Zygel's CBD Gel Could Treat Autism-Related Symptoms

Zygel, a topical CBD gel developed by Zynerba Pharmaceuticals, reduced fragile X-related irritability and disruptive behavior in clinical trials. The company plans to conduct further research to determine if the new investigational treatment can ease irritability and other behavioral symptoms associated with autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that impacts social communication, expressive and receptive language skills, and behavior. It's called a "spectrum" condition because its symptoms vary in severity. For example, some autistic individuals may have relatively intact communication skills, while others are nonverbal.

In addition to language and communication symptoms, certain individuals with autism can experience bouts of agitation, irritability, aggression, and self-injurious behavior. These behaviors can be challenging for the person with autism and their caregivers and significantly interfere with daily functioning.

Treating these symptoms involves behavioral approaches, such as applied behavior analysis (ABA), sensory integration therapy, and, in some cases, medication.

While there are no medications available that treat the primary symptoms of autism, two antipsychotic drugs — risperidone (Risperdal) and aripiprazole (Abilify) — are U.S. Food and Drug Administration (FDA) approved to treat ASD-related irritability in children and adolescents.

Although these medications can be effective, they can cause significant side effects, which is why many autistic individuals and their parents or caregivers may wish to avoid them.

However, a new treatment for autism-related irritability is on the horizon that may provide an alternative to antipsychotics. The investigational treatment, called Zygel, is a topical cannabidiol (CBD) gel that has already shown promise in clinical trials for treating irritability and disruptive behaviors in children with fragile X, a genetic cause of autism.

Pharmaceutical firm fast-tracks new topical CBD-based option

Developed by Zynerba Pharmaceuticals, Inc., acquired by Harmony Biosciences Holdings, Inc. in 2023, Zygel (ZYN002 cannabidiol gel) is a pharmaceutically manufactured cannabidiol gel specifically formulated to be absorbed through the skin into the bloodstream.

It is not derived from the cannabis plant and does not contain tetrahydrocannabinol (THC), the compound that causes the "high" effect of cannabis.

The new CBD gel is currently in clinical trials for treating behavioral symptoms of fragile X syndrome, a common genetic cause of autism. The new drug is also under investigation as a treatment for behaviors associated with 22q11.2 deletion syndrome, a complex genetic condition that can cause developmental delays.

An earlier open-label phase 2 study showed that Zygel (when used in addition to a stable standard of care) reduced irritability, inappropriate speech, and hyperactivity in participants with ASD, with no severe side effects. However, since this study was preliminary, the company plans to conduct more trials to determine the safety and effectiveness of Zygel in autistic individuals.

Fragile X studies show promising results

In a phase 1 and 2 clinical trial, the CBD gel was administered twice a day for 12 weeks (up to 250mg of CBD per day) to children and teens with fragile X syndrome. The results showed a reduction in anxiety and behavioral symptoms associated with fragile X, including irritability.

Among the participants, 85% reported treatment-related adverse effects, including gastrointestinal issues, skin irritation, or application site pain, but they were mild to moderate in severity. Moreover, the study only involved 20 participants.

In a follow-up phase 3 trial involving 212 participants aged 3 to 17 with fragile X, scientists administered a placebo or CBD gel in dosages of 250 or 500 mg daily for 12 weeks, as an add-on to the standard of care.

As reported by caregivers, participants who received the gel showed improvements in irritable and disruptive behaviors and social interactions. However, the results were only significant in patients with ≥ 90% methylation in the FMR1 gene, who typically show the more severe symptoms. Specifically, this group of participants using Zygel saw an estimated 58% improvement in social avoidance and a 40% reduction in irritability.

The most common treatment-related side effect noted in this trial was application site pain.

An additional phase 3 randomized, controlled trial is currently underway to confirm the results of the previous trials. If the study's findings show that Zygel is safe and effective, the company will likely submit it to the FDA for review and approval as a treatment option for fragile X-related behaviors.

How does Zygel compare to current FDA-approved medications?

During Zygel clinical trials, the primary side effects reported were gastrointestinal issues and skin irritation or pain. Risperidone and aripiprazole can also cause digestive disturbances. However, other side effects of the medications include anxiety, sleep problems, and weight gain.

Dr. David Berger, a board-certified pediatrician and founder of Wholistic ReLeaf, Wholistic Pediatrics & Family Care, and health education company Dr. David, M.D., tells Healthnews, "From a side effect perspective, I am more concerned about [antipsychotic] medications due to the weight gain effects, which are sometimes very dramatic."

Berger says that although uncommon, antipsychotics can cause a severe side effect called tardive dyskinesia — a movement disorder that may not resolve even after the medication is stopped.

The medications' administration methods also differ. For example, risperidone and aripiprazole come in pill or injectable form, whereas Zygel is applied to the skin.

Moreover, while risperidone and aripiprazole are considered safe and effective for treating irritability and aggression in autism, they might not work for everyone.

Since scientists have yet to determine whether CBD, even in a gel form, can ease autism-related irritability and behaviors, its effectiveness is unclear.

Can CBD help manage autism symptoms?

According to Healthnews researcher Rimgaile Blekaitiene, using CBD for treating autism-related symptoms has some theoretical backing, yet it’s quite limited.

"Preliminary evidence shows that endocannabinoid levels may be altered in (ASD)," Blekaitiene says. "There are some possible mechanisms of action proposed, on how cannabinoids may have multi-systemic effects in autism. However, these are largely hypothetical."

Still, Blekaitiene notes that when it comes to cannabidiol, the evidence is limited, and it remains to be established whether it's safe and effective in managing behavioral symptoms of autism.

Berger tells Healthnews that he has been using CBD for patients who have symptoms such as anxiety, irritability, and agitation for over 10 years, and has seen success using cannabidiol when compared to medications such as risperidone and aripiprazole.

"I have seen many patients experience clinical improvements, and often, we find enhanced benefits when not just a single ingredient isolate with CBD is used," Berger explains.

However, Berger notes that CBD's effects can vary among autistic people.

"I have seen two patients who have experienced irritability with taking CBD, but they also had negative reactions to other cannabinoids, so it was not specific to the CBD," he says.

Still, CBD products, except for the prescription medication Epidiolex, are not FDA-approved, so despite their availability on the market, there are no federal standards to guarantee purity or potency.

When will Zygel be available?

If the current clinical trials show that Zygel is a safe and effective treatment for irritability in fragile X, it could be FDA-approved relatively soon for people with this condition. However, it's unclear when Zynerba will submit the investigational drug for review.

Whether the FDA will eventually approve Zygel for treating autism-related behaviors remains to be seen, as further clinical trials are only in the planning stages.

Nonetheless, Berger says it's exciting to see the pharmaceutical industry take notice of cannabinoids.

"It would be great to have clinically proven effective, accurately dosed, well tolerated, easy to administer and effective products become available," Berger says. "The phase two trials [for Fragile X] look promising and I look forward to seeing larger study results."