from Fapesp, Capes, and CNPq.
Declarations
Conflict of interest JAC is a member of the International Advisory
Board of the Australian Centre for Cannabinoid Clinical and Re‑
search Excellence (ACRE) – National Health and Medical Research
Council (NHMRC). JAC and JEH have received travel support to at‑
tend scientific meetings and personal consultation fees from BSPG-
Pharm. JAC, JEH, FSG, and AWZ are co-inventors of the patent
“Fluorinated CBD compounds, compositions and uses thereof.
Pub. No.: W.O./2014/108899. International Application No.: PCT/
IL2014/050023,” Def. U.S. number Reg. 62193296; July 29, 2015;
INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi
AW, Kapczinski F, Hallak JEC, Guimarâes FS, Crippa JAS, Breuer A).
Universidade de São Paulo (USP) has licensed this patent to Phytecs
Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement
with Prati-Donaduzzi to “develop a pharmaceutical product contain‑
ing synthetic CBD and prove its safety and therapeutic efficacy in the
treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety
disorders.” JAC, JEH, FSG, and AWZ are co-inventors of the patent
“Cannabinoid-containing oral pharmaceutical composition, method
for preparing and using same,” INPI on September 16, 2016 (BR
112018005423–2). JAC and JECH have received personal consultation
fees from BSPG-Pharm, and PurMed Global in the past. JAC received
speaking fees from Torrent, Green Care Store and Janssen. The other
authors declare no competing interests.
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