Medical Marijuana for Autism
Cannabis is prescribed as a treatment for autism in 14 states. Is it the wonder drug patients and families have been waiting for?
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CLINICAL REFLECTIONS
Although the research on cannabis and autism spectrum disorders is in its infancy, there has been much controversy and confusion. Over the years, more patients and their families are seeking guidance from doctors on using cannabis to alleviate symptoms. From preventing seizures to calming aggression, a slow trickle of research is suggesting that cannabidiol (CBD), a component of cannabis, may be the wonder drug families have been searching for. But does it hold up to this standard? Should we be recommending it to patients? How do we weigh the benefits and the risks?
Unfortunately, many clinicians lack adequate training on the subject, making them unprepared to have a meaningful discussion with patients and families. Efforts to advance research have been limited for technical and logistical reasons, often leaving doctors with just as many questions as patients.
Cannabis: An Overview
Cannabis is a genus of flowering plants belonging to the family Cannabaceae that includes 3 species: cannabis sativa, indica, and ruderalis. Marijuana specifically refers to the parts of the cannabis plant that contains high amounts of delta-9-tetrahydrocannabinol (THC). Medicinal use of the cannabis plant dates back thousands of years in cultures all around the world. Today, it is used to treat an assortment of conditions, such as arthritis, cancer, HIV/AIDS, glaucoma, seizures, and more.
Used recreationally, it produces a high or mind-altering effect when smoked or consumed. It is also used therapeutically. The National Institute on Drug Abuse defines medical cannabis as “using the whole, unprocessed marijuana plant or its basic extracts to treat symptoms of illness and other conditions.”1
The plant produces more than 500 different chemical substances. These include 100 unique cannabinoids, which bind to the CB1 and CB2 receptors in the body’s endocannabinoid system. CB1 receptors are more common in the central and peripheral neurons, while CB2 receptors are expressed only in peripheral tissues, predominating the immune system.2
THC and CBD are 2 cannabinoids found in cannabis that have particular clinical importance.3
In medical applications, THC is typically used to relieve pain, nausea, insomnia, and poor appetite. THC is a partial agonist of the CB1 and CB2 receptors.4 It produces the high, which is why it is included in so many recreational marijuana products.
CBD is less controversial than THC because it does not produce mind-altering or euphoric effects. It has low affinity for CB1/CB2, acting as an antagonist.5 It affects various receptor systems in the body (TRPV1, GPR55, PPAR.) Of note is its agonism on the 5HT1A (serotonin) receptor at high concentrations to help with anxiety, sleep, pain perception, and nausea.6 It also appears to be a partial dopamine receptor agonist, pointing toward its possible antipsychotic properties. Additionally, CBD appears to influence the glutamate-GABA system.7
Endocannabinoids are naturally occurring lipid mediators in the body that bind to the cannabinoid receptors. Unlike other neurotransmitters, they are produced on demand in the body and are quickly inactivated. The most common ones include: N-arachidonoylethanolamine (anandamide), 2-arachidonylglycerol (2-AG), and 2-arachidonylglyceryl ether.
Anandamide, also known as the “bliss molecule,” is currently one of the most-studied endocannabinoids.8 The cannabinoid receptor system has a very complex role in the body, which includes regulation of cell function, maintenance of homeostasis, motor coordination (basal ganglia), brain reward system, stress response, memory function (hippocampus), appetite, modulation of pain, and reduction of inflammation.
Anandamide causes inhibition of the release of neurotransmitters such as glutamate and gamma aminobutyric acid (GABA). It also affects norepinephrine, dopamine, serotonin, histamine, prostaglandins and opioids.9 An imbalance in the GABA and glutamate system is often linked with autism.
The Challenges of Autism
Autism spectrum disorder (ASD) is a neurodevelopmental disability characterized by impairment in 3 major domains: social interaction, communication, and behavior patterns. It is called a spectrum disorder because it has a broad range of severity and symptom type. These usually appear within the first few years of life, although it can be diagnosed at any age.
In 2016, 1 in 54 children by the age of 8 was diagnosed with ASD, according to Centers for Disease Control and Prevention statistics. This was a 10% increase over 2014, when the estimate was 1 in 59. Boys are 4 times more likely than girls to be diagnosed.10
The causes of autism are not clearly understood. It is a complex disorder thought to be multifactorial in origin, involving genetic and environmental factors.11 It is associated with several conditions, such as Fragile X, Rett syndrome, tuberous sclerosis, phenylketonuria, and certain genetic conditions involving the deletion or duplication of chromosomes. Additionally, roughly 20% to 25% of individuals with autism are diagnosed with epilepsy at some point during their lives. Intellectual disability is also highly prevalent in autism, and there is a close association with seizure risk in autistic individuals.6
Environmental factors being explored by research include viral infections, air pollutants, dietary factors, medications, and perinatal complications. Other common risk factors include children born to older parents, siblings of affected children (especially in the case of identical twins), and a family history of autism.11,12
There are no medications that address autism’s core symptoms. Existing medications are used to target comorbid symptoms such as anxiety or mood symptoms and aggressive behavior. But these may not be very effective and often cause several side effects, limiting their use.
The Case for and Against
With autism cases on the rise, the need for effective treatments is rising too. Treatments in childhood carry special risks and potential rewards. Because a child’s brain is still developing, it is a good opportunity to make significant changes, but for the same reason, it is a dangerous time to experiment with certain compounds like THC and cannabis. Many of us have encountered desperate families who have found traditional treatments inadequate or resulting in undesirable side effects. At their wit’s end, they are willing to try just about anything. By not approaching the topic, patients and families may seek unsubstantiated advice on the Internet, leading them to use substandard and potentially dangerous products in an unregulated market.
Today, cannabis is easily accessible and popular with millions of Americans, but as noted, cannabis can be a mixture of many things. While the federal government considers cannabis a Schedule I drug, it has been legalized in 33 states and Washington, DC. Meanwhile, CBD is a schedule 5, the lowest degree of regulation by the US Food and Drug Administration. As a treatment for autism, cannabis has been prescribed in 14 states since 2019, according to the Autism Support Network.13
Whether we accept cannabis as a psychiatric treatment or not, our patients and their families are curious and interested in learning about all options. That is why it is vital for us as psychiatrists to educate ourselves on the use of cannabis to treat autism spectrum disorder (ASD), recognizing that the both the risks and benefits of use in ASD are indirect and insufficient. This might be the only way we can guide our patients to weigh all the facts before making a treatment choice.
Current Research Results
Research on cannabis’ impact on autism is still very much in its infancy, but there are several important studies to consider, with more on the way. In a 2018 Stanford University study, anandamide concentration was significantly lower in children with ASD as compared to controls.14 Research studies have suggested that anandamide produces effects similar to, but less intense than, those associated with THC.15 Because of this similarity, researchers theorize THC has therapeutic potential in the treatment of autism.
Another study in 2013 found an increased expression of CB2 receptors in peripheral blood mononuclear cells in autistic children, suggesting an imbalance in the endocannabinoid system.16 Oxytocin is a neuropeptide crucial for social behavior, and studies indicate the oxytocin-driven anandamide signaling system may be defective in autism patients, leading researchers to theorize whether CBD can correct this.17
Terpenoids are aromatic compounds present in the cannabis plant that give each strain its unique smell. Cannabinoids and terpenoids are thought to interact with each other as well as the brain in an entourage effect to produce synergistic results. This effect potentially increases the therapeutic value and tames the mind-altering effects of THC in a product. Similarly, there is some evidence proposing that the simultaneous use of THC and CBD is more effective than either alone. While still theoretical, it explains why both are often used together in medical applications.18 Further, the ratio of THC to CBD in a preparation determines the fine balance between its therapeutic use and mind-altering effects.
Epidiolex is the first CBD prescription approved by the US Food and Drug Administration (FDA) in 2018 to treat seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis (TS) in patients as young as 1 year old. It does not contain THC. This approval was based on 3 double-blind randomized controlled trials (RCT) and an open label extension study for LGS and DS, and one RCT for TS, all with positive findings.19-22 About 25% of children with treatment-resistant epilepsy have comorbid ASD. Both LGS and DS have been commonly linked to ASD.
It is important to note that medical cannabis has its own significant side effects (Table 1). A 2012 research study by Duke University found that persistent users of cannabis had reduced neuropsychological functioning, with adolescent onset users experiencing greater decline in IQ and executive functioning.23 These effects did not reverse fully on stopping cannabis use for one year or more, suggesting it has potential neurotoxic effects.
Table 1. Side Effects of Cannabis
Another study shows that cannabis use in adolescence can significantly increase the risk of developing psychotic symptoms and persistent use can precipitate psychotic disorders in later life.24 Studies have also shown that cannabis use and the development of psychosis in adolescents is dose-dependent, with poorer outcomes associated with an earlier age and higher frequency of use.24
One 2015 to 2017 study conducted in Israel sought to gauge the safety and efficacy of cannabis.25 It observed 188 autism patients, most of whom were treated with an oil containing 30% CBD and 1.5% THC. It was not placebo controlled. After 6 months of treatment, parameters of activities of daily living, mood, and quality of life were assessed. It found that 30.1% of patients reported significant improvement, 53.7% moderate and 6.4% slight improvement, while 8.6% experienced no change to their condition. About 25% of self-reporting patients experienced at least 1 side effect from the treatment, the most common of which was restlessness. The study concluded that CBD and THC in autism patients appeared to be well-tolerated, safe, and effective.
In 2018, a study conducted at the Shaare Zedek Medical Center assessed the effect of a whole plant cannabis extract (20:1 CBD:THC ratio) on 60 autistic children with severe behavioral problems.26 Parents reported that 61% of behavioral symptoms in patients had either “much improved” or “very much improved,” 39% of children experienced improved anxiety level, and 47% improved in communication. Additionally, 24% of children were able to stop taking medication, 30% received either lower dose or fewer medications, while 8% had to increase medication intake. The incidence of side effects and adverse effects was quite high, reported by 57 parents. Common side effects included hypervigilance leading to sleeping difficulty (14%), irritability (9%), loss of appetite (9%), and restlessness (9%).
In another Israeli study published in 2019, 53 children with autism were given a 20:1 ratio CBD to THC dose for a median duration of 66 days in order to study its effect on comorbid symptoms with ASD.27 Symptoms were assessed every 2 weeks through phone call interviews with parents. Changes in individual symptoms cohorts were compared to available data from published studies. Of note, significant improvement was noted in self-injury and rage attacks (67.6%), hyperactivity symptoms (68.4%), sleep problems (71.4%), and anxiety (47.1%) within the groups of patients reporting these symptoms. The overall improvement in ASD comorbidities was calculated to be 74%. Common side effects included somnolence and reduced appetite.
It is important to note, however, that the aforementioned studies are limited because they were observational studies conducted without a placebo control group for comparison. Additionally, results were based on parental reports, which may have been heavily influenced by expectations, thus undermining results.
Adi Aran, MD, MSc, PhD, the Shaare Zedek study’s26 lead author, recently published a double-blinded, randomized placebo-controlled trial in February 2021 to study the role of cannabis in autism further.28 The study used 2 oral cannabinoid solutions (whole plant extract and purified forms of cannabis) with a 20:1 CBD to THC ratio along with a placebo. The purpose was to assess behavioral problems in 150 children and youth with autism with a unique crossover design that included 2 phases of 12 weeks, separated by a 4-week washout phase. It showed mixed results with no difference in one of the primary and secondary outcomes among the groups.
The study assigned 2 primary outcome measures to assess behavioral problems: the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale, with anchor points related to behavioral difficulties (CG-I). Secondary outcomes were measured by the Social Responsiveness Scale-second edition (SRS-2,) the Autism Parenting Stress Index (APSI) and modified Liverpool Adverse Events Profile. There was no difference in the total score of HSQ-ASD and APSI between the groups. However, disruptive behavior assessed by CGI-I scale was “much” or “very much” improved in 49% of participants who were given a whole-plant extract, versus 21% of participants on placebo (P = .005). The SRS-2 scale median score also improved by 14.9% on plant extract versus 3.6% placebo (P = .009). Common side effects included somnolence and decreased appetite. The study advised caution that while the CBD/THC solution was well-tolerated, the study had several limitations. The data on efficacy was mixed or insufficient, warranting more research.28
A study conducted by the Institute of Psychiatry, Psychology, and Neuroscience at King’s College in London used magnetic resonance spectroscopy to examine the effects of a single oral dose of CBD versus a placebo on the brains of 34 male participants, half of whom were diagnosed with autism.29 It is important to note that the study excluded any comorbid major psychiatric or neurological conditions, including traumatic brain injury, certain genetic disorders linked with autism, low IQ, and those receiving medicines with effects on glutamate-GABA pathways. The study found that while CBD affected the glutamate-GABA systems, the prefrontal-GABA systems responded differently in patients with autism. The authors were clear that the results did not apply to the efficacy of CBD.
Future Trials
There are other clinical trials currently underway that are worth following to see what they discover. Children’s Hospital of Philadelphia recently completed an observational study in collaboration with Zelda Therapeutics, an Australian biopharmaceutical company, to track children with autism who are independently using medical cannabis to address symptoms. Results have not been published yet.30 Another ongoing phase 2, 12-week double-blind, randomized, placebo-controlled trial study, funded by the US Department of Defense, is studying how behavior in children with autism might be affected by cannabidivarin, a nonpsychoactive phytocannabinoid, which is a safer alternative to CBD.31
The University of San Diego is conducting a phase 3 clinical trial in partnership with the Wholistic Research and Education Foundation through the Center for Medicinal Cannabis Research. It seeks to explore the role of CBD on behavioral symptoms in children with autism.32 The University of Colorado, Denver, is currently also recruiting participants for a randomized placebo-controlled study with a predetermined crossover design to assess CBD’s impact on common behavioral problems related to autism.33 All participants will receive CBD for at least 12 weeks. Some will receive CBD for the entire 27 weeks of treatment.
New York University’s Langone Health research facility is in the recruiting stage for a 6-week open trial to study CBD use in participants aged 7 to 17 with autism. It will assess dosing, symptoms changes, side effects, and primary and secondary outcomes to guide future controlled studies.34
Barriers to Research
While interest grows in cannabis, the medical community is eager for more research on how it might affect autism. In the United States, tight controls and a lack of adequate funding limits how cannabis is studied.
The National Institute on Drug Abuse (NIDA) contracts with the University of Mississippi, the only facility in the country registered with the Drug Enforcement Agency (DEA) to grow and supply the cannabis that scientists are allowed to study. However, these strains are often not the ones widely distributed to the public in states that have legalized medical cannabis.
Different strains of cannabis have diverse chemical variations, according to Donald Abrams, MD, an integrative oncologist at Zuckerberg San Francisco General Hospital and Trauma Center.35 Products with higher amounts of THC, for example, are often used to treat cancer-related nausea and poor appetite, while CBD tends to be used for chronic pain, inflammation, and insomnia. Abrams also pointed out that NIDA’s supply included mostly low-THC, zero-CBD strains, which can challenge researchers struggling to move with the times and study emerging products on the market. NIDA’s focus on substance abuse also means it is more focused on the negatives of cannabis, rather than any potential benefit.
Even NIDA has acknowledged federal limitations on cannabis research. In 2015, Nora Volkow, MD, NIDA’s director, spoke before the US Senate Caucus on International Narcotics Control.36 She acknowledged application barriers to research and the lack of well-controlled clinical trials. She also noted CBD’s potentially positive effect on a variety of symptoms, including children with drug-resistant epilepsy.
Approval to conduct cannabis research comes from both the FDA and the DEA. The process takes more than a year, with some researchers waiting even longer. Strict protocols govern how cannabis is stored, requiring limited access in an alarm-controlled, locked container physically attached to a floor or wall, according to the UCSF report.35 These obstacles create a catch-22 for medical marijuana research, according to the State of Cannabis Research Legislation in 2020, a report led by Ali Zarrabi, MD, associate director of outpatient support and palliative care at Emory University.37
“Investigators cannot conduct research on cannabis until they demonstrate that it has a medical use, and they cannot show that it has a medical use until they conduct research,” the report states.37
Treading With Caution
The American Academy of Child and Adolescent Psychiatry discourages the use of marijuana and cannabinoids in children with autism, a stance that has not changed despite the FDA’s approval to use cannabidiol to treat seizures. The American Academy of Pediatrics holds a similar stance, although it acknowledges it may provide an option for children with life-limiting or severely debilitating conditions when current therapies are inadequate.
Despite these cautions, individuals with any number of ailments are flocking to cannabis for treatment. But there is a huge gap between the desire for treatment and the research needed for doctors to give approval. Additionally, it is rare for any cannabis curriculum to be included in residencies and fellowships, but this is changing.
We are taught to practice evidence-based medicine as psychiatrists, placing the highest importance on meta-analysis and well-designed double-blinded RCT in research. Most psychiatrists try to adhere to the established standards of evidence-based medicine. However, there are times when we prescribe medications for off-label purposes based on clinical experience, often with reasonable or good results. Could CBD be used in the same way, especially in cases where we are hitting a dead end with existing treatment strategies?
There is some anecdotal evidence that cannabis can positively affect autism. But there is a lack of well-designed clinical trials with adequate sample sizes to study its efficacy and assess for safety. We need to study pure CBD separate from pure THC, without the confounding unknown effects of other molecules present. At this time, however, clinical trials of THC in individuals under the age of 20 are probably unwise.
As of today, we lack evidence-based recommendations to support CBD and cannabis use in children with autism. We lack guidelines on overall safety and efficacy, as well as factors like dosage, the required ratio of CBD to THC, symptoms that will likely respond, and the duration of treatment. We also lack guidance on how to discuss this sensitive topic with our patients, who may be asking for advice and are ready to pursue it on their own. See Table 2 for some tips on how to advise patients.
Table 2. Open Channels of Communication
Therefore, psychiatrists must direct patients and families in their approach toward this treatment option with exercised caution to its risks, benefits, and costs. Additionally, they must understand the data that does exist, and then explain that current data, with its significant lack of evidence-based results, to our patients and their families.
Dr Parmar is a double board-certified adult and child psychiatrist with Community Psychiatry based in Newark CA. She earned her medical degree at Terna Medical College & Hospital in Mumbai, India.
References
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