Cannabinoids in Autism and Fragile X Syndrome: Value-Based Treatment Revolution Ahead-Juniper Publishers
Global Journal of Intellectual & Developmental Disabilities (GJIDD)
Cannabis has a long history in Central and South
Asia, as it was used to produce hemp fibre for rope, clothing and paper,
but was also consumed both for recreational and medicinal purposes. The
two major neuro active components in cannabis are the psychoactive
A9-tetrahydro-cannabinol (A9-THC) and the non-psychoactive cannabidiol
(CBD). Recent years have seen a resurgence in interest in the
therapeutic potential of compounds derived from cannabis, due to
significant advances in our understanding of cannabis ingredients and
endogenous brain cannabinoid (ECB) system, which consists of G-protein-
coupled cannabinoid (CB) receptors, endocannabinoids such as
N-Arachidonoylethanolamide (Anandamide) and 2-Arachidonoylglycerol
(2-AG), synthetic and degradative enzymes, and transporters.
Common medical conditions for which marijuana is
allowed in the US (i.e., those conditions shared by at least 80 percent
of medical marijuana states) are: Alzheimer's disease, Amyotrophic
Lateral Sclerosis, cachexia/wasting syndrome, cancer, Crohn's disease,
epilepsy and seizures, glaucoma, hepatitis C virus,human
immunodeficiency virus/acquired immunodeficiency syndrome, Multiple
Sclerosis and muscle spasticity, severe and chronic pain, severe nausea
and Post-Traumatic Stress Disorder [1].
The advances in our understanding of exogenous cannabinoids actions and
the physiology of ECB system, have led to important new insights, which
are likely to result in the development of novel therapeutic strategies
forkey CNS disorders.
Autism
Autismis characterized by deficits in communication
and social interaction, as well as by stereotypic behaviors, restricted
patterns of interest, and abnormal sensory issues [2].
Frequently, comorbid conditions include intellectual disability (65 %),
seizures (30 %), and different forms of sleepproblems [3,4].
Two of the most prominent features of autism are abnormal brain neuron organization [5] and immune system dysregulation [6,7].
During foetal life, CB1 receptors and their associated ECBs are
important for neuron differentiation and proper axonal migration [8].
Modulation of CB1 receptors could trigger autism by
interrupting normal brain development, as they are particularly abundant
in forebrain sub-ventricular zones and cortical structures, which play a
key role in cell proliferation and migration, respectively. They are
also transiently located in forebrain white matter structures, which are
essential for cell migration and axonal elongation during brain
development [9,10].
In contrast to CB1 receptors, CB2 receptors were primarily detected in
immune cells and at too much lesser extent in the brain, where they are
acting as immunomodulators.
Neuro inflammation is a frequent finding in autistic
individuals and include differential monocyte responses, abnormal
T-helper cytokine levels, decreased T-cell mitogen response, decreased
numbers of lymphocytes, abnormal serum immunoglobulin levels. antibodies
against central nervous system and maternal proteins [11].
If we postulate that autism is neuro-immunological disorder, modulation
of CB1 and CB2 receptors signaling could offer one of the promising
therapeutic options.
ECB signaling and social interaction processing systems:
Initial stages of social interaction require overcoming, negative
valence systems (e.g. fear, anxiety), in order to initiate the
interaction and are reinforced by positive valence systems (e.g. reward
learning, reward valuation). Cognitive systems (i.e. attention,
perception, working memory) then guide the exchange after social
interaction has commenced, while social process systems (i.e.
affiliation and attachment, social communication, perception of self and
others) exert supramodal control to coordinate germane practices.
Dysfunction in one construct intrinsically affects social information
processing and impacts the ability to function typically. Role of
cannabis in modulating social interactions was first observed by French
psychiatrist Dr. Jacques Moreau de Tours in 19th century. Dr
Moreau noted similarities between experiences in healthy humans after
ingesting North African hashish (which contains very high concentration
of THC), and dysfunctions in his patients that he called 'neurological
dysregulation' and 'social alienation’ [12].
He described these symptoms as fluctuations of emotions (i.e. negative
valence), extreme happiness and excitement (i.e. positive valence),
errors of time and space, illusions and hallucinations
(arousal/regulatory) and irresistible impulses and dissociation of ideas
(i.e. cognitive domain) [13]. Human studies have shown that marijuana heightens the saliency of social interactions [14], enhances interpersonal communication
[15] , and decreases hostile feelings within small social groups
[16]
. The neural mechanisms underlying these prosocial effects are unclear
but are likely to involve activation of CB1 receptors, the main
molecular target of marijuana in the human brain. Consistent with this
idea, CB1 receptors are highly expressed in associational cortical
regions of the frontal lobe, but also in subcortical structures involved
in social-emotional functioning [17,18]. Moreover, the receptors and their endogenous lipid-derived ligands, anandamide and 2-AG [19], have been implicated in the control of social play [20] and social anxiety [21]
in laboratory animals, which are two crucial aspects of animal social
experience. Plausible explanation of all these effects, is that
oxytocin, which has primary physiological function to heighten the
saliency of social stimuli, triggers an anandamide-mediated signal in
the nucleus accumbens (NAc), thus influencing synaptic plasticity via
activation of local CB1 receptors. Other modulatory neurotransmitters
may also play a role in regulating the interaction between oxytocin and
anandamide, such as serotoninwhich is needed for the expression of
oxytocin-dependent plasticity in the NAc [22], and dopamine which has been implicated in striatal anandamide signaling [23].
Additional hypothesis is that some of social behavioral deficits in
autism arise dueto deficits in reward system functioning [24,25].
This is supported by studies that report a lack of social motivationin
children with autism,who do not find social stimuli rewarding and hence
do not attend to them as much as normal children [26,27].
An alternative formulation of the social motivationhypothesissuggests
that the attention of individuals with andwithout autism is drawn to
social stimuli to a comparable extent,but individuals with autism find
social stimuli less rewarding [28,29].
All scientific research findings mentioned above
suggest that ECB system is involved in regulation of at least three key
features known to be atypical in autism:
i. Neural development.
ii. Immunological system modulation and
iii. Social interaction/reward responsivity.
Further research of this system is necessary, to
develop valid and reliable diagnostic biomarkers and specific
therapeutic interventions.
Fragile X syndrome
Fragile X syndrome (FXS) is a neuro developmental
disorder characterized by cognitive impairment, attention deficit,
hyperactivity, anxiety, unstable mood, autistic behaviors, language
delay and seizures [30]. This X-linked chromosome disorder is the most common known cause of autism with 30% of boys meeting full autism criteria [31].
FXS is caused by a trinucleotide repeat expansion (CGG) in the
FMR1gene, which results in the loss of expression of fragile X-mental
retardation protein (FMRP) [32], an RNA binding protein that negatively regulates synaptic protein synthesis [33].
Recent advances in FMR1 allele analysis, allow rapid and inexpensive
assessment of CGG repeat size, the number of AGG interruptions and
methylation status from blood or saliva samples [34].
This FMR1 DNA test is currently used for detection of
Fragile X carriers and early diagnosis of FXS. In research settings
animal model used to mimic FXS in humans is the FMR1 knockout mice,
where knockout of FMR1 gene removes FMRP [35].
It was shown that mutations in this gene are linked to enhancement of
mGluR Gpl signaling, especially at mGluR5, and lead to altered synaptic
plasticity in FXS [36].
Possible interpretation of this finding, is that activation of
metabotropic glutamate receptor (mGluR) Group I (Gpl) i.e. mGluR1 and
mGluR5, enhances FMRP synthesis [37],
while its absence results in a loss of translational controland
enhancement of cerebral and mGluR protein synthesis. This
interconnection supported the development of "mGluRtheory of fragileX”,
published in 2004., that identifies FMRP as a key downstream regulator
of mGluR activation (specifically mGluR5) [37].
The theory in line with current scientific knowledge
about cross-talk between glutamatergic and ECB system, which acts as an
neuromodulatory system that fine-tunes excitatory glutamatergic synaptic
transmission [38].
This fine control is obtained through CB1 receptors which are profusely
expressed in presynaptic terminals of glutamatergic cells [39], where they preclude release of glutamate upon stimulation by ECBs. Maejima et al. [40]
have confirmed that heightened postsynaptic activation of mGluR5
inFMR1knockout mice, increased Gp1 mGluR dependent ECB mobilization
(synthesis and release), anddesensitizedCB1 receptors which led to
increased propensity for uncontrolled neuronal firing.
Unfortunately, results from animal models did not
translate to humans with FXS, as targeted stimulation of mGluR5 did not
lead to symptom improvement [41].
Since then the focus shifted to GABA and the hypothesis that decreased
GABA transmission in cerebral cortex underlies FXS pathophysiology. GABA
ergic neurotransmission is also modulated by ECB system, especially by
CB1 receptors, which are 10-20 times more expressed in inhibitory than
in excitatory terminals,in specific brain regions such as hippocampus
andcerebellar cortex [42],
Therefore targeting disturbed GABAergic neurotransmission via CB1
receptors, might represent a novel concept in development of effective
treatment options for FXS.
Future studies especially in human population are
needed for better understanding of interactions between FMRP and ECB
system, as these would pave the way for development of FXS specific
biomarkers and treatment interventions.
Conclusion
Although basic research and preclinical data support
the use of exogenous cannabinoids THC and CBD in neuro developmental
disorders such as Autism, Fragile X Syndrome and other Autism Spectrum
Disorders. double blind placebo controlled trials are urgently needed to
establish efficacy, safety and extent of benefit on the quality of life
of all endocannabinoid-mimetic compounds.
vast numbers of siblings, only two of which need to survive to reproduce and continue the genetic line.
Thus, nurture (learning) reigns among anthropoids and
nature (genetics) at the other extreme where simple instinctive
patterns of behavior suffice for survival of the species.
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