Cannabis for Treating Core and Comorbid Autism Symptoms – Where are we at?
Cannabis for autism – an introduction
Several new studies published in recent months (first half of 2019) investigated the effects of various cannabis-based medical products (CBMPs) for reducing symptoms of autism. Although all of the studies were open-label and relatively small in scale, the overall results were overwhelmingly positive and encouraging, with statistically significant improvements observed across all measured domains, including social communication, language, and restrictive and repetitive behaviours and interests, the core symptoms of autism.
The biggest positive changes in most of the studies were measured in the domain of so-called ‘challenging behaviours’ and comorbid disorders that are frequently present in autism and that severely affect quality of life of individuals with autism and their families. These included behaviours and difficulties such as aggression and self-harming, anxiety, hyperactivity, lethargy, irritability, stereotypy and inappropriate speech, sensory difficulties, food acceptance, feeding and sleep disorders and seizures.
As all the studies were limited in scope, possible mechanisms were not investigated in most cases. One notable exception was a preliminary investigation by a team at King’s College London, which noted clear effects of cannabidiol (CBD) on brain functional connectivity and brain excitation and inhibition systems in individuals with autism by magnetic resonance spectroscopy and magnetic resonance imaging (Pretzsch et al., 2019, 2019).
This article contains the following chapters:
- Cannabis as medicine – a brief overview
- A short history of medical cannabis research for autism
- Multi-systemic effects of cannabinoids in autism – possible mechanisms of action
- Brain signalling and neuronal connectivity
- Cannabinoid signalling regulates sensory processing
- Cannabinoids in stress response and HPA axis modulation
- Importance of ECS in motor function
- Epilepsy link
- ECS modulates social behaviours via oxytocin, vasopressin and dopamine signalling
- Neuroinflammation and immune system abnormalities in autism
- Cannabinoid signalling in immunity and inflammation
- Cerebrospinal fluid abnormalities in autism & CSF volume regulation by cannabinoids
- Low bone density in autism & cannabinoid regulation of bone metabolism
- The role of ECS in glucose and energy metabolism
- Cannabinoid regulation of progenitor and neural stem cells
- Additional actions of cannabinoids
Cannabis as medicine – a brief overview
The two main species of cannabis genus of plants are Cannabis sativa and Cannabis indica. A cannabis plant contains more than 500 known active compounds–cannabinoids, flavonoids and terpenes, fatty acids and others. The most well-known cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC), of which only the latter has psychoactive properties. Different strains of the plant are cultivated to contain varying amounts of THC and CBD. Cannabis indica species usually has higher levels of CBD compared to THC, and Cannabis Sativa on average has lower levels of CBD to THC, but there are hundreds of different strains being cultivated of each, and countless hybrid variations. The word ‘hemp’ relates to cannabis plants with in which the levels of THC are very low, usually up to 1%. (At present time the legal limit of THC in hemp oils is 0.2% in the UK and most European countries), while ‘marijuana’ is an unofficial term for strains with high THC content that were originally cultivated primarily for recreational use.
Cannabis has been cultivated in many parts of the world and used as medicine since ancient times. In ancient China it was used to target malaria, rheumatism, constipation, gout and menstrual cramps, and used as a remedy for earache, edema, and inflammation by the ancient Greeks. Since the medieval times practitioners in the West have used cannabis for pain, depression, epilepsy, nausea and vomiting. Around the beginning of the twentieth century over 100 scientific papers had been published in Western medical journals, and medical cannabis preparations were widely used by clinicians and available in local pharmacies.
Recent years have seen renewed research interest and further evidence has accumulated on the therapeutic potential of cannabis—the whole plant extract (sometimes called CBD oil extract, or hemp extract), as well as some of its individual active constituents and their synthetic mimics—in many different conditions.
A growing number of studies points to a major role of the endocannabinoid system (ECS) in human biology. The ECS developed early in evolutionary history and is found in many diverse species. The system comprises of endocannabinoids (natively produced cannabinoids), mediators responsible for their synthesis and metabolism, and the cannabinoid receptors (CRs) that serve as their molecular targets. Endocannabinoids are derivatives of integral components of cellular membranes and act as hydrophobic lipid messengers.
Since CRs are richly expressed throughout the body in various types of tissue and since ECS plays an important regulatory role in many processes, ranging from the regulation of cellular energy metabolism to the modulation of complex cognitive functions, modulating ECS has a great potential for treating a wide range of pathologies, including neurological and neurodegenerative disorders, movement disorders, depression and stress-related disorders, epilepsy, pain, glaucoma, stroke, cancer, inflammation, cardiovascular and metabolic disorders and many others.
At the present time, CBMPs have been approved in several countries for epilepsy, pain management, nausea and spasticity. In many countries clinicians are able to prescribe medical cannabis products off label for numerous conditions including for example Crohn’s disease, ulcerative colitis, Tourette’s Syndrome, post-traumatic stress disorder, glaucoma, migraine and psoriasis, to name a few.
Autism is a qualifying condition for medical cannabis in several US states.
A short history of medical cannabis research for autism
One of the first studies on the potential efficacy of medical cannabis for the treatment of autism was a study on 10 patients published in 2006. A cannabis-based medication dronabinol (delta-9-THC) was administered to adolescent patients with autism and intellectual disabilities and self-injurious behaviours (SIB). A significant and lasting improvement in the SIB and overall mood and wellbeing was achieved in 7 out of 10 patients (Kruger and Christophersen 2006). Another case report published in 2010 described significant and lasting improvements in hyperactivity, lethargy, irritability, stereotypy and inappropriate speech in a child with autism after administration of dronabinol (Kurz and Blaas 2010).
Several years later a mixture of CBD:THC was trialled as treatment for autism by a group of Chilean investigators. Several CBD:TCH formulations were given to 20 children over a course of several months, resulting in significant improvements in core symptoms of autism in two thirds of participants. In addition to improving social communication, language, and/or repetitive behaviours, the treatment had a positive effect on sensory difficulties, food acceptance, feeding and sleep disorders, and seizures (Kuester et al. 2017).
In 2018, a brief report on canabidiol-rich cannabis treatment in 60 children with autism, aged between 5-18 years, was published in the Journal of Autism and Developmental Disorders. The formulation used had 20:1 CBD:THC ratio, taken sublingually over 2-4 weeks, with doses up-titrated to effect and tolerability. The treatment led to improvements in behaviour (61%), anxiety (39%) and communication (47%) (Aran et al. 2019).
In 2019, a larger scale retrospective study was published in Nature which analysed data that was collected between 2015 and 2017 as part of the treatment program of 188 ASD patients aged between 5 to 19 years. The treatment was in most cases based on cannabis oil containing 30% CBD and 1.5% THC. After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) had been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and only 8 (8.6%) had no change in their condition (Bar-Lev Schleider et al. 2019).
Another study published in 2019 assessed effects of cannabis oil on behaviours, quality of life and comorbidities in 53 children with autism. Cannabinoid oil solution at a concentration of 30% and 1:20 CBD:THC ratio was administered for a median duration of 66 days. The study was open label and used parental reports to assess treatment effects. Improvements were noted in self-injury and rage attacks (67.6%), hyperactivity (68.4%), sleep problems (71.4%) and anxiety (47.1%) (Barchel et al. 2018).
“66,7% of patients had significant improvement according to CGI-I and APSI. Most cases improved at least one of the core symptoms of ASD, including social communication, language, or repetitive behaviors. Additionally, sensory difficulties, food acceptance, feeding and sleep disorders, and/or seizures were improved in most cases. 71,5% of patients received balanced CBD:THC extracts; 19,0%high-CBD; and 9,5% high-THC extracts.”
(Kuester et al. 2017)
Multi-systemic effects of cannabinoids in autism – possible mechanisms of action
The exact mechanisms of effects of CBMPs in patients with autism are not yet fully understood. Findings from various animal models of autism as well as human studies and clinical experience point to dysregulation of ECS in autism, and dysregulated ECS has been proposed a unifying pathophysiology of autism regardless of individual etiology (Debra S Karhson et al. 2018; Brigida et al. 2017; Siniscalco et al. 2013; Zou et al. 2019; Krueger and Brose 2013).
Activation of ECS has been shown to attenuate autism-related symptoms and behaviours and improve cognitive function in both genetic and environmental animal models of autism (Zamberletti, Gabaglio, and Parolaro 2017). Regulating ECS in diverse monogenetic models such as Fmr1, neuroligin and BTBR improves social and cognitive impairments in affected animals (Gomis-González et al. 2016; Speed et al. 2015; Wei et al. 2016). Similarly, cannabidiol treatment reverses neurochemical deficits and abnormal neurodevelopment in environmentally-induced valproic acid (Servadio et al. 2016; Melancia et al. 2018; Zamberletti et al. 2019), immune activation and early inflammation models of autism (Osborne et al. 2019; Doenni et al. 2016).
In addition to the findings from divergent animal models, evidence is emerging of ECS playing an important role in several human disorders with strong links to autism. Improvements in autism-related symptoms following cannabidiol (CBD) administration have been reported in patients with Fragile X Syndrome (FXS) (Tartaglia, Bonn-Miller, and Hagerman 2019). In a recent study a novel transdermal CBD gel formulation produced clinically meaningful reductions in social avoidance, irritability and anxiety symptoms in children and adolescents with FXS (Heussler et al. 2019). In children with tuberous sclerosis complex (TSC), another disorder with extremely high prevalence of autism, treatment with CBD leads to improvements in autism-related symptoms and behaviours. In a recent study on TSC significant positive effects were observed in verbal communication, vocalizations, cognitive availability, and initiation of emotional and physical connections in a large majority of participants irrespective of reduction in seizure activity (Hess et al. 2016).
Observations from clinical settings and parental accounts mirror the results of small trials of CBMPs for autism. Positive clinical results are being reported by clinicians for cases of idiopathic autism with widely different presentation and severity of symptoms.
It is of relevance in this context that a genetic mutation has recently been identified for the first time in a patient presenting with anxiety, mild cognitive dysfunction and early onset autism, which links functional impairments in ECS-linked FAAH2 gene activity with patient’s neurologic and psychiatric symptoms (Sirrs et al. 2015).
ECS is a major regulator of brain development, synaptic plasticity, sensory processing and sensory integration, stress regulation and neuromodulation. It modulates social interactions, including social anxiety and social reward, aggressive behaviours, cognition and memory.
Cannabinoid receptors are present in many organs and types of tissue, including brain and peripheral neurons, the vagus nerve (the central ‘line of communication’ between the gut and the brain), gastrointestinal lining, immune cells, skin, and others. ECS is involved in the modulation of many of the molecular pathways that are altered in autism, such as GABAergic and glutamatergic transmission, immune dysregulation and inflammation, oxidative stress, and altered energy metabolism.
Autism is frequently accompanied by multiple factors that influence severity of symptoms and level of disability of affected individuals such as anxiety, impulsivity and lack of control, agitation and irritability, aggression and self-harming behaviours, depression, cognitive dysfunction, heightened stress response, attention and processing issues, sleep disturbances, immunological and metabolic disturbances, abnormal sensory processing, tics and motor dysfunction.
Rates of nearly all physical health conditions are much higher in autism than in the general population and include gastrointestinal disorders (constipation, reflux, IBD), epilepsy and seizures, migraines, asthma, cancer, immune conditions, obesity, dyslipidemia, hypertension, and diabetes. Rarer conditions, such as movement disorders and Parkinson’s disease are also significantly more common among adults with autism (Alabaf et al. 2019; Croen et al. 2015; Bell, Wittkowski, and Hare 2019).
ECS is known to be affected in many of the conditions that are frequently encountered in autism, and numerous studies have demonstrated the promising effects of various cannabinoids for many of those conditions.
Mechanism of action for the effect of cannabinoids on ASD may possibly involve their effects on: brain signalling and neuronal connectivity; modulation of oxytocin, vasopressin and dopamine signalling; modulation of HPA and stress response; sensory processing; motor functioning; seizures; immunity and inflammation; gastrointestinal function and gut-brain signalling.
“…this study suggests that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors, and that the endocannabinoid system may be a therapeutic target for the core and associated symptoms displayed by autistic patients.”
(Servadio et al. 2016)
Cannabinoids in brain and behaviours
Brain signalling and neuronal connectivity
Abnormal neuronal connectivity is a frequent finding and many neuronal signalling pathways are known to be disturbed in autism including, for example, mGluR- or NMDAR-dependent signalling cascades, or signalling molecules downstream of mTOR pathway. Neuronal abnormalities found in autism include alterations in pre- and postsynaptic structure and signalling. Synaptic activity plays an important role in proper brain function and disrupted synaptic signalling is generally believed to be linked to autism pathogenesis.
Cannabinoids are key regulators of brain functions and behaviours, including learning and memory. They are known to modulate synaptic activity, mainly via activation of their receptors that are abundantly expressed throughout the brain and in particular in the hippocampus, cortex, basal ganglia, and cerebellum.
CRs are preferentially located at the synaptic terminals, and are coupled to neuronal ion channels that regulate membrane excitability, action potential firing, intracellular signal transduction pathways, synaptic plasticity and synapse formation. Some of the therapeutic effects of cannabinoids on central and peripheral neurons, such as neuroprotection, mood regulation, stimulation of appetite etc., are thought to derive from the mechanism of CR-linked inhibition or potentiation of neuronal ion channels.
In addition to CRs being widely distributed in both excitatory and inhibitory neurons, they are also richly expressed on astrocytes and microglia, brain immune cells (see ‘Inflammation & Immune Modulation by Cannabinoids’ section below)
Imbalances in the brain excitation and inhibition GABAergic and glutamatergic signalling are a frequent finding in autism, and excitation/inhibition disturbance has been proposed as a potential mechanism behind autism symptoms. Investigations by a team at King’s College London published in recent months noted clear effects of cannabidiol on brain functional connectivity and brain excitation and inhibition systems in individuals with autism (Pretzsch et al. 2019, 2019).
Abnormal sensory processing is a hallmark of autism. Most individuals with autism are hyper- or hypo-sensitive to auditory, visual and tactile, olfactory and gustatory input, and have difficulties processing and integrating multisensory information from their environment.
A large body of evidence shows that the severity of sensory dysfunction is strongly correlated with severity of core autism symptoms and difficulties in daily functioning. As optimal sensory processing is needed for higher-order social and cognitive functions, deficits in multiple sensory domain are thought to underlie at least some of the core symptoms and impairments experienced by individuals with autism (Baum, Stevenson, and Wallace 2015; Kaiser et al. 2016).
In addition to core symptoms of autism, sensory processing dysfunction underlies many of the odd or difficult-to-manage behaviours that greatly affect the individual’s daily life, independence and quality of life, as well as the lives of their carers.
Investigations of therapeutic strategies aimed at reducing over-reactivity to sensory stimulation and reduce ‘sensory overload’ belong to some of the most promising areas of autism research (Orefice et al. 2019).
The ECS plays an important role in sensory processing as part of a mechanism that modulates the encoding of sensory stimulus information and peripheral autonomic and sensory neurotransmission. During early development the ECS is known to mediate synaptic plasticity in sensory cortices, the parts of the brain where sensory information is received and interpreted. The ECS modulates the balance of excitation and inhibition in sensory neuronal circuits (Zhao, Rubio, and Tzounopoulos 2009; Ohiorhenuan et al. 2014), and is central in pain processing (Wang 2019; Woodhams et al. 2017).
Endogenous and exogenous cannabinoids like THC and CBD modulate brain activity in areas that process auditory, visual and other types of sensory stimuli. In addition to being richly expressed in the sensory cortices, CB receptors are also abundant in various parts of the brainstem and are involved in processing of sensory information at brainstem level (Ralevic 2003; Winton-Brown et al. 2011; Baek et al. 2008).
Findings of the activation of cannabinoid signalling in the auditory brainstem and its importance in encoding acoustic stimuli at the earliest stages in the brain (Zhao, Rubio, and Tzounopoulos 2009; Stincic and Hyson 2011) could be particularly relevant to autism. Brainstem pathology and deficits in encoding of speech at the brainstem level are thought to be responsible for many difficulties experienced by individuals with autism, including ineffective processing of complex auditory input such as speech, poor sound localisation and difficulty listening in background noise (Pillion, Boatman-Reich, and Gordon 2018; Ramezani et al. 2019).
Another finding of potential relevance to autism is that cannabinoid signalling specifically targets olfactory (smell) circuits to increase odour sensitivity and promote food intake (Soria-Gómez et al. 2014). Impairments in the olfactory processing in autism are strongly correlated to the severity of core autism symptoms including social difficulties, and a contributing factor in feeding problems and refusal of novel foods that are common in autism (Luisier et al. 2015).
Endocannabinoids and their receptors expressed in brainstem vestibular nuclei play a significant role in the neurochemical control of the central vestibular system (Baek et al. 2008), suggesting that ECS could be functionally important in the control of balance and vestibular reflexes, which are frequently impaired in autism.
Cannabinoids in stress response and HPA axis modulation
Individuals with autism exhibit marked fight-or-flight stress responses in otherwise benign situations. They overact to environmental stimuli, are unable to control cortical activity according to varying levels of uncertainty, and their body’s sympathetic stress response is longer lasting (slow to ‘switch off’).
This heightened arousal mode and hyper-responsivity to stress in individuals with autism correlates with deficiencies in adaptive functioning and use of language, and possibly causes or exacerbates many of the additional problems frequently present in individuals with autism, such as anxiety, avoidance of novel situations, rigid and/or challenging behaviours such as aggression and self-harm, and many others.
Ongoing exposure to elevated cortisol is known to negatively impact both physical and mental health. Chronic dysregulation of the HPA axis in response to stress, as is seen in autism, can have neurotoxic effects, potentially predisposing to a number of mental and health disorders. The rates of both major depression and suicide are significantly increased in autism.
ECS is known to regulate stress responses and to modulate sensitivity of various body systems to the effects of stress. Cannabinoid receptors are present throughout the HPA axis and control its activity in stressful situations (De Laurentiis et al. 2010). ECS facilitates appropriate stress recovery and serves as an ‘emotional buffer’ to regulate the effects of stress on behaviour, emotion and cognition (Patel and Hillard 2008; Bluett et al. 2017; Fogaça et al. 2018; Sharkey and Wiley 2016).
Dysregulated cannabinoid signalling thus leads to enhanced vulnerability and risk of developing various stress-related disorders, including psychiatric ones; both depression and PTSD are associated with reduced levels of circulating endocannabinoids. Lack or decreased cannabinoid signalling has been observed to lead to chronic stress‐like state. In addition, ECS modulates neurotransmitter release (excitotoxic/ neuroinflammatory response, including GABA signalling, see above) and cannabinoids are neuroprotective in the events of brain-damaging cascade triggered by stress (Patel and Hillard 2008; Bluett et al. 2017; Fogaça et al. 2018).
Many people with autism experience substantial motor difficulties. Deficits in motor skills in early life – gross motor skills as well as fine motor skills and oral motor function – are strong predictors of expressive language development and severity of autism symptoms and impairments later in life (Bedford, Pickles, and Lord 2016; Bal et al. 2019; Belmonte et al. 2013).
In addition to poor motor executive skills, various movement disorders are common in autism and include ataxia, akinesia, dyskinesia, bradykinesia, Tourette syndrome, and catatonic-like symptoms (Bell, Wittkowski, and Hare 2019).
Cannabinoid signalling regulates neuronal plasticity in areas of the brain that are critical to motor function. It plays an important role in refining and consolidating sensory-motor maps during learning of new motor task, in integrating incoming sensory inputs and transforming them into appropriate motor behaviour, as well as in initiation of movement and control of its precision, to quote: ‘by tuning synaptic transmission, this novel signaling mechanism can provide a long-term buffer that stabilizes the decision-making process, initiation, and the control of precision of movement, thus permitting the motor programs to be effortlessly and unconsciously executed.’ (El Manira and Kyriakatos 2010)
Preliminary results on using CBD as a treatment of movement disorders are encouraging (Peres et al. 2018). One recent study of possible relevance to autism reported marked improvement of motor dysfunction in Huntington’s Disease patients after administration of cannabinoids. In addition to improvements in dystonia and fine motor skills, significant behaviour changes including a reduction in apathy and irritability were also observed (Saft et al. 2018).
“Beyond the direct therapeutic effect of CBD in reducing epileptic seizures, reports about improvement in “secondary” health aspects were very common…The main secondary effects were improvements in awareness (147/285, 52%), quality of sleep (88/285, 31%), mood (87/285, 30%), behavior/aggression (56/285, 20%), language/cognition (19/285, 7%), and motor skills (19/285, 7%).”
(Pamplona et al. 2018)
“Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects.”
(Rosenberg et al. 2017)
“Cognitive gains, including improved alertness, verbal communication, vocalizations, cognitive availability, and initiation of emotional and physical connections, were reported in 12 (85.7%) of 14 patients…In addition, of the nine patients with physician‐ and parent‐observed behavioral problems, behavioral improvements were reported in six (66.7%). With respect to seizures, both responders and nonresponders experienced cognitive and behavioral improvements during treatment with CBD.”
(Hess et al. 2016)
“The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder.”
(Karhson et al. 2016)
Inflammation & immune system modulation by cannabinoids – implications for autism
Neuroinflammation and immune system abnormalities in autism
Autism is characterized by immune system dysregulation and neuroinflammation. The severity of immune alterations has been found to correlate with the severity of core autism symptoms (Onore, Careaga, and Ashwood 2012). Published evidence from population-wide studies, results from clinical trials, as well as experimental research on rodent and primate models all point to immune-related pathways being involved in the development of autism symptoms and manifestations.
Epidemiological studies have consistently shown correlations between the risk of developing autism and either maternal or infantile atopic diseases, food allergies and food intolerance and family history of autoimmunity (Atladóttir et al. 2009; Spann et al. 2019; Theoharides et al. 2016; Vinet et al. 2015). Many of autism genetic risk factors are in genes involved in immune system pathways (Bennabi et al. 2018; Saxena et al. 2012), and recent findings suggest association between predisposition to autoimmunity, and immune/inflammatory activation and autistic regression, characterised as emergence of autism symptoms and functional impairments after an initial period of normal development (Bilbo et al. 2018; Scott et al. 2017; Thompson et al. 2019).
Immune system alterations that have been repeatedly observed in autism include increased incidence of allergies and autoimmune disorders, differential monocyte and macrophage responses, abnormal cytokine levels, decreased T cell mitogen response, decreased numbers of lymphocytes and abnormal serum immunoglobulin levels. Another frequent finding is high levels of antibodies against brain and central nervous system proteins, as well as against maternal proteins (Masi et al. 2017; Gładysz, Krzywdzińska, and Hozyasz 2018; Marchezan 2019).
It is well known from studies based on animal models that prenatal or early-life immune activation following environmental insults results in physiological and behavioural abnormalities that mirror those in human autism. Offspring of mothers exposed to immune stressors such as infections and allergies, or animals exposed to inflammation-inducing challenges in early postnatal period, develop many of the defining features of autism including defects in social interactions, communicative impairments, and repetitive/stereotyped behaviours, as well as biomedical abnormalities similar to those found in individuals with autism (Bilbo et al. 2018; Lewis et al. 2018; Missig et al. 2018; Li et al. 2018; Schwartzer et al. 2015). In the context of the prevalence of autism having 4:1 male to female ratio, it is interesting to note that the consequential immunological and neurological abnormalities appear to be sex-specific, with male animals having stronger negative outcomes (Haida et al. 2019; Missig et al. 2019; Xuan and Hampson 2014).
Repeated investigations have found chronic inflammatory processes in multiple areas of the brain and cerebral spinal fluid in autism, including increased inflammatory cytokine and chemokine production and consistent activation of astrocytes and microglia in autism (Morgan et al. 2010; Vargas et al. 2005; Suzuki et al. 2013; Young et al. 2011). While the role of microglia in host defence in response to perturbations of body or brain homeostasis, including infection, trauma, or hypoxia–via their production of cytokines, chemokines, and reactive oxygen species, is well known, their activity is also critical for brain development and connectivity (Gupta et al. 2014).
Some of the pro-inflammatory molecules found in increased levels in the brain in autism are the monocyte chemoattractant protein-1 (MCP-1/CCL2), tumor necrosis factor alpha (TNF-α) and protein complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB is involved in cellular responses to environmental stressors such as infections, pollutants or irradiation. MCP-1 recruits monocytes, memory T cells and dendritic cells to the sites of inflammation produced by either tissue injury or infection. MCP-1, TNF-α, and NF-κB are the first pro-inflammatory mediators to be activated after exposure to environmental stress (see ‘Cannabinoids in stress response’ section above). In this context, it should be noted that pro-inflammatory effects of stress can be blocked by manipulating levels of cannabinoids and expression of CRs in the brain (Zoppi et al. 2014).
Cannabinoid signalling in immunity and inflammation
The involvement of ECS in immunological abnormalities found in autism has already been suggested by some investigators (Brigida et al. 2017). Results from animal studies show that disturbances in ECS are a major contributing factor in neurodevelopmental abnormalities caused by perinatal inflammation and immune activation, and that manipulation of cannabinoid signalling restores both biochemical and behavioural abnormalities in diverse experimental animal models (Doenni et al. 2016; Kerr, Gilmartin, and Roche 2016).
It has been well established that cannabinoids can modulate the function of the immune system. Cannabinoid receptors are widely expressed on various types of immune cells in humans, including NK cells, T and B lymphocytes, and macrophages. ECS is one of the central regulators of both innate – via TLR-linked signalling –and adaptive immune systems, and manipulating cannabinoid signalling can also greatly influence immune responses in processes involving inflammation, autoimmunity, antitumor and defensive antipathogen immune responses (McCoy 2016; Tanasescu and Constantinescu 2010; Downer 2011; Lunn, Reich, and Bober 2006; Oláh, Szekanecz, and Bíró 2017).
Various CDMPs are currently being investigated for their potential therapeutic actions in many diseases marked by inflammation and autoimmune activation in various types of tissue and parts of the body, such as multiple sclerosis, lupus, rheumatoid arthritis, inflammatory bowel syndrome and many others.
In the brain, ECS regulates the release of proinflammatory molecules primarily through inhibition of NF-κB activation and subsequent reduction in the levels of pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 (Kozela et al. 2010; Juknat et al. 2019), all of which are increased in autism. On the other hand, the production of anti-inflammatory/regulatory cytokine IL-10 is increased by cannabinoids (Correa et al. 2010). These effect has been observed in different models of microglial activation including maternal immune activation or valproic acid models (Guo. et al. 2018; Zamberletti et al. 2019; Guo et al. 2014).
Since cannabinoids regulate the brain–immune axis and inhibit microglial cell activation, ECS is thought to function as the link between the immune and central nervous systems (Lisboa et al. 2016; Suárez-Pinilla, López-Gil, and Crespo-Facorro 2014). In addition, evidence is accumulating for the central role of ECS in the regulation of immune homeostasis in the gut and the gut-brain axis (see below).
Cannabinoids in the gut, the vagus nerve and gut-brain signalling
Gastrointestinal (GI) disorders are significantly overrepresented in autism compared to the general population. A large number of individuals with autism present with functional GI problems: diarrhoea, constipation, gastroesophageal reflux, stomach pain and others, and the severity of GI symptoms correlates with the severity of autism and challenging behaviours. The rates of Inflammatory Bowel Disease are also increased in autism. Pathological findings are numerous and include increased intestinal permeability, systemic inflammation, digestive enzyme deficiency and bacterial dysbiosis.
Cannabinoid receptors are expressed in various types of tissue and parts of the GI tract, from the oesophagus to intestinal lining to enteric neurons, and ECS plays a major regulatory role in multiple aspects of gut function, including gastrointestinal transfer and motility, secretion, hunger signalling, swallowing, nausea and vomiting, gut inflammation, gut permeability (DiPatrizio 2016; Hasenoehrl et al. 2016), and in the gut-brain axis (Sharkey and Wiley 2016). Cannabinoids are involved in the modulation of visceral sensation and likely contribute to the effects of stress on GI function (Hornby and Prouty 2004).
In addition, ECS is strongly involved in the maintenance of the delicate balance in the gut between effective pathogen defence and immune tolerance to antigens that are beneficial to host, such as commensal bacterial or food components (Acharya et al. 2017).
In recent years novel data has emerged on cannabinoids interacting with and influencing the resident gut microbiome. A combination of THC and CBD was observed in a recent study to mitigate experimental autoimmune encephalomyelitis in animals by changing the composition of their gut microbiota. It is primarily through their interplay with the microbiome that cannabinoids are thought to modulate gastrointestinal metabolomic regulatory pathways and in this way directly influence host energy metabolism (Cani et al. 2016; Oza et al. 2019).
The vagus nerve connects the enteric nervous system of the gut with the brain stem, and serves as the ‘communication highway’ for the exchange of signals between the two organs; the brain and gut bidirectionally communicate via the vagus nerve to control a variety of physiological processes. CRs are richly expressed on the vagus nerve and recent research has revealed a major role of ECS in modulating its activity and the transmission of information between the gut and the brain. For example, vagal control of gut motility is regulated by cannabinoids acting on CRs and related receptors in the brainstem (Storr and Sharkey 2007).
Agents that modulate the ECS are in early stages of development as treatments for gastrointestinal disorders, including Inflammatory Bowel Disease (Ambrose and Simmons 2019).
New horizons in cannabinoid research with potential relevance to autism
New knowledge is slowly emerging on previously-unknown effects of cannabinoids, many of which could be highly relevant to autism pathologies and/or comorbid health conditions that are frequently found in individuals with autism.
Cerebrospinal fluid abnormalities in autism & regulation of CSF volume by cannabinoids
Recent MRI studies have revealed increased volume of cerebrospinal fluid (CSF) in autism. The abnormalities were characterised by excessive CSF levels in the subarachnoid space (space between the brain and the surrounding membranes) and the increase in CFS volume was correlated with greater sleep disturbances and greater communication impairments. The unusual pattern of anomalies that was found lead the investigators to suggest the possibility that there is an imbalance between CSF production and absorption in autism, with relatively normal CSF production coupled with impaired CSF circulation and absorption (Shen 2018).
Several studies have indicated that cannabinoid signalling could be one of the regulatory mechanisms in the production and flow of CSF. Cannabinoid receptors are expressed in the lining of choroid plexus and their activation is thought to play a role in regulating aqueous flow between the CSF and vascular circulation (Ashton et al. 2004; Mancall et al. 1985).
Low bone mineral density in autism & cannabinoid regulation of bone metabolism
Individuals with autism and other developmental disabilities have significantly lower bone mineral density, and a higher risk of demineralisation and osteoporosis compared to controls. This is commonly hypothesised to be due to lower rates of physical activity, restricted diets or higher prevalence of gastrointestinal conditions in autism resulting in reduced absorption of nutrients. However, none of the studies so far uncovered a clear correlation between any of those factors and low mineral bone density in autism (Barnhill et al. 2017; J S Jaffe, Timell, and Gulanski 2001; Joshua S Jaffe and Timell 2003).
ECS is essential for the maintenance of normal bone mass. CRs are richly expressed in osteoblasts and osteoclasts, and their activation by cannabinoids regulates bone formation and bone resorption. Manipulation of cannabinoid signalling in experimental animals leads to changes in their bone mineral density and age- or hormonal-related bone loss. Certain genetic polymorphism in CRs in women are associated with low bone density and osteoporotic fractures, and cannabinoid signalling is being explored as a molecular target for the diagnosis and treatment of osteoporosis (Bab et al. 2008; Ofek et al. 2006; Idris 2010).
The role of endocannabinoid system in glucose and energy metabolism
Prevalence of obesity is significantly greater among children and adults with autism compared with the general population, and higher odds of obesity are reported in individuals with severe autism compared to those with milder impairments. In addition, adults with autism suffer higher rates of other metabolic disorders such as dyslipidemia, hypertension, and diabetes (Croen et al. 2015; Fortuna et al. 2016).
Maternal obesity has been confirmed as a significant risk factor for autism by multiple studies, while the role of maternal hypertension and diabetes is also suspected but less clear at present time (Cordero et al. 2019; Healy, Aigner, and Haegele 2018; Maher et al. 2018; Sanchez et al. 2018; Xiang et al. 2015).
While the difference in obesity rates in autism is commonly hypothesised to be due to lack of physical activity and/or medication, the differences in unhealthy weight gain were recently reported to be present in children with autism as early as ages 2 to 5 years (Hill, Zuckerman, and Fombonne 2015). Those findings of differential weight gain among children with autism beginning in very early childhood point to intrinsic differences in metabolic homeostasis.
In addition to disturbances in body energy metabolism, brain energetic failure has also been implicated in autism and related neurological disorders such as epilepsy (Schifter et al. 1994; McDonald, Puchowicz, and Borges 2018).
Growing evidence suggests that ECS plays an important role in the control of whole-body energy homeostasis, including lipid and glucose metabolism and development as well as maintenance of obesity and its inflammatory complications (Capasso, Milano, and Cauli 2018; Cluny, Reimer, and Sharkey 2012; Hirsch and Tam 2019). Modulation of cannabinoid signalling can lead to changes in body weight and associated metabolic profile and various compounds that target cannabinoid receptors are currently being investigated for their potential effects in preventing obesity and metabolic dysfunction in various murine models and in humans (Lipina et al. 2012).
Interestingly, recent studies have linked gestational exposure to high-calorie high-fat maternal diets with a disrupted ECS in offspring. The results of experimental studies in animals show that the maternal diet has long-term sex-specific effects on offspring development in great part due to alterations in offspring ECS homeostasis (Ramírez-López et al. 2016).
Cannabinoid regulation of progenitor and neural stem cells
ECS is involved in the regulation of several aspects of brain development. CRs are expressed in the brain and throughout the nervous system since early embryonic development, and cannabinoids play a central role in creating the architecture and wiring of the brain. In the adult brain, CRs are present in neural progenitor/stem cells and control their self-renewal, proliferation and differentiation. These findings open the door for exploring cannabinoids in combination with stem cell therapy as a potential treatment for various neurological disorders (Rodrigues et al. 2019; Aguado et al. 2005).
In addition to neural stem cells, CRs also play a prominent role in regulating the development of non-neural progenitor cells, including immune cell differentiation, haematopoiesis and bone remodelling (Galve-Roperh et al. 2013).
Additional actions of cannabinoids
Apart from their own receptors, cannabinoids also directly interact with other types of receptors in the human body such as transient receptor potential vanilloid type 1 (TRPV1) and peroxisome proliferator-activated receptors (PPARs) receptors.
TRPV1 receptors are involved in regulation of the body temperature and fever response to infection; sensation of pain, especially in response to heat or noxious stimuli (the spicy ‘chili pepper’ taste), and thermal and pain hypersensitivity in inflammatory states (Iida et al. 2005; Caterina et al. 2000; Costa et al. 2004).
PPARs are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. At least some of the biological actions of cannabinoids including neuroprotection, anti-inflammatory action, and analgesic effects are partly mediated by PPAR-activation (Pistis and O’Sullivan 2017).
A Flashman MD, interview excerpt
The future of medical cannabis for autism – research directions and clinical considerations
When considering CBMPs for autism and related symptoms several important factors are taken into consideration: route of administration; single substance preparation (e.g. pure CBD isolate, synthetic cannabinoid-mimicking molecules etc) versus whole-plant extracts; ratio of CBD vs. THC (if any) in the preparation; route of administration, and dosage/strength of the preparation.
Route of administration of cannabinoids determines bioavailability
Bioavailability of cannabinoids, or how fast and how successfully they are entered into circulation and absorbed by the brain and other organs, largely depends on their route of administration.
While inhalation is the most effective in terms of bioavailability, at present time the safest and easiest route of administration, and the one that has been used in the majority of autism studies, is the oral one. One major disadvantage of oral route administration is the risk of the active substances being metabolised by the liver and broken down into inactive molecules before they can have a therapeutic effect; according to some studies only slightly over 5% of the CBD that is administered orally makes it through the liver unaltered. (One recent study revealed strong positive effects of dietary fat on absorption of CBD (Birnbaum et al. 2019).
Alternative compounds based on cannabinoids, and alternative routes of administration, including transdermal ones, are being actively investigated. Since CBD is highly lipophilic, one major challenge is to prevent the accumulation of the drug in the skin and to develop novel formulations with improved skin absorption. One such formulation is the aqueous gel solution containing synthetic CBD developed by Zynerba Pharmaceutical, currently entering Phase II trial for autism.
While there are no published studies at this time, individual practitioners have reported good results from transdermal formulations in their clinical practice by targeting a specific area of patient’s body for optimal absorption.
CBD vs. THC
CBD was the first identified active ingredient in cannabis, and the most widely researched one to date. It can be extracted from the plant by various methods and this pure crystalised isolate form is then added to various other carrier compounds to create ‘pure CBD’ oils, transdermal and other formulations.
The majority of recently published studies on cannabinoids for autism used whole-plant extracts that contained high levels of CBD and up to 1.5% THC, amongst other ingredients. Several older studies used single synthetic compounds, such as synthetic THC dronabidiol. A couple of ongoing studies are investigating a pure CBD extract and a synthetic CBD compound in oral and transdermal form, respectively.
Studies in animal models of autism, as well reports from experienced clinicians and patient advocates, indicate that formulations containing THC in at least 20:1 CBD:THC ratio might be more beneficial for at least some individuals with autism than products using pure CBD and/or hemp extracts containing only trace amounts of THC.
Single substance preparations versus whole-plant extracts
The advantages of using and studying formulations that contain isolated or synthetic compounds versus whole plant extracts are widely debated. By using single compounds the exact dosages and blood levels are easier to achieve, making such products more suitable for targeted treatment and ‘precision medicine’ applications.
On the other hand, the evidence is accumulating on the claims that some of the active ingredients that are present in a whole plant extract but are naturally absent in extracted isolates or synthetic compound products have additional beneficial effects of their own. Apart from the more well-researched effects of cannabinoids such as CBC or CBG, the evidence is emerging on bioactivity of various terpenes. Myrcene, for example, has calming, muscle-relaxing, analgesic, and anti-inflammatory effects, while pinene, another terpene, has demonstrated broad-spectrum antibiotic effects in addition to its antidepressant-like activity (Russo 2011; Baron 2018; Guzmán-Gutiérrez et al. 2015).
Terpenes and other non-cannabinoid compounds also act in synergy with cannabinoids to enhance their bioavailability and effects. This is also known as ’entourage effect’ (Pamplona, da Silva, and Coan 2018; Russo 2011). For example, CBD has a very narrow therapeutic window and seems to require higher doses when used in isolated form; its bioactivity appears to be both strengthened and prolonged in the presence of other active constituents in whole plant extracts. When administered together, CBD and THC can enhance each other’s effectiveness and/or levels while lowering side effects (Boggs et al. 2018; Aso et al. 2019).
A major challenge in using full-spectrum (or ‘broad-spectrum’ – where only one or several components have been removed) formulations is that even though many research studies did in fact use plant extracts rather than isolated compounds or their synthetic mimics, it is often difficult or impossible for other researchers and clinicians to obtain products with the exact same specifications and plant strains, extraction methods, strength ratios etc. as those used in previous studies. Secondly, given that cannabis contains several hundred known active ingredients, with more being discovered daily, it will never be possible to study and fully elucidate the effects of all possible combinations.
The challenges surrounding full spectrum usage has prompted calls to develop and study 2-or 3-factor formulations that contain a limited number of isolated compounds; for example, a patented formulation consisting of isolated CBD and another anti-inflammatory plant botanical known as spilanthol is soon entering clinical trials as a treatment for gastritis.
Cannabis-based medicinal products – contraindications and potential drug interactions
Cannabis and CBMPs have excellent safety profile in comparison to many other medications. A recent large review revealed no increase in serious adverse events in chronic administration. CBMPs are generally contraindicated in pregnancy and lactation. Preparations with high THC content are contraindicated in psychosis. CBMPs, especially THC-dominant preparations, should be utilised with caution in unstable cardiac conditions, such as angina, due to tachycardia and possible hypotension due to THC.
CBMPs may also be susceptible to pharmacodynamic drug-drug interactions. CBD and THC act as enzyme inhibitors of cytochrome P-450, and caution should be taken when CBMPs are co-administered with medications that are CYP inhibitors or inducers. Existing studies have not demonstrated toxicity or loss of effect of concomitant medications, with the exception of high dose CBD with clobazam, where CBD has been found to increase serum levels of the active metabolite norclobazam (MacCallum and Russo 2018; Alsherbiny and Li 2018; Franco and Perucca 2019).
Ongoing studies on medicinal cannabis for autism
Several larger studies of cannabinoids for autism are currently ongoing or awaiting publication. Amongst them is the observational study led by Zelda Therapeutics and Children’s Hospital of Philadelphia (CHOP), the initial results of which are reported to be extremely encouraging and informative for design of future randomised trials.
Cannabidiol for ASD Open Trial clinicaltrials.gov/ct2/show/NCT03900923 (pure CBD isolate)
Cannabinoids for Behavioral Problems in Children With ASD (CBA) clinicaltrials.gov/ct2/show/NCT02956226
Medical Cannabis Registry and Pharmacology (Med Can Autism) clinicaltrials.gov/ct2/show/NCT03699527
(preliminary outcome analysis)
Cannabidivarin (CBDV) vs. Placebo in Children With Autism Spectrum Disorder (ASD) clinicaltrials.gov/ct2/show/NCT03202303
The information contained in this article in no way constitutes medical advice. If you wish to consider cannabis-based medicinal products as a treatment option please consult a qualified practitioner
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‘From Bench to Biopharma’ International Conference on Translational Research in Autism – Day 1 Recap
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