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.
Authors
- Berra Yazar-Klosinski
Published
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.
Research Summary of 'MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults'
Introduction
Danforth and colleagues frame this paper as an overview of the rationale and methods for a pilot trial of MDMA-assisted therapy targeting social anxiety in autistic adults. They note overlap between lines of autism research and MDMA research—neurobiological work on oxytocin, vasopressin and serotonin, cognitive studies such as face-recognition mechanisms, and functional imaging findings implicating atypical amygdala and fusiform responses in autism—that together suggest MDMA’s multi-level effects could be relevant to social perception and affect regulation in this population. Earlier human MDMA studies showing attenuated amygdala response to angry faces and reports of reduced fearfulness are invoked to motivate testing MDMA in autistic adults with clinically significant social anxiety. The paper sets out to describe the design of an FDA‑compliant, Institutional Review Board‑approved pilot study to evaluate feasibility, safety parameters and preliminary efficacy of MDMA-assisted psychotherapy for moderate to severe social anxiety in autistic adults. In doing so, the authors draw on three supporting strands of evidence: (1) legacy clinical observations from early psychedelic work with autistic minors, (2) more rigorous modern safety and trial methodologies for psychedelic research, and (3) numerous first-person reports from autistic adults who have used MDMA recreationally. The planned pilot is positioned as a cautious, dose-finding, placebo-controlled first step toward assessing whether MDMA-assisted therapy warrants further development in this clinical indication.
Methods
The investigators describe a small, double-blind, placebo-controlled pilot trial with a dose-finding component. Twelve MDMA‑naïve adults with confirmed autism and moderate to severe social anxiety will be randomised in a 2:1 ratio to active MDMA (n = 8) or inactive placebo (n = 4). Blinding will include the participant, the clinical treatment team, and an Independent Rater who assesses outcomes. Each participant will receive two experimental treatment sessions approximately one month apart; those assigned to placebo may optionally receive one or two open‑label MDMA sessions after the blind is broken following six months of follow-up. Active‑drug dosing is staggered across two subgroups to explore tolerability and dose response in this population. One subgroup (n = 4) will receive 75 mg at session one and 100 mg at session two, while the second subgroup (n = 4) will receive 100 mg then 125 mg. The investigators chose a conservative dose‑finding strategy because anecdotal reports and autism‑related sensory and emotion‑regulation differences suggested a possibly lower optimal dosing range than typically employed in other populations. Placebo participants will undergo the same therapeutic procedures and assessments but receive inactive capsules on both sessions. Eligibility and screening procedures are described in detail. Inclusion criteria require age 21 or older, at least two years of college or equivalent, an autism diagnosis confirmed by an independent, research‑reliable rater, moderate to severe social anxiety, and the ability to discontinue psychotropic medications safely. Participants must have normal cardiovascular function by ECG and history and be free of certain medical conditions (for example diabetes, seizures, hypertension, liver disease, glaucoma) and active substance‑use disorders. Psychiatric exclusions include personal or first‑degree family history of schizophrenia or bipolar I disorder, active or past psychotic disorder, borderline personality disorder, dissociative identity disorder, eating disorder, or active suicidal ideation. Baseline laboratory measures will include plasma oxytocin, vasopressin and cortisol. The therapeutic model combines preparatory psychotherapy, core mindfulness skills training, and two drug‑assisted sessions conducted in a sensory‑adapted room with a male–female co‑therapist team. Preparatory sessions aim to establish rapport and set expectations; psychodynamic therapy is used only minimally, while mindfulness training is emphasised as an evidence‑informed alternative for autistic populations. Treatment‑session activities include listening to preselected music, art, journalling, silent introspection and structured social‑perception tasks, including administration of The Awareness of Social Inference Test (TASIT). Physiological monitoring (blood pressure, heart rate, temperature) will occur hourly for seven hours post‑dose; subjective distress, suicidal ideation screening and safety checks are included. Water intake will be monitored to reduce risks of hyponatraemia and dehydration. Outcome measurement and follow-up are specified: the Liebowitz Social Anxiety Scale (LSAS) is the primary outcome, assessed at baseline, the day after sessions, at two‑week intervals for one month, and at six months. Secondary measures include TASIT, Emotion Regulation Questionnaire, Beck Depression Inventory, Perceived Stress Scale, Interpersonal Reactivity Index, Rosenberg Self‑Esteem Scale, and State‑Trait Anxiety Inventory. Biomarkers (plasma oxytocin, vasopressin, cortisol) will be sampled during sessions and at one‑month and six‑month follow‑up. The authors state that subsequent analyses will compare active drug versus placebo outcomes, but the extraction does not specify statistical models, power calculations, or detailed analysis plans.
Conclusion
The authors conclude that three converging lines of evidence justify initiating a cautious pilot trial of MDMA‑assisted therapy for social anxiety in autistic adults: promising but methodologically limited early psychedelic work with autistic minors, the development of improved clinical and ethical standards for psychedelic research, and numerous first‑person reports from autistic adults who describe prosocial and anxiolytic effects following MDMA/Ecstasy use. They emphasise that modern trials are designed to mitigate many shortcomings of earlier work by using rigorous screening, medical monitoring, careful attention to set and setting, therapist training, and standardised outcome measurement. Danforth and colleagues stress the importance of proceeding gradually and cautiously, noting that clinical MDMA research to date (as of their report) involved over 1,133 research subjects with only rare, non‑life‑threatening serious adverse events in controlled settings. They argue that MDMA’s pharmacological profile—potent serotonergic release, elevation of peripheral oxytocin, and short course of dosing that can catalyse lasting psychological change without daily medication—may offer advantages for treating social anxiety in autistic adults. At the same time, the authors acknowledge risks reported in uncontrolled recreational contexts (for example hyperthermia, hyponatraemia, cardiovascular strain and the confounding effects of impure “Ecstasy” tablets) and reiterate the need for careful medical screening and supportive clinical environments. In their view, the pilot study represents an optimal and responsible next step to evaluate safety, feasibility and preliminary efficacy before broader implementation or larger trials.
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INTRODUCTION
The purpose of this paper is to provide an overview of the rationale and to summarize the method for a pilot study of 3,4methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of social anxiety in autistic adults. Multiple areas of investigation in autism research have paralleled MDMA research. Some examples include neurobiological studies, particularly on the effects of the neuropeptides oxytocin (OT) and vasopressin, which are believed to play a role in interpersonal connection and bonding, and the neurotransmitter serotonin. Cognitive studies, such as investigations of the mechanisms of face recognition, also appear in the literature of both autismand MDMA research. Functional brain imaging studies with anxiogenic stimuli in autistic individuals suggest that the amygdala may be differentially activated, with greater activation in the anterior cingulate gryus and superior temporal cortex, and less activation in the left amygdala and left orbito-frontal cortex, or it may signal in an atypical manner to the fusiform gyrus, a key brain region involved in facial recognition, resulting in differences in social perception between autistic and typically developing (TD) individuals. In TD healthy volunteers, MDMA administration acutely decreases activity in the left amygdala, a brain region involved in the interpretation of negative cues, and attenuates amygdalar response and emotional reactivity to angry faces. This action of MDMA is compatible with its reported reduction in fear of emotional injury or defensiveness. The multi-level effects of MDMA on brain circuits, monoaminergic neurotransmitters, and neurohormones that have been studied extensively in autistic individuals suggest that further study of the effects of MDMA in autistic populations is warranted. In addition, MDMA has been proposed as a treatment for anxiety disorders, which are prevalent in autistic individuals. The current review takes into account these areas of overlap and explores a parallel indication by studying MDMA-assisted therapy as an intervention for social anxiety in autistic adults.
RELEVANT HISTORY
MDMA, also known as the street drug Ecstasy or Molly, is a psychoactive compound with structural similarities to both amphetamine and the hallucinogenic phenethylamines. MDMA is a laboratory-synthesized compound that does not exist on its own in nature. Even though MDMA has been illegal in the United States since the mid-1980s, there were 0.8 million past-year initiates who reported first-time Ecstasy use in 2013. MDMA was developed as a byproduct of a styptic compound at Merck in Germany in 1912. University and industry based medicinal chemists started conducting initial scientific investigations during the 1970s after chemist Alexander Shulgin began exploring MDMA's potential to create controllable altered states of consciousness. Despite reported therapeutic potential, concerns about potential neurotoxicity resulted in suppression of FDA-approved research with human subjects in clinical investigations. Gross errors in reporting on MDMA's effects, side effects, and risk factors in non-human primate studies (e.g.,, in addition to problems with interspecies scaling algorithms leading to overdosing by an order of magnitude in animal studies, have contributed to confusion about which policies and approaches are optimal regarding regulation and research. Early investigators noted MDMA's capacity to help people talk openly and honestly about themselves and their relationships, without defensive conditioning intervening. For several hours, anxiety and fear appeared to decrease, even in subjects who were chronically constricted and apprehensive. Of particular interest to psychiatric researchers were clients with disorders such as chronic post-traumatic stress disorder (PTSD) and depression who were nonresponsive to conventional treatment models. Beginning in the mid-1970s, therapists and psychiatrists provided the still-legal MDMA to thousands of clients as an adjunct to therapy, but unfortunately no methodical research was published from this period. Formal hearings commenced in 1985 to determine MDMA's legal status. Weighing the interests of the therapeutic community against the growing perception of MDMA's abuse liability and the threat it posed to public health and safety, the U.S. Drug Enforcement Administration (DEA) eventually ordered that it be placed in the most restrictive category, Schedule I, in 1986. In the decades following the DEA scheduling, discord and divisiveness escalated in the research world. At the center of the debate was the question of whether or not MDMA use caused neurotoxicity resulting in brain damage. Histopathological findings in animal studies with repeated "binge administration" injections demonstrated that distal serotonergic axonal degeneration could result with doses much higher than recreational users consume. Implications of such pre-clinical findings are further confounded by observations of proximal axonal regeneration, cell body sparing, and absence of standard laboratory markers of neurotoxicity. Some studies suggested that even modest use could lead to irreparable organic and psychiatric damage, which included emotional and memory deficits, although these reports were often marred by flawed research methodologies, questionable data analyses, and biased conclusions. The Ecstasy user literature base also contains multiple factors that limit the generalizability of naturalistic studies of street Ecstasy to clinical settings in which pure MDMA is administered from one to several times within a psychotherapy paradigm. The most substantial of these limitations are the high quantities of doses taken in nearly all publications on recreational Ecstasy users, often on the order of several hundreds of doses. Critics of MDMA-assisted psychotherapy use this data to suggest a higher level of risk than logically can be inferred from no more than six exposures reported in MDMA-assisted psychotherapy clinical trials (e.g.,. Additionally, "Ecstasy" refers to MDMA obtained from street sources which currently is almost always cut with other drugs as seized shipments from 2007 show only 3% of tablets destined for North American markets containing pure MDMA(). Authors commonly cite Ecstasy user data and use it to draw conclusions about MDMA without citing the above purity limitation. Furthermore, Ecstasy users are also almost always polysubstance abusers as indicated in the 2007 National Epidemiologic Survey on Alcohol and Related Conditions (n = 43,093), and high polysubstance abuse rates confound nearly all of the Ecstasy correlations found in the medical literature to date. Other common notable hazards include adverse environmental conditions, polydrug use in dangerous combinations, and ingestion of high doses or stacking multiple doses to prolong drug effects. Therefore, research on recreational Ecstasy use has limited applicability to determining the safety of clinical investigations of MDMA-assisted therapy.
PHARMACOLOGY AND BEHAVIORAL EFFECTS IN ANIMALS
Research into the pharmacological, physiological, or psychological effects of MDMA began in the 1950s, when the U.S. Army administered MDMA to guinea pigs, monkeys, mice, rats, and dogs as part of a military research program, possibly intended to develop chemical incapacitants or means of enhancing interrogation. Investigations of the pharmacology, functional effects, and toxicity of MDMA in animals have generally included injections of large and often repeated doses of MDMA in an attempt to produce human-equivalent doses. Recent reports re-examining these effects have questioned the applicability of interspecies scaling models for MDMA, and have supported nonlinear pharmacology. A study directly comparing MDMA pharmacokinetics in humans and monkeys found that the two species metabolized MDMA in a similar but not identical manner and that MDMA had a shorter half-life in monkeys than in humans. Both species exhibited nonlinear pharmacokinetics, and it appears that monkeys and humans exhibit similar plasma MDMA levels after receiving the same dose of MDMA). An investigation in rats also demonstrated nonlinear pharmacokinetics in that species as well, finding that humanequivalent doses of MDMA in rats are close to or identical to those in humans and drug half-life is rapid. Doses of 10 mg/kg, but not 2 mg/kg, produced signs of serotonin syndrome in rats, but neither dose reduced total serotonin levels in the brain two weeks after drug administration. These discoveries suggest that toxicological and behavioral studies of MDMA used doses exceeding human equivalent doses. As a consequence, it is difficult to interpret the relevance of findings in nonclinical studies employing these dosing regimes. Early studies in rodents suggest that 5HT 1A receptors reduce anxiety and aggression, and some drug discrimination studies suggest that the 5HT 1A agonist 8-OH-DPAT partially or fully substitutes for MDMA. Administering a 5HT 1A antagonist attenuates the prosocial behavior of rats, measured by preference to lie adjacent to each other, possibly because it prevents elevation in OT. At least some direct or indirect effects of MDMA on serotonin receptors may cause changes in GABA uptake in the ventral tegmental area of rats. In rodents, doses of MDMA equivalent to human doses produce either few or no behavioral effects. However, doses of 5 mg/kg or greater have several specific behavioral effects, including increased locomotor activity, increased anxiety at moderately high doses, and decreased anxiety at higher doses. In contrast, rhesus monkeys do not exhibit increased locomotor activity after receiving up to 2.4 mg/kg MDMA. To date, no empirical investigations have been conducted on the effects of MDMA on primate social interactions. Morley and colleagues observed rat behavior after receiving 5 mg/kg MDMA, noting that this dose correlated with prosocial behavior, such as lying next to each other. Recent studies conducted by the same team of researchers suggest that MDMA increases prosocial behavior in rats by elevating OT in the paraventricular nucleus through 5HT1A receptor agonism, with the OT increase arising from the indirect effects of MDMA on 5HT1A receptors. At present, there have been no human pharmacological challenge studies combining MDMA with 5HT1A agonists, while 5HT1A antagonists have negligible effects on subjective or physiological effects of MDMA in humans. As a result, it is unclear whether the rat behavior is analogous to human reports of increased feelings of empathy or interpersonal closeness while under the influence of MDMA.
SUMMARY OF EFFECTS OF MDMA IN HUMANS
MDMA is primarily a potent releaser of serotonin as well as an inhibitor of presynaptic serotonin, dopamine, and norepinephrine (de la. Pharmacologically it exhibits effects similar to amphetamine type drugs, with a chemical structure that also resembles the classic hallucinogen mescaline. The primary mode of action of MDMA is as an indirect serotonergic agonist, increasing the amount of serotonin released into the synaptic space. MDMA interacts with the serotonin transporter, and is transported into the nerve terminal, facilitating the release of serotonin. After oral ingestion, MDMA is readily absorbed from the gastrointestinal tract. At doses of at least 1 mg/kg (or approximately 70 mg) and higher, active doses of MDMA alter mood and cognition and produce slight alterations in perception. Its onset of action is within 30-45 min of intake, and effects peak 90 to 120 min after oral administration, and they are near to or at pre-drug levels 3 to 6 h later. Sub-acute effects may occur one to three days after drug administration, but are no longer apparent seven to 14 days later. The elimination half-life is approximately 7 h. MDMA's primary metabolite, 3-4 methylenedioxyamphetamine (MDA), has a longer half-life of approximately 16-38 h. Primary enzymatic activity responsible for the metabolism of MDMA occurs at the hepatic cytochrome P45 CYP2D6 enzyme. MDMA is metabolized in a non-linear manner with relatively small increases in dose causing disproportionate elevation in MDMA plasma concentration, consequently necessitating vigilance for the development of signs of acute adverse reactions.
PHYSIOLOGICAL EFFECTS
MDMA acutely increases cortisol, prolactin, and adrenocorticotropic hormone concentrations in a dose-dependent manner. MDMA also produces a robust increase in the neurohormone OT. OT is a neuropeptide associated with pair bonding and social affiliation in mammals that also attenuates amygdalar response to anxiogenic stimuli. Exogenous OT administration is associated with increased interpersonal trust and changes in social perception, including attenuated reactivity to threatening faces. OT administration also improves empathic accuracy in some individuals who are shy or lack adequate social skills. Alterations in OT signaling have also been proposed as a potential mechanism for the underlying neurological basis for the core social differences in autism and have been implicated as a possible novel therapy for enhancing social adaptability. MDMA elevates OT in peripheral blood, which is an imperfect but somewhat reliable indicator of elevated OT in the brain. Findings of an association between elevated OT and detectable MDMA in peripheral blood were first reported in a naturalistic study of London nightclub attendees with and without detectable plasma MDMA levels. Dumont and colleagues reproduced these results in humans and found that MDMA significantly elevated peripheral plasma OT levels in a placebo-controlled study in healthy volunteers, in addition to a positive association between elevated levels of OT and prosocial feelings. Hysek and colleagues replicated these results and further reported that administering a serotonin reuptake inhibitor, but not a norepinephrine uptake inhibitor nor several adrenergic antagonists, attenuated the effects of MDMA on OT levels, suggesting a serotonergic mechanism in producing elevated. The effects of MDMA on OT could be partially responsible for changes in empathy. However, the multi-level effects of MDMA on monoaminergic signaling and OT, combined with a therapeutic setting focused on enhancing functional skills, are more likely to provide the opportunity for a corrective emotional experience greater than OT alone, and could be useful in the treatment of social anxiety in autistic adults. Hyperthermia has occurred in people using Ecstasy in unsupervised and non-medical conditions (e.g., vigorous dancing in hot, underventilated spaces without adequate access to water), and though rare, it is one of the most frequently reported SAEs occurring in Ecstasy users. In rare but sometimes lethal cases, naïve users have consumed too much water without ingesting required amounts of electrolytes, leading to water intoxication (hyponatremia). Taking MDMA with monoamine oxidase inhibitors (MAOIs) or with certain antiretroviral medications can induce a life-threatening hypertensive crisis. MDMA produces sympathomimetic effects that include elevation in blood pressure and heart rate. Elevation in blood pressure above 140/ 110 or higher occurred in approximately 5% of research participants receiving at least 100 mg MDMA in research studies. However, blood pressure returned to normal as drug effects waned. The elevation of blood pressure and increased heart rate produced by MDMA, like that produced by other sympathomimetic drugs, can lead to additional risks and complications, such as stroke, cardiac events or other cerebrovascular events, including cerebral venous sinus thrombosisand cerebral hemorrhage. First-time users with congenital heart defects are especially vulnerable to cardiac events. Due to properly conducted medical screening, there have been no such events to date in any clinical trial of MDMA. Some researchers expressed concern that MDMA activity at 5HT 2B receptors might be indicative of increasing risk of valvular heart disease (VHD) with repeated use. Studies in Ecstasy users indicated that only people reporting average lifetime exposure of 900 tablets had cardiac abnormalities indicative of potential VHD, and a case of VHD has occurred in a man reporting approximately 16 years of Ecstasy use. No abnormalities were found in people reporting lifetime exposure of approximately 200 tablets in the same study. Since VHDassociated changes and VHD only occurred after extremely heavy Ecstasy use, they are unlikely to be a risk within the research or therapeutic context. Hepatotoxicity (liver disease or damage) was reported in approximately 16% of 199 case reports from non-medical, uncontrolled Ecstasy users, making it the third most SAE reported in the literature. No cases of liver disease or hepatotoxicity have occurred in a controlled clinical trial with MDMA. MDMA is not considered physically addictive, but there have been reports of both acute and chronic psychological reactions in vulnerable individuals. Nevertheless, these cases generally have been in the context of frequent polydrug use, Ecstasy or Molly use of dubious quality, adverse environmental settings, and significant underlying psychological vulnerability. Even though Ecstasy is considered a drug of abuse, pure MDMA is not considered a drug of dependence on the order of opioids, amphetamines, methamphetamines, and cocaine. This lack of dependence is evidenced by rodents and nonhuman primates self-administering MDMA at much lower rates than the aforementioned drugs, and even heavy Ecstasy users fail to report the intensive patterns of use seen with other stimulants. Hence, MDMA possesses moderate abuse liability that is greater than that for serotonergic hallucinogens but less than that for stimulants.have studied the relative harm of a variety of drugs and have identified MDMA as being among the least dangerous recreational compounds.
NEUROPSYCHOLOGICAL EFFECTS
Most of the therapeutic effects of MDMA result from changes in affect, cognition and social interaction.reported that MDMA produced acute "increased responsiveness to emotions, a heightened openness, and a sense of closeness to other people" (p. 247). When combined with psychotherapy that supports one or more of these effects, MDMA permits individuals to confront and consider emotionally intense memories, thoughts or feelings and perhaps through changes in mood and perception increases empathy and compassion for others and one's self. MDMA facilitates states of positive mood as well as transient anxiety. MDMA users report feeling more talkative and friendly after receiving MDMA, and at least one research team informally reported increased feelings of closeness to others. However, subjects have also reported feeling anxious and undergoing negatively experienced derealization, including increased anxiety related to loss of control and experiences of racing or blocked thoughts. Subjects receiving active doses of MDMA experienced euphoria, positive mood, vigor and positively experienced derealization, and they also experienced anxiety, tension and dysphoria, as concern over losing control over the self. Available data is unclear regarding whether the increases in positive and negative mood occur simultaneously or occur at different times throughout the duration of MDMA effects; data in reports from two different teams suggest that peaks in negative mood may precede peaks for positive mood. Tablelists major studies implicating the effects of MDMA.
CLINICAL ADVANTAGES OF MDMA
As a clinical intervention to increase social adaptability, MDMA provides specific advantages. In supportive settings, a typical oral dose of 75-125 mg produces psychological effects that are distinct from those of classic hallucinogens. Beginning in the late 1970s, proponents saw the benefits of MDMA, compared to classic hallucinogens, making it uniquely suited as an adjunct to therapy. It was comparatively mild, shorter acting, and induced an enhanced ability to facilitate heightened states of introspection, all without distracting cognitive distortions and alterations in perception, body image, and sense of self commonly seen with classic hallucinogens, such as LSD, psilocybin, and mescaline. Users were reported as losing defensive anxiety and feeling more emotionally open thus giving them access to feelings and thoughts not ordinarily available to them. In informal settings, MDMA was 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. Lasting improvement was often reported in patients' self-esteem, ability to communicate with significant others, capacity for achieving empathic rapport, interest in and capacity for insight, strengthened capacity for trust and intimacy, and enhanced therapeutic alliance.
ESTABLISHING SAFETY AND FEASIBILITY
Recent research with human subjects has focused on establishing safety parameters for limited use of MDMA-assisted therapy in U.S. and European clinical settings (e.g.,. The first double-blind, placebo controlled U.S. Phase 1, FDA-compliant study was conducted in 1994, with findings that suggested MDMA may cause a statistically significant increase in body temperature, heart rate, and blood pressure in some healthy volunteers. However, these increases were found to be transient and generally tolerable in a controlled clinical setting. Subsequent trials confirmed that MDMA produced significant increases in heart rate and blood pressure that were likely to be well tolerated by healthy individuals. As of November 2014, MDMA had been administered to more than 1133 research subjects, in both Phase 1 and Phase 2 studies. Only one expected SAE that was probably drug-related has been reported, which was an increase in frequency of premature ventricular contractions experienced during treatment, which resolved with full recovery to baseline after the effects of MDMA ceased. No acute cardiac damage occurred, and hospitalization during this SAE was a cautionary measure. No unexpected, life-threatening SAEs have occurred in published or ongoing research studies2.2. MDMA-assisted therapy for PTSD The first placebo-controlled Phase 2 pilot study of MDMA-assisted psychotherapy for the treatment of chronic, treatment resistant PTSD demonstrated promising results in a sample of 20 subjects. Scores on the Clinician-Administered PTSD Scale (CAPS), an established gold-standard measure of PTSD symptoms, declined to a statistically and clinically significant degree after undergoing MDMA-assisted psychotherapy. The group of subjects randomized to receive MDMA showed a mean CAPS score reduction of 53.7, with a mean starting score of 79.2, whereas, participants in the placebo arm who also received psychotherapy had a mean starting score of 79.6 and showed a mean CAPS score reduction of 20.5. As a point of comparison, a reduction of mean CAPS scores of 10.2 in a clinical trial of 187 patients resulted in FDA-approval of sertraline (Zoloft) for PTSD. Improvements in PTSD symptoms observed in the proof of principle study were maintained an average of 3.8 years later (N = 16).reported that, "MDMA-assisted psychotherapy with close follow-up monitoring and support can be used with acceptable and short-lived side effects in a carefully screened group of subjects with chronic, treatment-resistant PTSD" (p. 449). A double blind pilot study of MDMA-assisted psychotherapy conducted by a Swiss therapist team in an equivalent Swiss clinical population (N = 12) comparing 125 mg MDMA to 25 mg MDMA as an active placebo found a clinically but not statistically significant effect, although trends toward symptomatic improvement were noted using a German translation of the CAPS. The improvement continued to increase during the twelve-month follow-up. Currently, four Phase 2 pilot studies of MDMA-assisted psychotherapy are underway for treatment of chronic PTSD (NCT01689740, NCT01793610, NCT01211405, NCT01958593), including one in traumatized war veterans and as well as first responders, such as police officers and fire fighters. These studies have shown promise for MDMA-assisted psychotherapy to help people overcome PTSD, an anxiety-related disorder, and suggest that this treatment could also be useful in treating social anxiety in autistic adults.
THE NEED FOR INNOVATIVE MENTAL HEALTHCARE OPTIONS FOR AUTISTIC ADULTS
A major revision of autism diagnostic criteria in the in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (American Psychiatric Association, 2013) eliminated the distinctions between autism categories and combined them under one diagnosis. The revised DSM-5 definition includes the former diagnoses of Asperger's Disorder and Pervasive Developmental Disorder. The term autism refers to a spectrum of congenital and pervasive neurocognitive variants, characterized, in part, by atypical development of social and communication skills. At present, there are no published research data in support of any compound that can influence the course of autism or be a causative agent. Autistic adults often present for treatment of conditions such as anxiety, trauma, depression, and social adaptability challenges. However, responses to conventional prescription medications evaluated in TD individuals are often ineffective in autistic individuals (e.g.,, and mutual difficulties establishing therapeutic rapport between clinicians and clients can interfere with conventional, psychodynamic psychotherapy. The search for new supportive treatments is relevant given the lack of established or effective treatment options for anxiety, depression, trauma, and other psychological distress in autistic adults.
PHARMACOTHERAPY: FEW EFFECTIVE OPTIONS
Clinical diagnoses such as anxiety disorders, depression, obsessivecompulsive disorder, Tourette's syndrome, tics, and epilepsy are common in autistic populations. Conventional anti-anxiety medications, including selective serotonin reuptake inhibitors (SSRIs), MAOIs, and benzodiazepines, lack substantial clinical effectiveness in autistic adults, potentially due to physiological differences between autistic and TD individuals. There may be underlying biological reasons for this difference, including some reported evidence for a lower number of benzodiazepine binding sites in the brains of autistic adults. Medications approved for the treatment of other indications are often prescribed "off-label" without the Food and Drug Administration (FDA) approval for the use in autistic children, adolescents, and adults. For example, off-label prescription of SSRIs is on the rise in this population. The data on SSRIs in the treatment of autistic individuals are of varied nature. Given the paucity of confirmed efficacy in clinical trials and clinical practice, the search for effective, complementary and alternative interventions for mental health issues in autistic populations remains urgent.
SOCIAL ANXIETY AND AUTISM
Social anxiety, also known as social phobia, is characterized by fear of scrutiny and avoidance of social interactions (American Psychiatric Association, 2013). Social anxiety is prevalent, begins early, and follows a chronic course. Impairment is substantial in TD individuals, and fear and avoidance behaviors interfere with ability to work, attend school, and develop relationships, leading to low quality of life. Comparative studies suggest that autistic adults, especially those who can speak and whose autism might not be immediately recognizable to others and who are faced with strong pressure to conform to non-autistic social norms, are at greater risk for lifetime and current psychological disorders, especially social anxiety. Social anxiety frequently compounds the considerable social challenges experienced by autistic adults.
FACTORS IN SUPPORT OF MDMA-ASSISTED THERAPY FOR SOCIAL ANXIETY IN AUTISTIC ADULTS
The primary purpose of this paper is to provide an overview of three main factors that supported the rationale for commencing the first pilot study of an MDMA-assisted therapy treatment model for an adult autistic population. The first factor is clinical findings in reports from early research with psychedelics in studies with autistic minors. The second factor is improved methodology for conducting safe and ethical research with psychedelics and MDMA, especially in vulnerable populations. The third, and most recently available, factor in support of commencing a pilot study is copious anecdotal support culled from public sources and scholarly exploratory inquiry.
EARLY PSYCHEDELICS RESEARCH WITH AUTISTIC MINORS
Psychedelics are a large class of natural and synthetic substances with limited abuse liability and psychoactive properties that alter thought, mood, and perception in characteristic ways that can resemble dreaming, psychoses, and ecstatic religious experiences. The term is often used synonymously with hallucinogens in the medical literature. However, with psychedelics, the perceiver retains awareness of the illusory and personal nature of the altered perceptions. MDMA is difficult to classify because it causes fewer and attenuated hallucinogenic effectswith less cognitive distortionthan other classes of psychedelics. MDMA also has mild to moderate amphetamine-like effects and produces subjective prosocial effects which are distinct from the mysticospiritual effects of the classic hallucinogens. Whereas MDMA and classic hallucinogens have different neurobiological mechanisms of action, they share similar psychological effects of catalyzing states of openness and introspection. Therefore, a review of prior research with classic hallucinogens with autistic minors is relevant to a discussion of MDMA-assisted therapy for autistic adults with social anxiety. From the late 1950s to the early 1970s, researchers in the United States, Europe and Argentina (e.g.,experimented with therapeutic applications of synthetic psychedelic compounds, mainly LSD, UML (a methylated derivative of LSD), and psilocybin, in attempts to "treat" autistic children during an era when autism was mistakenly considered a form of juvenile schizophrenia until clinical interest declined when funding for research and access to psychedelics decreased due to illicit use and political pressure. Whereas giving powerful psychedelics to distressed, non-speaking children seems inappropriate according to current ethics and safety standards, in the 1950s and 1960s, synthetic psychedelics were considered new and novel medications with a favorable safety profile that held promise for treating, what were considered at the time, autistic-type developmental disorders in youth. Researchers shared the common goal of breaking through what they interpreted as the "autistic barrier" toward increased empathic affect and attachment in the absence of effective interventions for behaviors such as self-harm. However, the rationales for conducting the research varied. Some studies emphasized a medical approach. For example, the prospect of restoring speech as a means to reduce isolation inspired some investigators after case reports were published on catatonic schizophrenic adults who were electively mute at baseline but who spoke while under the effects of LSD. Employing a neurobiological approach,made early attempts to understand the role of the neurotransmitter serotonin by including biochemical tests in LSD study protocols. Other researchers emphasized subjective considerations., for example, took a psychodynamic approach when providing LSD and psilocybin to autistic children. Fisher emphasized the potential of psychedelics to augment the psychotherapeutic alliance: "Little of what may be called health or growth can occur without legitimate and honest relationships between people. The drugs were, however, in our judgment, of extreme importance in making the psychotherapeutic experience" (p. 112). From 1959 to 1970, more than 100 minors with the obsolete diagnosis of juvenile schizophrenia, autistic type or similar descriptions were given psychedelics in approximately a dozen trials of varying sizes and durations. In at least six studies, children as young as five years old were given repeated moderate to high doses (100-300 μg) of LSD (e.g.,. In retrospect, the methods employed were flawed to varying degrees according to current standards, including: small sample size (e.g.,, vague and subjective assessment of positive and negative drug effects (e.g.,, absent or incomplete baseline data (e.g.,, and inadequate follow-up data collection. A majority of the early researchers were primarily concerned with observing drug effects and proceeded without a clearly stated treatment hypothesis or random assignment to control groups, and reports on the persistence of postsession effects were vague and inconsistent.published a comprehensive review of seven independent studies of LSD for treatment of emotional distress and social isolation in 91 autistic children. Despite "gross shortcomings") and inconsistencies across the seven studies, the reviewers concluded that there was general consensus among the research teams that the LSD treatment sessions were "effective in characteristic ways," (p. 1) including increased vocabulary, increased emotional responsiveness to others, an elevation in positive mood, and decreases in compulsive behavior (p. 13). Social behaviors, such as eye-to-face contact and engaging with the researchers, were observed more frequently during LSD sessions than in placebo or control sessions. No researchers reported serious side effects, toxicity, or permanent regression following treatment with psychedelics. The general consensus resulting from the early research was that psychedelics were unlikely to restore speech in non-speaking autistic children. However, most researchers concluded that psychedelics allowed subjects a greater degree of contact with others, regardless of demographics, dose, schedule, or setting. Nevertheless, the Controlled Substances Act of 1970 resulted in an abrupt cessation of virtually all clinical research with psychedelic compounds. The diagnostic distinctions for less readily apparent manifestations of autism have emerged over the past several decadesbut were not recognized in the research literature until well after clinical research with psychedelics had ended. Now that research with psychedelic-assisted therapy to promote social adaptability is resuming, investigators can recruit autistic adults who speak or who use text-to-speech technology instead of working with non-speaking children. In the early studies, investigators could not collect self-reported baseline or follow-up data, conduct interviews, confirm informed assent, or communicate verbally with subjects during most experimental psychedelic treatment sessions.
IMPROVED METHODS AND STANDARDS FOR PSYCHEDELIC RESEARCH
Few, if any, of the clinical studies conducted with psychedelics between the 1950s and early 1970s would satisfy current design, safety, and ethics requirements for research with human subjects. Among numerous serious shortcomings, 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 (e.g., adequate informed consent, random assignment to placebo control groups, double-blinded dosing regimens). Due to restrictions on research using psychedelics with human subjects and the flawed methodology of earlier trials, researchers have had few resources to consult regarding the best methods for optimizing safety during challenging psychedelic experiences. However, guidelines and suggestions for improvements in clinical studies and psychotherapy with psychedelics have been published by reputable investigators and are available to inform new research (e.g.,. A significant innovation in support of resuming clinical research with psychedelics is the evolved understanding of the importance of set and setting. In psychedelic therapy, set refers to the traits, mind state, and expectations of the subject regarding the session.also considered the psychotherapist's perception of the nature of the experience, the preparation and presession psychotherapy, and the specific technique of guidance employed during the drug experience as contributing to set. Setting refers primarily to the external factors that influence the ambiance of the experience for the client. For an ideal setting,recommended a safe and pleasant environment plus reassuring and nurturing interpersonal support.
FIRST-PERSON REPORTS OF MDMA/ECSTASY USE BY AUTISTIC ADULTS
The introduction of the Internet has provided new and effective means for autistic individuals to communicate with others who are both autistic and non-autistic, often with greater ease than in face-toface situations. Ample anecdotal data regarding the MDMA/Ecstasy experiences of autistic individuals available through spontaneous, first-person accounts posted in online discussion forums provided foundational support for clinical research on MDMA-assisted therapy for social anxiety with autistic adults. Unsolicited accounts of personal MDMA/Ecstasy use have provided consistent statements about its effects on social behavior. Some comments have included descriptions of overall improvement in functioning, whereas other examples have described psychosocial healing and relief from symptoms such as anxiety and trauma. Another common theme reported is improved connectedness to others. Over 250 accounts that were posted in online discussion forums between 2006 and 2011 (e.g.,,,,) were reviewed prior to commencing original data collection for exploratory doctoral research on the qualitative MDMA/Ecstasy experiences of autistic adults. The majority of the testimonials included descriptions of positive outcomes. However, robust dialog about potential drawbacks of improper use also has occurred in online forums. The overall impression presented was that MDMA/Ecstasy can be helpful for some autistic individuals, attention to appropriate set and setting is crucial for positive outcomes, and, as with other interventions, MDMA-assisted therapy might be contraindicated for individuals at risk for potential abuse or adverse outcomes (e.g., individuals with history of addiction or who do not have access to sufficient post-session support). As a caveat, the authors would advise any individual against taking Ecstasy or Molly, which are manufactured and marketed on the illicit market and are subject to rampant drug substitution and often low-quality MDMA. The dissertation was published as a mixed-methods study to explore how autistic adults experience the subjective effects of MDMA/Ecstasy. The purpose of the qualitative component was to document a comprehensive analysis of emergent themes from interviews and to identify themes of clinical relevance. In addition, subjects from 13 countries submitted quantitative survey data, including 100 MDMA/Ecstasy-experienced individuals (76% males; 24% females) and a 50-subject MDMA/Ecstasy-naïve comparison group (54% males; 46% females). Respondents' ages ranged from 21 to 74 years. The majority of respondents reported accounts of sustained benefits after MDMA/Ecstasy experiences, including improvement of conditions such as trauma and social anxiety that are common in autistic populations. Two notable findings from survey questions about drug effects were that 91% of respondents reported that they experienced "Increased Feelings of Empathy/Connectedness," and 86% indicated "Ease of Communication" as an effect of their MDMA/Ecstasy use. Positive effects (e.g., joy, openness, enjoying being touched) were reported as more strongly experienced than negative effects, and no subjects rated anxiety symptoms in the "strongly experienced" category. A finding particularly relevant to treating social anxiety was that 72% of MDMA/Ecstasyexperienced participants reported "more comfort in social settings," and 12% indicated that the effect lasted for two or more years. Another positive outcome reported was that 78% of the MDMA/Ecstasy-experienced group reported "feeling at ease in my own body" as an effect, and 15% indicated that the effect lasted two years or longer. A finding that might have particular relevance to establishing rapport with therapists in clinical settings was that 77% of the MDMA/ Ecstasy-experienced group reported that they found it "easier than usual to talk to others" as an effect of taking MDMA/Ecstasy, and 18% indicated that the effect lasted up to one year or longer. A final finding about the duration of effects that could have implications for psychotherapy for autistic adults was that 22% of the MDMA/Ecstasyexperienced group reported "increased insight into own thought processes" that persisted for two or more years. Despite the researcher's multifold efforts to encourage subjects to disclose negative outcomes and to provide balanced accounts of their experiences, there were no reported moderate or serious, long-term adverse outcomes in the final data set.
METHOD
For the present FDA-compliant, IRB-approved pilot investigation of the effects of MDMA-assisted therapy on social anxiety in autistic adults, a placebo-controlled, double-blind methodology is being employed, utilizing an MDMA dosage in the range of 75 mg-125 mg. Twelve subjects will be screened and enrolled into the study and randomized into two groups, with one group of eight subjects receiving the experimental drug (MDMA) and the control group of four subjects receiving an inactive placebo. Both the subject, the clinical treatment team, and Independent Rater assessing treatment outcomes are blind to the condition of treatment. All subjects will receive two separate treatment sessions, spaced approximately one month apart. Participants who receive placebo in the first treatment phase can return for one or two optional openlabel treatment sessions with MDMA after the blind is broken after six months of follow-up data collection (Fig.). Subjects receiving MDMA will be divided into two sub-groups, the first group of four subjects receiving 75 mg MDMA at the first session and 100 mg MDMA at the second session. The second sub-group of four subjects will receive 100 mg MDMA at the first session and 125 mg at the second session. The researchers opted for a dosefinding regimen due to anecdotal data that suggested that types of sensory hypersensitivity and emotion regulation challenges common with autism might indicate a lower optimal dosing range for this population. Subjects randomized into the placebo condition will receive inactive placebo at each of the two treatment sessions, but otherwise will participate in the identically structured treatment model and assessment battery as those receiving the active drug.
SCREENING, ELIGIBILITY, AND PREPARATION
After signing an informed consent, prospective subjects will be screened into the study based on eligibility established 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). All subjects must be 21 years or older, have at least two years of college education or the equivalent, have an autism diagnosis confirmed by an Independent Rater who is certified based on research reliability, have moderate to severe symptoms of social anxiety, and be able to safely discontinue any psychotropic medications they are currently being prescribed. They must also have healthy cardiovascular function, as per electrocardiogram and medical history, and not suffer from diabetes, glaucoma, seizures, hypertension, liver disease, glaucoma or any other condition that the investigator or medical monitor believes might interfere with subject participation and safety in the study. Subjects must also be MDMA-naïve and without active substance use disorders. Psychiatric exclusion criteria include family history in first-degree relatives of schizophrenia or bipolar I disorder, or subject diagnoses of active or past psychotic disorder, borderline personality disorder, dissociative identity disorder, eating disorder or active suicidal ideation. Prior to entry into the study, all subjects will have a physical examination, EKG and baseline labs drawn for measurement of plasma OT, vasopressin and cortisol. Baseline performance using The Awareness of Social Inference Test (TASIT), Emotion Regulation Questionnaire (ERQ), Beck Depression Inventory (BDI), Perceived Stress Scale (PSS), Interpersonal Reactivity Index (IRI)), Rosenberg Self-Esteem Scale (RSES), and State-Trait Anxiety Index (STAI)will be examined. The LSAS will be the primary outcome measure. Prior to the first treatment session, all subjects will receive several preparatory psychotherapy sessions, where the structure of treatment and range of possible effects will be discussed, as will any past or current salient issues in the subject's life. These preparatory sessions will also focus on establishing effective rapport between the subject and the treatment team. Conventional psychodynamic psychotherapy will be employed only on a limited basis, as this type of approach is not indicated in general in autistic populations due to mutual interpersonal barriers to the psychotherapeutic alliance with non-autistic therapists (e.g.,. As an alternative, research findings support mindfulness training in autistic populations. In, autistic children and their parents reported improvement in attunement to others, happiness, attention problems, personal goals, self-control, and other measures that contribute to quality of life after receiving mindfulness training. Consequently, all subjects will receive core mindfulness skills training as part of their therapy. An anticipated advantage of this intervention is that it will provide vocabulary, concepts, and skills that support research subjects with transitioning into MDMA-influenced cognitive and affective states as well as communicating with others during a novel, often ineffable, altered state of consciousness.
TREATMENT SESSIONS
On the days of the two treatment sessions, subjects will arrive at the clinical research center early in the morning, accompanied by a study partner, who has previously committed to driving the subject to and from research sessions, as well as to and from day-after integrative sessions. Office visits as well as treatment sessions will take place in a specially prepared room, which has been designed to minimize sensory distress (e.g., soft lighting, comfortable seating, minimal noise) and to resemble a comfortable den-like space more than a clinical setting. Water intake will be monitored to avoid dehydration or water intoxication, and optional snacks and a light meal will be made available two hours after the study drug is administered. The treatment sessions will be videotaped, though contingent upon subject consent. Prior to experimental drug administration on treatment session days, subjects will have baseline blood pressure, heart rate and temperature measured, with hourly repeat measurements following administration of active drug or placebo for the next seven hours until the conclusion of the treatment session. Suicidal ideation with the Columbia Suicide Severity Rating Scaleand subjective units of distress (SUDs) will also be assessed during hourly intervals. During the second experimental treatment session, in the late morning, blood will be drawn for later analyses of OT, vasopressin and cortisol. During the actual drugassisted treatment sessions, both structured and unstructured tasks will be employed, including but not limited to listening to preselected music, working with art supplies, writing in journals, silent introspection, and engaging in rapport building interactions with therapists. In addition, subjects will complete the TASIT, which is an interactive, video-based assessment of social inference skills. The co-therapists, always one male and one female to manage potential transference during therapy, will emphasize creating and communicating a setting of safety and support for the subject during periods of inner focus. More structured interaction during experimental sessions will focus on challenges subjects have had with social perception and function.
POST-SESSION FOLLOW-UP
The day following each of the two experimental treatment sessions, subjects will return to the study location for an integrative session, where safety data will be collected, the content of the previous day's experience will be examined and methods for adjusting back to daily life after treatment will be reviewed. Additional in-person integrative psychotherapy sessions will be scheduled at two week intervals for one month and then again at the six-month follow-up point. Telephone safety checks will occur daily for the week following treatment sessions, overlapping with the 3-4 days for the drug to be excreted from the body. One day, two weeks and four weeks post experimental drug treatment subjects will complete the BDI, STAI, and PSS. At monthly intervals, between the one-month post-treatment integrative psychotherapy session and the six-month in-person final integrative psychotherapy session, subjects will complete the BDI, STAI, and PSS via remote, secure internet connection. In addition to baseline measures, the LSAS will be conducted the day after experimental treatment sessions, at two-week intervals for one month and then at the sixmonth follow-up. TASITs will be conducted at baseline, the day of the two experimental treatment sessions, two weeks following each of the treatments and at the six-month follow-up. A subsequent data analysis will evaluate outcomes of active drug versus placebo. Additionally, two post-treatment late-morning blood draws for plasma OT, vasopressin and cortisol will be conducted one month and six months after experimental treatment.
CONCLUDING REMARKS
Promising findings from early psychedelics studies with autistic minors, development of safer clinical research models and methods, clarification around optimal set and setting, and an abundance of selfreported accounts of potential benefits all support the case for initiating a pilot trial with MDMA-assisted therapy for autistic adults who have moderate to severe social anxiety. Researchers gradually and cautiously are exploring a broader range of potential risks and benefits of MDMA-assisted therapies. In the opinion of the authors, this is the optimal and responsible option for addressing the public health concerns that have been raised, as well as to investigate the potential of developing new and novel models for some psychiatric conditions that are refractory to conventional treatment. Informed understanding of the facts about MDMA, a psychotherapeutic compound known to enhance prosocial behaviors, is as relevant to clinicians, researchers, the public, and policymakers now as in any earlier point in its history.
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