MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults

This overview/review paper lays the groundwork for offering MDMA-assisted psychotherapy for the treatment of social anxiety in autistic adults.

Abstract

“The first study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of social anxiety in autistic adults commenced in the spring of 2014. The search for psychotherapeutic options for autistic individuals is imperative considering the lack of effective conventional treatments for mental health diagnoses that are common in this population. Serious Adverse Events (SAEs) involving the administration of MDMA in clinical trials have been rare and non-life threatening. To date, MDMA has been administered to over 1133 individuals for research purposes without the occurrence of unexpected drug-related SAEs that require expedited reporting per FDA regulations. Now that safety parameters for limited use of MDMA in clinical settings have been established, a case can be made to further develop MDMA-assisted therapeutic interventions that could support autistic adults in increasing social adaptability among the typically developing population. As in the case with classic hallucinogens and other psychedelic drugs, MDMA catalyzes shifts toward openness and introspection that do not require ongoing administration to achieve lasting benefits. This infrequent dosing mitigates adverse event frequency and improves the risk/benefit ratio of MDMA, which may provide a significant advantage over medications that require daily dosing. Consequently, clinicians could employ new treatment models for social anxiety or similar types of distress administering MDMA on one to several occasions within the context of a supportive and integrative psychotherapy protocol.”

Authors: Alicia L. Danforth, Christopher M. Struble, Berra Yazar-Klosinski & Charles S. Grob

Notes

This study was supported by MAPS and the Betsy Gordon Foundation.

This paper is followed by Danforth et al. (2018), where they find a reduction in social anxiety in autistic adults.

Summary

1. Introduction

A pilot study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of social anxiety in autistic adults was conducted. The study compared the effects of MDMA on neuropeptides, serotonin, and the mechanisms of face recognition.

Functional brain imaging studies suggest that the amygdala is differentially activated in autistic individuals, and that the left amygdala and left orbito-frontal cortex are less activated in autistic individuals compared to typically developing individuals. MDMA has been proposed as a treatment for anxiety disorders in autistic individuals.

1.1. Relevant history

MDMA, also known as Ecstasy or Molly, is a psychoactive compound that was laboratory-synthesized and does not exist on its own in nature.

MDMA was developed as a byproduct of a styptic compound at Merck in Germany in 1912. Despite reported therapeutic potential, concerns about potential neurotoxicity led to suppression of FDA-approved research with human subjects in clinical investigations.

Early investigators noted that MDMA helped people talk openly and honestly about themselves and their relationships, without defensive conditioning intervening. It was used to treat disorders such as chronic post-traumatic stress disorder and depression, but no methodical research was published from this period.

In the decades following the DEA scheduling, there was much debate about whether or not MDMA use caused neurotoxicity resulting in brain damage. However, many studies were marred by flawed research methodologies, questionable data analyses, and biased conclusions.

Multiple factors limit the generalizability of studies on Ecstasy users to clinical settings, including the high quantities of doses taken and the fact that Ecstasy is almost always cut with other drugs. Authors commonly cite Ecstasy user data to draw conclusions about MDMA without citing the above purity limitation, and Ecstasy users are almost always polysubstance abusers.

1.2. Pharmacology and behavioral effects in animals

In the 1950s, the U.S. Army administered MDMA to animals as part of a military research program. The effects of MDMA on animals have been questioned, and recent reports have supported nonlinear pharmacology.

A study in rats found that MDMA metabolized in a similar manner to humans, and that rats had a shorter half-life than humans. The study also found that toxicological and behavioral studies of MDMA used doses exceeding human equivalent doses.

In rodents, 5HT1A receptors reduce anxiety and aggression, and 8-OH-DPAT partially or fully substitutes for MDMA. MDMA causes changes in GABA uptake in the ventral tegmental area of rats, which may be why rats prefer to lie adjacent to each other.

To date, no empirical investigations have been conducted on the effects of MDMA on primate social interactions. Recent studies suggest that MDMA increases prosocial behavior in rats by increasing OTin theparaventricular nucleus through 5HT1A receptor agonism.

1.3. Summary of effects of MDMA in humans

MDMA is a potent releaser of serotonin and an inhibitor of presynaptic serotonin, dopamine, and norepinephrine. Its primary mode of action is as an indirect serotonergic agonist, increasing the amount of serotonin released into the synaptic space.

At doses of at least 1 mg/kg and higher, MDMA alters mood and cognition and produces slight alterations in perception. Sub-acute effects may occur one to three days after drug administration, but are no longer apparent seven to 14 days later.

1.3.1. Physiological effects

MDMA acutely increases cortisol, prolactin, and adrenocorticotropic hormone concentrations in a dose-dependent manner, and produces a robust increase in the neurohormone OT. OT is associated with pair bonding and social affiliation in mammals, and attenuates amygdalar response to anxiogenic stimuli.

MDMA elevates OT in peripheral blood, which is an imperfect but somewhat reliable indicator of elevated OT in the brain. The effects of MDMA on OT could be partially responsible for changes in empathy, and could be useful in the treatment of social anxiety in autistic adults.

In rare but lethal cases, people using Ecstasy in unsupervised and non-medical conditions have experienced hyperthermia and water intoxication. MDMA taken with MAOIs or certain antiretroviral medications can induce a life-threatening hypertensive crisis.

MDMA produces sympathomimetic effects that include elevation in blood pressure and increased heart rate. This increased blood pressure and increased heart rate can lead to additional risks and complications, such as stroke, cardiac events or other cerebrovascular events.

Some researchers have expressed concern that MDMA might be associated with increased risk of valvular heart disease. However, only people who used MDMA for 900 tablets had cardiac abnormalities indicative of potential VHD.

MDMA is not considered physically addictive, but there have been reports of acute and chronic psychological reactions in vulnerable individuals. However, these reactions have generally been in the context of frequent polydrug use, Ecstasy or Molly use of dubious quality, adverse environmental settings, and significant underlying psychological vulnerability.

1.3.2. Neuropsychological effects

MDMA produces therapeutic effects through changes in affect, cognition and social interaction. This allows individuals to confront and consider emotionally intense memories, thoughts or feelings, and perhaps increases empathy and compassion for others and one’s self.

MDMA facilitates states of positive mood as well as transient anxiety. Subjects have reported feeling talkative and friendly after receiving MDMA, as well as experiencing anxiety, tension and dysphoria, as well as concerns over losing control over the self.

1.4. Clinical advantages of MDMA

MDMA provides specific advantages as a clinical intervention to increase social adaptability. It is milder, shorter acting, and induces heightened states of introspection without distracting cognitive distortions and alterations in perception, body image, and sense of self.

MDMA has been reported to be useful in treating a wide range of conditions, including post-traumatic stress, phobias, psychosomatic disorders, depression, suicidality, drug addiction, relationship difficulties and the psychological distress of terminal illness.

2.1. Establishing safety and feasibility

Recent research has focused on establishing safety parameters for limited use of MDMA-assisted therapy in U.S. and European clinical settings. Only one expected SAE that was probably drug-related has been reported, and no unexpected, life-threatening SAEs have occurred in published or ongoing research studies.

2.2. MDMA-assisted therapy for PTSD

A placebo-controlled Phase 2 pilot study of MDMA-assisted psychotherapy demonstrated promising results in a sample of 20 subjects with chronic, treatment-resistant PTSD. The study’s results were maintained an average of 3.8 years later in a carefully screened group of subjects. A double blind pilot study of MDMA-assisted psychotherapy found clinically but not statistically significant improvement in symptoms, but the improvement continued to increase during the twelve-month follow-up.

MDMA-assisted psychotherapy has shown promise in treating chronic PTSD in traumatized war veterans and first responders, and may also be useful in treating social anxiety in autistic adults.

3. The need for innovative mental healthcare options for autistic adults

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, eliminated the distinctions between autism categories and combined them under one diagnosis. The search for new supportive treatments is relevant given the lack of established or effective treatment options for autistic adults.

3.1. Pharmacotherapy: few effective options

Autistic individuals often suffer from anxiety disorders, depression, obsessive – compulsive disorder, Tourette’s syndrome, tics, and epilepsy. Conventional anti-anxiety medications are ineffective in autistic adults, possibly due to physiological differences between autistic and TD individuals.

Medications approved for other indications are often prescribed “off-label” for the treatment of mental health issues in autistic children, adolescents, and adults. The data on SSRIs in this population is of varied nature.

3.2. Social anxiety and autism

Social anxiety disorder, also known as social phobia, is characterized by fear of scrutiny and avoidance of social interactions, and can significantly impair ability to work, attend school, and develop relationships.

Autistic adults who can speak and who are faced with strong pressure to conform to non-autistic social norms are at greater risk for psychological disorders, especially social anxiety.

4. Factors in support of MDMA-assisted therapy for social anxiety in autistic adults

Three main factors supported the rationale for commencing a pilot study of an MDMA-assisted therapy treatment model for an adult autistic population: clinical findings, improved methodology, and copious anecdotal support.

Psychedelics are natural and synthetic substances that alter thought, mood, and perception in characteristic ways that can resemble dreaming, psychoses, and ecstatic religious experiences. MDMA is difficult to classify because it causes fewer and attenuated hallucinogenic effects with less cognitive distortion.

Researchers experimented with therapeutic applications of synthetic psychedelic compounds in the 1950s and 1960s, mainly LSD, UML and psilocybin, to “treat” autistic children, but clinical interest declined when funding for research and access to psychedelics decreased due to illicit use and political pressure.

Researchers shared the goal of breaking through the “autistic barrier” by increasing empathic affect and attachment in the absence of effective interventions for behaviors such as self-harm. However, the rationales for conducting the research varied.

More than 100 minors with the obsolete diagnosis of juvenile schizophrenia were given psychedelics in approximately a dozen trials. The methods employed were flawed to varying degrees according to current standards, including small sample size, vague and subjective assessment of positive and negative drug effects, and inadequate follow-up data collection.

Despite “gross shortcomings” and inconsistencies across the seven studies, Mogar and Aldrich (1969) concluded that LSD treatment sessions were effective in increasing vocabulary, increasing emotional responsiveness to others, elevating positive mood, and decreasing compulsive behavior in 91 autistic children.

The early research concluded that psychedelics were unlikely to restore speech in non-speaking autistic children, but the Controlled Substances Act of 1970 ended clinical research.

Autism was not recognized in the research literature until well after clinical research with psychedelics had ended. Now, investigators are resuming research with autistic adults who speak or who use text-to-speech technology.

4.2. Improved methods and standards for psychedelic research

Most early psychedelic trials lacked rigorous oversight by institutional review boards, adequate data and safety monitoring, or adherence to current best practices for scientific research. However, guidelines and suggestions for improvements in clinical studies and psychotherapy with psychedelics have been published by reputable investigators.

In psychedelic therapy, the subject’s set refers to their traits, mind state, and expectations, while the setting refers to the psychotherapist’s perception of the experience, the preparation, and the technique of guidance employed during the drug experience.

4.3. First-person reports of MDMA/Ecstasy use by autistic adults

The Internet has provided new and effective means for autistic individuals to communicate with others who are both autistic and non-autistic. These accounts provide consistent statements about the effects of MDMA/Ecstasy use on social behavior and connectedness to others.

The majority of testimonials included descriptions of positive outcomes, but there was also robust dialog about potential drawbacks of improper use. As with other interventions, MDMA-assisted therapy might be contraindicated for individuals at risk for potential abuse or adverse outcomes.

This dissertation was a mixed-methods study that included 100 MDMA/Ecstasy-experienced individuals and 50 MDMA/Ecstasy-naive comparison group. The majority of respondents reported accounts of sustained benefits after MDMA/Ecstasy experiences.

Two notable findings from survey questions about drug effects were that 91% of respondents experienced increased feelings of empathy/connectedness and 86% indicated ease of communication as an effect of their MDMA/Ecstasy use.

MDMA/Ecstasy users reported increased insight into own thought processes and easier than usual talk to others as long term effects, which could have implications for psychotherapy for autistic adults.

5. Method

For the present FDA-compliant, IRB-approved pilot investigation of MDMA-assisted therapyon social anxiety in autistic adults, 12 subjects will be screened and randomized into two groups, with eight subjects receiving the experimental drug (MDMA) and four subjects receiving an inactive placebo.

Subjects will receive 75 mg MDMA at the first session and 100 mg MDMA at the second session. The researchers opted for a dose-finding regimen due to anecdotal data suggesting a lower optimal dosing range for this population.

Subjects will be screened based on a number of diagnostic instruments, including the Structured Clinical Interview for Diagnoses Axis I Research Version (SCID-I-RV), the Leibowitz Social Anxiety Scale (LSAS) and the Autism Diagnostic Observation Schedule (ADOS-2) . They must be 21 years or older, have moderate to severe symptoms of social anxiety, and be MDMA-naive.

All subjects will receive several preparatory psychotherapy sessions, and will receive core mindfulness skills training as part of their therapy. This training will help them transition into MDMA-influenced cognitive and affective states and communicate with others during a novel, often ineffable, altered state of consciousness.

5.2. Treatment sessions

Subjects will arrive at the clinical research center early in the morning, be accompanied by a study partner, and will have baseline blood pressure, heart rate, temperature, and subjective units of distress measured. Blood will be drawn for later analyses of OT, vasopressin and cortisol. During drug-assisted treatment sessions, subjects will do structured and unstructured tasks, including listening to music, working with art supplies, writing in journals, silent introspection, and engaging in rapport building interactions with therapists.

5.3. Post-session follow-up

Subjects will complete the BDI, STAI, and PSS before, two weeks after, and six months after the two experimental treatment sessions. Blood will be drawn one month and six months after the two experimental treatment sessions to evaluate outcomes of active drug versus placebo.

6. Concluding remarks

Early psychedelics studies with autistic minors have shown promising results, and a pilot trial with MDMA-assisted therapy is warranted.

Researchers are gradually exploring the potential risks and benefits of MDMA-assisted therapies, and are also investigating the potential of developing new models for some psychiatric conditions that are refractory to conventional treatment.

Acknowledgments

Sponsor funding support provided by the Multidisciplinary Association for Psychedelic Studies (MAPS) and the Betsy Gordon Foundation. Nick Walker, M.A. provided consultant services.