Autism Spectrum Disorder
Seriousness of medical condition(s)
Autism Spectrum Disorder is a very serious disorder. Children with ASD commonly exhibit comorbid symptoms of hyperactivity, self-injury, aggressiveness, restlessness, anxiety and sleep disorders (Mannion and Leader, 2013; South et al., 2017).
According to the Centres for Disease Control and Prevention data on ASD:
- About 1 in 54 children have been identified with autism spectrum disorder (ASD) according to estimates from CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network.
- ASD is reported to occur in all racial, ethnic, and socioeconomic groups.
- ASD is more than 4 times more common among boys than among girls.
- About 1 in 6 (17%) children aged 3–17 years were diagnosed with a developmental disability, as reported by parents, during a study period of 2009-2017. These included autism, attention-deficit/hyperactivity disorder, blindness, and cerebral palsy, among others.
Who could benefit from this treatment?
Clinical justification for using Medicinal Cannabis
a. The medicinal cannabis’s suitability for the intended indication
b. The medicinal cannabis’s efficacy and expected benefits
In the journal “Oral Cannabidiol Use in Children with Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities”. 53 children at a median age of 11 (4–22) received cannabidiol for a median duration of 66 days (30–588). Self-injury and rage attacks improved in 67.6% and worsened in 8.8%. Hyperactivity symptoms improved in 68.4%, did not change in 28.9% and worsened in 2.6%. Sleep problems improved in 71.4% and worsened in 4.7%. Anxiety improved in 47.1% and worsened in 23.5%. Adverse effects, mostly somnolence and change in appetite were mild (Barchel, Stolar, De-Haan, et al, 2019).
Another recent review has suggested cannabidiol as a candidate for treatment of ASD (Poleg et al., 2019). Cannabis contains numerous chemically active compounds, including 19-tetrahydrocannabinol (19-THC), cannabidiol (CBD) and terpenoids (Russo, 2011). 19-THC activates the endocannabinoid system in the central nervous system, affecting appetite, anxiety, cognitive function and memory (Palmieri et al., 2017). In contrast, CBD is anxiolytic, anti-inflammatory, antiemetic and antipsychotic (Detyniecki and Hirsch, 2015).
c. any unknown or expected adverse effects, risks and safety issues & d. related toxicology:
A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.
According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration (2017):
Cannabis is not appropriate for patients who:
- Are under the age of 25 (with the exception of intractable epilepsy, autism spectrum disorder or severe pain syndrome)
- Have a personal history or strong family history of psychosis
- Have a current or past cannabis use disorder, or active substance use disorder
- Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)
- Are pregnant, planning to become pregnant, or breastfeeding
Cannabis should be authorized with caution in patients who:
- Smoke tobacco
- Have risk factors for cardiovascular disease
- Are heavy users of alcohol
- Are taking sedating medications or any other medication metabolized by the CYP450 pathway
- At risk or have liver disease
Drug Interactions – CYP P450 Enzyme System
THC and CBD are metabolized by Cytochrome P450 enzyme system, including CYP1A2, CYP2C9, CYP2D6, CYP2C19 and CYP3A4. Based on in vitro and animal studies with cannabis, there is a potential for interactions with the medications metabolized by the P450 enzymes (2C9, 2C19, 3A4). It’s notable, however, that the inhibitory effects in vitro and in animal models were only seen at exposures significantly higher than the maximum observed in clinical trials. For instance, in clinical trials were Sativex® has been taken concomitantly with other drugs metabolized by the Cytochrome P450 enzyme system, no clinically apparent drug-drug interactions have been seen in these trials at clinical doses. In an in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS, no relevant induction of the Cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses of up to 1µM (314ng/mL) (Stout and Cimino, 2014).
Potential drug interactions
Increasing THC concentration:
Examples of inhibitors:
– Antidepressants (e.g. Fluoxetine, Fluvoxamine)
– Proton Pump Inhibitors (e.g. Omeprazole)
– Macrolides (Clarithromycin, Erythromycin)
– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)
– Calcium Antagonists (e.g. Diltiazem, Verapamil)
– HIV protease inhibitors (e.g. Ritonavir)
– Grapefruit juice
Increasing CBD concentration:
– Metabolized by CYP 2C19 and CYP 3A4
– Bioavailability could be increased by many of the same substances as for THC
Decreasing THC and CBD concentration:
- CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism
- Examples of inducers:
– Saint John’s Wort
Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex®) and commonly used antiepileptic drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).
- Caution with blood thinners like Warfarin, Heparin, Clopidogrel (Plavix)
- Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia, hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).
Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.
Approved treatments for this medical condition
The types of treatments for ASD generally can be broken down into the following categories:
- Behaviour and Communication Approaches
- Dietary Approaches
- Complementary and Alternative Medicine
The following pharmacological therapies are used to assist in various symptoms of ASD:
Irritability and aggression – Risperidone, Aripiprazole, Clozapine, Haloperidol, Sertraline
Aberrant social behaviours – Oxytocin, Secretin
Hyperactivity and inattention – Methylphenidate, Venlafaxine
Repetitive behaviours – Fluoxetine, Citalopram, Bumetanide
Cognitive disorders – Memantine, Rivastigmine
Insomnia – Mirtazapine, Melatonin
Why is medicinal cannabis appropriate for use?
Standard treatments, as listed above, are not always effective for symptomatic control of ASD and importantly are associated with a range of side effects. Whilst some people are able to tolerate these, in many cases, they are not and/or the long-term potential side effects of their use may be unacceptable.
Patients taking the above medications are significantly more likely to experience adverse events such as increased energy, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, or dry skin or pruritis.
Risperidone and aripiprazole are the most common ASD medications and have a long list of side effects, some more severe than others; nausea, vomiting, diarrhea, constipation, heartburn, dry mouth, increased saliva, decreased appetite, weight gain, stomach pain, anxiety, agitation, restlessness, vivid dreams, insomnia, breast enlargement or discharge, late of missed menstrual periods, decreased sexual activity, vision impairment, muscle or joint pain, dry or discoloured skin, difficulty urinating, dizziness, fever, muscle stiffness, fast or irregular heartbeat, perspiring, uncontrollable movements, seizures, rash/hives.
These side effects can inhibit a person with ASD’s quality of life and can be potentially life-threatening. Cannabidiol has been seen to display little side effects in relation to treating some symptoms of ASD.
“Oral Cannabidiol Use in Children with Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities” suggests that cannabidiol may improve ASD comorbidity symptoms; however, the long-term effects should be evaluated in large scale studies (Barchel, Stolar, De-Haan, et al, 2019).
Cannabis contains numerous chemically active compounds, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and terpenoids (Russo, 2011). Δ9-THC activates the endocannabinoid system in the central nervous system, affecting appetite, anxiety, cognitive function and memory (Palmieri et al., 2017). In contrast, CBD is anxiolytic, anti-inflammatory, antiemetic and antipsychotic (Detyniecki and Hirsch, 2015).
Reports on 38 children with hyperactivity symptoms were recorded. Of them, 68.4% had improvement of symptoms, 28.9% had no change and worsening of symptoms was reported in 2.6%. Of 34 reports on self-injury and rage attacks, 67.6% were reported to experience improvement of symptoms, 23.5% had no change, and worsening of symptoms was reported in 8.8%. There was a borderline significance in improvement of symptoms comparing to the conventional treatment (p = 0.063), and no statistical difference in worsening of symptoms (p = 0.307). Reports on 21 patients with sleep problems were recorded. Of 21 reports, 71.4% improved, 23.8% had no change, and worsening of symptoms was reported in one patient (4.7%). The overall change in ASD comorbidities symptoms out of 51 out of 53 patients sees an overall improvement reported in 74.5%. No change was reported in 21.6% and worsening in 3.9%. (Barchel, Stolar, De-Haan, et al, 2019).
In general, the often-described favourable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects. (Iffland and Grotenhermen, 2017)
- Barchel, D., Stolar, O., De-Haan, T., Ziv-Baran, T., Saban, N., Fuchs, D. O., Koren, G., & Berkovitch, M. (2019). Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities. Frontiers in pharmacology, 9, 1521. https://doi.org/10.3389/fphar.2018.01521
- Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Sep;58(9):1586-1592. doi: 10.1111/epi.13852. Epub 2017 Aug 6. PMID: 28782097.
- Iffland, K., & Grotenhermen, F. (2017). An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis and cannabinoid research, 2(1), 139–154. https://doi.org/10.1089/can.2016.0034
- LeClerc, S., & Easley, D. (2015). Pharmacological therapies for autism spectrum disorder: a review. P & T : a peer-reviewed journal for formulary management, 40(6), 389–397.
- Mannion, Arlene & Leader, Geraldine. (2013). Comorbidity in autism spectrum disorder: A literature review. Research in Autism Spectrum Disorders. 7. 1595–1616. 10.1016/j.rasd.2013.09.006.
- Palmieri, B., Laurino, C., & Vadala, M. (2017). Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. The Israel Medical Association journal: IMAJ, 19(2), 79-84.
- Poleg, S., Golubchik, P., Offen, D., & Weizman, A. (2019). Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry, 89, 90–96. https://doi.org/10.1016/j.pnpbp.2018.08.030
- Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology, 163(7), 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
- South, M., & Rodgers, J. (2017). Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders. Frontiers in Human Neuroscience, 11, 20.
- Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456-73. Errata in: JAMA 2016;315(14):1522, JAMA 2015;314(21):2308, JAMA 2015;314(5):520, JAMA 2015;314(8):837.