Social anxiety disorder (SAD) is a prevalent and often debilitating psychiatric disorder that can assume a chronic course even when treated. Despite the identification of evidence-based pharmacological and behavioral treatments for SAD, much room for improved outcomes exists and 3,4-methylenedioxymethamphetamine (MDMA) has been proposed as a promising adjunctive treatment to psychological interventions for disorders characterized by social dysfunction. A small randomized, placebo-controlled trial of MDMA-assisted therapy (MDMA-AT) for social anxiety in autistic adults offered encouraging results, but more research is sorely needed to explore the potential for MDMA-AT in treating SAD.
This review aims to stimulate future study by summarizing research on disruptions in neurological, perceptual, receptive, and expressive systems regulating social behavior in SAD and proposing how MDMA-AT may alter these systems across four domains. First, we review research highlighting the roles of social anhedonia and reduced social reward sensitivity in maintaining SAD, with specific attention to the reduction in positive affect in social situations, infrequent social approach behaviors, and related social skills deficits. We posit that MDMA-AT may enhance motivation to connect with others and alter perceptions of social reward for an extended period following administration, thereby potentiating extinction processes, and increasing the reinforcement value of social interactions. Second, we review evidence for the central role of heightened social evaluative threat perception in the development and maintenance of SAD and consider how MDMA-AT may enhance experiences of affiliation and safety when interacting with others. Third, we consider the influence of shame and the rigid application of shame regulation strategies as important intrapersonal processes maintaining SAD and propose the generation of self-transcendent emotions during MDMA sessions as a mechanism of shame reduction that may result in corrective emotional experiences and boost memory reconsolidation. Finally, we review research on the role of dysfunctional interpersonal behaviors in SAD that interfere with social functioning and, in particular, the development and maintenance of close and secure relationships. We discuss the hypothesized role of MDMA-AT in improving social skills to elicit positive interpersonal responses from others, creating a greater sense of belonging, acceptance, and social efficacy.
Introduction
Social anxiety disorder (SAD) is the fourth most commonly diagnosed psychiatric disorder in the United States. Approximately 13% of the population in the U.S. will have SAD at some time in their life, with as many as 8% reporting SAD over the past year. SAD is characterized by a frequent and intense fear in social situations in which the person is afraid of being scrutinized by others and, as a result, avoids or experiences social situations with significant tension or discomfort. Epidemiological research has found that people with SAD report overall reduced quality of life, with negative consequences on their social and occupational lives, even at levels below the diagnostic threshold. Indeed, behaviors associated with SAD have been shown to contribute to delayed and fractured relationships, reduced likelihood of partnering and having children, workplace absenteeism, lower worker productivity, and inability to maintain or initiate employment. SAD is often associated with the concurrence and development of other psychological disorders, particularly alcohol use disorder and major depressive disorder (MDD). Although the exact nature of these relations remains unclear, SAD often occurs first and confers approximately a four-fold risk and five-fold risk for developing alcohol dependence and MDD, respectively, relative to the general population. SAD may also confer greater risk for adverse physical health outcomes. SAD increases the risk for chronic social isolation and loneliness, robust longitudinal predictors for cardiovascular disease and increased mortality.
Among people with SAD, intense fears of being negatively evaluated in social situations often arise during adolescence and the problem often goes unrecognized as something that could be treated. Evidence-based pharmacological and behavioral treatments for SAD have been identified, but much room for improved outcomes exists. Meta-analytic data on medication-based therapies suggests that SSRIs and SNRIs are associated with favorable outcomes compared to placebo yet are also associated with higher dropout rates over the treatment course. The efficacy of pharmacotherapies also appears dependent on continued adherence to medication, with as many as 25% of people reporting relapse after discontinuation of the drug. In terms of psychotherapies, cognitive-behavioral therapy has shown strong evidence for treatment efficacy and superior longevity to pharmacotherapy. Yet, in the case of both medication and psychotherapy a significant proportion of patients remain considerably symptomatic at the end of treatment, with social anxiety often assuming a chronic course in spite of intervention.
Recent research has begun to explore whether certain drugs can be used to augment the effectiveness of psychological interventions for SAD. A recent systematic review of d-cycloserine as a means to augment psychotherapy for SAD found that it provides a small augmentation effect for exposure therapy in treating SAD. A second drug that has been investigated as an augmentation strategy in the treatment of SAD is 3,4-methylenedioxymethamphetamine (MDMA). A small randomized, placebo-controlled trial of MDMA-assisted therapy (MDMA-AT) for social anxiety in autistic adults (N = 12) found a large between groups difference in social anxiety symptoms at the primary endpoint in favor of MDMA-assisted therapy (n = 8; seven completed treatment) vs. psychotherapy plus placebo after two doses of MDMA. Results from this trial suggest promise for the treatment of SAD in the absence of autism. Although autism spectrum disorder appears to confer greater risk of developing SAD relative to the general population, clinically elevated levels of social anxiety are found only in the minority of individuals with autism, demonstrating that SAD is a problem separable from autism itself, while still sharing some features. MDMA-AT has also been most extensively tested in the treatment of post-traumatic stress disorder (PTSD) and has shown to result in large effect size differences compared to placebo controls in Phase II and Phase 3 trials. In addition, both phase II and the existing phase 3 study suggest excellent safety and low abuse potential when MDMA is used under controlled conditions. However, little research has been conducted on its possible mechanisms of action in the context of treatment studies.
MDMA-AT Overview
MDMA has been proposed as a particularly promising treatment adjunct for disorders characterized by social dysfunction, such as SAD. This may be due, at least in part, to its stimulation of hormonal responses related to oxytocin, vasopressin, prolactin, and cortisol, all of which have profound impacts on social behavior. These effects are largely downstream of primary effects of MDMA on serotonin, norepinephrine, and dopamine systems. MDMA also functions as a stimulant and results in subjective effects including, most relevant to this paper, altered responses to social stimuli and experience of social emotion, including heightened feelings of empathy, and feelings of love and compassion.
MDMA-assisted therapy is typically delivered in the following format. Treatment begins with three preparatory sessions aimed at helping participants get ready for dosing sessions by providing information, answering questions, exploring relevant history, and teaching preliminary skills. This is followed by a dosing session, which is then followed by integration sessions aimed at helping the person make sense of what happened in the dosing sessions and how to generalize what they learned into their daily life. Studies typically have a total of 2-3 dosing sessions, each followed by three integration sessions.
Alongside the promise of MDMA-AT in augmenting current therapies for SAD to ameliorate social anxiety symptoms, evidence remains preliminary. One factor that may limit progress in this area is the lack of clear theorizing on potential processes of change that may occur in the context of MDMA-AT. A stronger theory will help identify potential processes of change that could guide research to improve integration between drugs and psychotherapy.
To address this gap in the literature, this review summarizes data on alterations in the affective, cognitive, and neurological systems related to social functioning in SAD and how MDMA-assisted therapy may alter these functions. We focus not on the immediate effects in dosing sessions, but rather on downstream effects that may occur in the weeks or months after dosing sessions.
We discuss four overarching domains in which therapeutic processes of change may occur and result in long-term improvements in functioning in SAD. First, the potential role of MDMA-AT in reducing social anhedonia and enhancing social reward sensitivity in SAD. Second, the role of social threat perception and functioning of the ventral vagus complex and associated neurological structures in SAD and how MDMA-AT may result in sustained alterations in their functioning. Third, the role of shame and shame-regulation strategies, such as self-criticism, in maintaining elevated threat perception in SAD and how MDMA-AT may interrupt these patterns. Fourth, the potential role of MDMA-AT in changing interpersonal behavioral patterns observed in SAD that may maintain the disorder.
We present these domains as distinct for the purpose of presentation clarity; however, we view them as related and interdependent processes of change that reciprocally affect one another to affect overall social functioning in SAD. This conceptualization has guided terminology used throughout this paper in that we have chosen to use the term process of change, rather than mechanism, as it allows for the existence of bidirectionality, feedback loops, and concurrent change, whereas mechanism often implies a linear or causal pattern of variable interaction.
Social Anhedonia / Reward Sensitivity & MDMA-AT
People with SAD often have broad impairments in positive emotions, particularly in response to social situations. For example, people with SAD experience diminished positive affect and increased negative affect in social interactions in general, and reduced positivity in response to social acceptance and enhanced negativity in response to social rejection. The reduction in positive affect in response to social situations, infrequent social approach behaviors, and related social skill deficits observed in SAD has been termed social anhedonia.
MDMA may enhance motivation to connect with others, enhance the likelihood that people find social interactions with strangers rewarding, and that this effect may extend beyond MDMA administration in a therapeutic, social context. These effects could have multiple therapeutic benefits in people with SAD. First, it could shift motivation to engage in social behavior that could potentiate extinction processes in post-dosing sessions.
It is possible that temporary increases in the reinforcement value of social interactions could initiate a new pattern of behavior in which individuals with SAD seek out previously avoided social situations and have more frequent positive social experiences, resulting in a positive chain of events in which affiliative behavior toward others elicits reciprocal affiliative behavior toward oneself. Over time, this new learning could reinforce social approach and result in a reduced perceived need to enact safety behaviors that interfere with effective social functioning thereby increasing perceptions of social efficacy.
Heightened Social Threat & MDMA-AT
A heightened tendency to experience social stimuli as threatening has been posited to be the central mechanism in the development and maintenance of SAD. People diagnosed with SAD show heightened amygdala activity to stimuli related to social-evaluative threat, such as negative emotion expressions or critical comments about oneself. Essentially, people with SAD do not feel safe in their relationships with others. This appears to be particularly true when interactions involve greater threat of revealing their authentic self, such as in laboratory tasks focusing on closeness generation through reciprocal self-disclosure. In fact, those with higher social anxiety have been shown to self-disclose less often in social tasks when they have high expectations of being liked by another person, whereas this pattern is inverse for people with low social anxiety.
MDMA-AT appears to help people feel safer with others. Anecdotal reports of early therapists using MDMA indicated that clients often report greater ease in relating in both close and more distant relationships for weeks or months afterwards. A qualitative analysis of reports from a clinical trial of MDMA-AT for PTSD found that reports of feeling safe were common, such as in the following quotes from participants,
“I think it allowed me to feel safe in my space. Now it was safe, and I had my tools and weapons to be able to tackle the obstacles that I never had before; There’s no words that’s going to explain this but I have never in my life relaxed like I did during this. Maybe like what you would feel in your mommy’s tummy or something, whatever being back in the womb, very safe, very warm.
Another possibility is that MDMA may potentiate changes in social safety through facilitating a greater focus on cues related to affiliation and intimacy and less of a focus on cues related to hierarchy and social rank. Moreover, MDMA has been shown to facilitate responding to positive social cues preferentially. Thus, MDMA may bolster internally experienced positive affect by shifting clients’ focus toward positive aspects of social experiences (e.g., being accepted and feeling connected), exploring positively valanced emotional experiences, and formulating social approach goals (relative to avoidance).
Shame / Shame-Related Coping & MDMA-AT
Different types of evidence point to the significance of shame in maintaining heightened social threat perception in SAD. Shame is a self-conscious emotion characterized by the perception of being inferior, unlikable, or unacceptable and a desire to hide the undesirable self from others. Negative self-representations, negative interpretation biases, negative self-imagery, and social-evaluative thoughts characteristic of shame are observed at higher levels among individuals with SAD than healthy controls. Indeed, shame is more highly correlated with SAD than other anxiety disorders and predictive of social anxiety symptom severity. Decreases in shame-proneness, but not guilt-proneness, are associated with decreases in SAD symptoms. Shame is theorized to have evolved to prevent humans from behaving in ways that have a high negative social cost and could result in social devaluation by others and loss of social rank (e.g., cheating, stealing). When people are informed that social devaluation has occurred, or perceive that it could occur, shame is triggered to organize their behavior around mitigating their loss of social standing and reducing risk of ostracism.
MDMA-AT may help individuals with SAD reduce shame by facilitating experiences of compassion or kindness toward the self through neurochemical changes, as well as through modeling from the therapist in the dosing session. With respect to the former, two experimental studies with ecstasy (presumably containing MDMA in one study and tested to confirm MDMA in the other) demonstrated that ecstasy increases feelings of self-compassion and reduces self-criticism. In addition, MDMA appears to elicit self-transcendent emotions more broadly. The most commonly reported experience while taking MDMA is a blissful state characterized by feelings of pleasure, peace, and love. Love and compassion are self-transcendent emotions, a family of emotions that increase prosocial behavior, perceptions of connectedness, and the tendency to transcend self-centered needs to focus on the needs of others. Self-transcendent emotions generated through loving kindness meditation have also been shown to increase social connectedness and reduce self-criticism.
Dysfunction Social Behaviour & MDMA-AT
SAD has been associated with a variety of social behaviors that function to decrease anxiety in social situations but inadvertently induce discomfort in others and evoke desires for social distance from people with SAD. These interpersonal behaviors are likely to contribute to the maintenance of SAD by evoking responses in others that further reinforce the person’s perceived low social status and their perceptions of defectiveness and social inadequacy. In addition, these behaviors have been shown to interfere with the development and maintenance of the kinds of close and secure relationships that are essential to adaptive functioning. Since people with higher levels of social anxiety have been shown to preferentially benefit from the presence of close others compared to those with lower levels of social anxiety, behavior that blocks the development of these close secure relationships may foster an overarching sense of social disconnection in some that further contribute to heightened arousal and reduced activation of the social engagement system.
Thus, interventions that help increase feelings of social safety, increase positivity in social interactions, and reduce social threat may improve outcomes for SAD via changes in spontaneous interpersonal behavior and improved responses from others signaling social inclusion and liking. Increases in social reinforcement might result in more positive emotion expressed during social situations, such as genuine smiling. Increased safety and reduced shame due to MDMA-AT would presumably result in a decrease in safety behaviors or expression suppression that have been shown to impede relationship development and intimacy. Furthermore, a qualitative study of people in MDMA-AT for PTSD, found that 12 out of 19 of the interviewees reported subjective improvements in relationships and social skills as a result of MDMA-AT. In addition, research shows that people taking MDMA feel more authentic, and experience enhanced positive emotions that might lead to shifts in interpersonal behavior that alter their social context, resulting in a beneficial feedback loop.
Discussion
Social anxiety disorder is a debilitating psychological problem with heavy costs to the individual and society at large. Although effective behavioral and pharmacological interventions exist, many people struggling with SAD experience ongoing symptoms following treatment or do not present for treatment indicating room for innovation in SAD treatment strategies. We believe MDMA-AT is particularly well-situated to be a novel, efficient, and effective intervention to help individuals with SAD alleviate psychological suffering and improve social functioning. In this paper, we put forth four domains where MDMA-AT may have lasting effects in altering processes hypothesized to maintain SAD beyond the dosing session: social anhedonia and decreased social reward, heightened social threat perception, increased shame and self-criticism, and dysfunctional interpersonal behavior. Evidence considered in this review for the role of MDMA in facilitating these changes was largely from basic scientific research using non-human animals and studies assessing humans who ingested MDMA outside the context of psychotherapy. Future clinical research examining the effectiveness of MDMA-AT will be necessary to test the hypothesized effectiveness of MDMA-AT for SAD beyond the single study conducted to date, as well as to directly test the respective roles of enhanced social reward sensitivity, decreased social threat perception, reduced shame and self-criticism, and alterations in interpersonal behavior in facilitating MDMA-AT treatment outcomes.
It is our hope that by understanding the relevant processes of change in MDMA-AT for SAD, therapists may be better equipped to tailor in-session interventions to fit the individual, thereby augmenting treatment outcomes and facilitating greater and more lasting changes in social functioning and quality of life.
