This article examines the role of trauma in psychiatric morbidity and analogous psycho-neurobiological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), however, trauma history is highly correlated with a variety of psychiatric conditions. Some evidence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. Overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid MDD + PTSD is a distinct phenotype of trauma-related psychopathology.
Regardless, similar treatment approaches have been employed historically, with varying success. The drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received Food and Drug Administration ‘breakthrough therapy’ designation for the treatment of resistant MDD and PTSD, respectively. This article reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.
Drug-Assisted Psychotherapy: Psilocybin and 3,4 Methylenedioxymethamphetamine (MDMA)
Classical psychedelic drugs include phosphoryloxy-N,N-dimethyltryptamine (psilocybin), dimethyltryptamine (DMT), d-lysergic acid diethylamide (LSD) and mescaline. They are agonists at serotonin receptors, with the subjective psychoactive effects dependent on partial agonism of the type 2 A serotonin receptor, which is predominantly expressed on layer V pyramidal neurons in the prefrontal cortex. Historical and present-day recreational, medicinal, and religious use of plant-based psychedelics by different, geographically isolated human societies has been observed. Some reports date this use extending back thousands of years, although this timeline is still debated. Subsequent to the serendipitous discovery and marketing of LSD in the Western world, from 1950 to the early 1970s, more than 1,000 clinical papers were published about the treatment of thousands of patients with psychedelics. Whilst these trials were suboptimal in many respects, a recent review of the pre-1970s literature concluded that they were likely to be safe when delivered in medically controlled settings and deserved further investigation with the benefit of modern paradigms of trial design.
1.1 MDMA: Overview
The Controlled Substance Act (CSA), 1970, in the US (and the largely synonymous Misuse of Drugs Act, 1971, and associated regulations in the UK) severely restricted the use of psychedelics in research and prohibited all routine clinical use. However, in 1992, the National Institute on Drug Abuse and the FDA reached an agreement that facilitated the resumption of clinical research with classical psychedelics.
Since then, modern pilot and feasibility trials have demonstrated encouraging preliminary safety and efficacy data for psilocybin as a treatment for anxiety and depression in end-of-life care, alcohol dependence, tobacco addiction, major depression and treatment-resistant depression.
The drug development process with psilocybin is now accelerating. More recently, a large, randomized placebo-controlled phase 1 trial compared the safety profile between a single dosing session of a placebo, 10 mg and 25 mg of psilocybin in 89 healthy volunteers. There were no serious adverse events recorded and no adverse events led to withdrawal from the study. The adverse event profile was of the expected ‘psychedelic’ nature, with the vast majority of ‘mood altered’ adverse events judged (post-hoc) to be positive in nature. This trial concluded that psilocybin was safe and well-tolerated when given to up to 6 healthy volunteers, simultaneously, in a controlled setting. It should be noted that the results from this trial have yet to be published in a peer-reviewed journal.
Furthermore, numerous phase 2 multi-site clinical trials with psilocybin in the treatment of the major depressive disorder (MDD) and treatment-resistant depression (TRD) are now ongoing (listed down below). The most notable of these from a medical regulatory perspective is a large multicentre randomized controlled phase 2b trial of single doses of psilocybin given to participants with treatment-resistant depression, taking place across Europe and North America.
1.2 MDMA: History
MDMA was first synthesized by Merck in 1912. Following the discovery of its psychoactive properties, MDMA was used as an adjunct for both individual and couples psychotherapy between 1977 and 1985 by an estimated 4000 psychiatrists and psychologists. Similar to psilocybin and the other classical psychedelics, MDMA became a controlled substance and was placed in Schedule 1 of the CSA in 1985 after becoming popular for recreational use (‘ecstasy’). It remains in this most restrictive category today. MDMA is an amphetamine derivative and stimulates the release of monoamines (serotonin, dopamine, norepinephrine), hormones (cortisol, oxytocin) and downstream signalling molecules (including brain-derived neurotrophic factor (BDNF)), which (amongst other things) may act to modulate neural circuitry implicated in the processing of traumatic memories.
1.3 MDMA: Psychological & Physiological Effects
MDMA elicits a wide range of subjective effects, including increased feelings of empathy, affiliation and interpersonal trust. MDMA is often categorized as an ‘entactogen’ (literally: ‘to produce touch within’). Since 2000, MDMA-assisted psychotherapy has been under clinical investigation for the treatment of PTSD, social anxiety in autistic adults and alcohol use disorder. A pooled analysis of six randomized, double-blind controlled clinical trials investigating MDMA-assisted psychotherapy for the treatment of PTSD found significantly greater reductions in PTSD symptoms (measured by The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV)). Following two-drug treatment sessions with either active doses of MDMA (75–125 mg) or placebo/control doses (0–40 mg), 54.2% of participants in the active group no longer met CAPS-IV diagnostic scores for PTSD in comparison to 22.6% in control groups.
1.4 MDMA-AT & P-AT
Treatment models of psilocybin- and MDMA-assisted psychotherapy overlap with both drugs used to facilitate salutary psychological change within a safe, comfortable, trusting and non-judgmental set and setting. Dosing sessions with MDMA and psilocybin take place in a comfortable, quiet, neutrally furnished room, with relaxing music and a supportive relationship with at least one therapist, which is thought to ‘deepen’ the therapeutic process. The psychotherapeutic approach to dosing is supportive but non-directive. ‘Preparation’ sessions are given before and ‘integration’ sessions are given after drug-dosing sessions. In MDMA-assisted sessions, both inner focus and dialogue occur under the drug effect. Inner focus and psychological support are crucial to both approaches, but treatment with psilocybin encourages sustained attention on internal processes with the aim to discuss the experience with the therapist after the drug session.
Both psilocybin- and MDMA-assisted psychotherapy have received ‘breakthrough therapy’ designation from the FDA, assigning priority in the regulatory drug development process. In 2017, MDMA was granted this designation for its use in psychotherapy for the treatment of PTSD. As of September 2020, The Multidisciplinary Association for Psychedelic Studies (MAPS) have completed one of two planned phase 3 randomized, double-blind, placebo-controlled, multi-site clinical trials to assess the safety and efficacy of MDMA-assisted psychotherapy in participants with PTSD. Psilocybin therapy has been designated in the same ‘breakthrough’ category for both the treatment of Major Depressive Disorder and Treatment Resistant Depression.
Given the status of current research and drug development efforts, PTSD and MDD seem likely to be the first psychiatric conditions to be treated with licenced MDMA or psilocybin outside of a research setting. In the present article, the role of trauma in psychiatric morbidity, and corresponding neurobiological changes in PTSD and MDD, are reviewed. Whilst PTSD and MDD are distinct disorders, they often co-occur and demonstrate a significant degree of clinical overlap. Furthermore, trauma exposure is a common driving factor underlying both conditions. Given the positions of psilocybin and MDMA in the drug development process, the potential mechanisms by which they may exert their therapeutic effects in both trauma-related MDD and PTSD are discussed. A practical point of interest is whether psilocybin before MDMA or MDMA before psilocybin might be, respectively, better for MDD and PTSD subtypes of trauma-related mental health problems.
Trauma & Psychopathology
Exposure to traumatic events, including serious accidents, physical or sexual abuse, war-related incidents and life-threatening illness (to oneself or loved ones), is a universal risk factor in the development of psychopathology. The World Health Organization’s World Mental Health (WMH) Survey found 70.4% of responders had experienced lifetime traumas. Reactions to traumatic events include low mood, anxiety, exhaustion, dissociation, heightened physical arousal, agitation and numbness, amongst others. Most can manage this stress response to regain optimal functioning, and not all who experience a traumatic event will subsequently meet the criteria for a mental health condition.
The ‘Trauma- and Stressor-Related Disorders’ outlined in The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) include Post-traumatic Stress Disorder (PTSD) and Acute Stress Disorder (ASD). Both cite trauma as a necessary diagnostic criterion. As ASD requires symptoms to resolve less than 1 month in the aftermath of the trauma, PTSD is the diagnosis that is most likely to represent a chronic or lifelong condition and a lifetime diagnosis occurs in around 4% of the global population. PTSD is characterized by recurring symptoms of depressive and negative thoughts and feelings (self-blame, isolation), hyperarousal (irritability, aggression, elevated startle response), re-experiencing (intrusive upsetting memories, flashbacks, nightmares) and avoidance of distressing memories, feelings, thoughts, or external reminders of the event. DSM-5 includes a PTSD dissociative subtype that includes experiences of depersonalization, derealisation and feeling detached. Severity can also be observed through the degree of functional impairment as a result of these symptoms, possibly contributing to an increased risk of suicidality. The International Classification of Disease, 11th Revision includes complex posttraumatic stress disorder (CPTSD), where all diagnostic requirements for PTSD must be met along with additional problems including affect regulation, beliefs about oneself (self-blame, worthlessness) and difficulties in sustaining relationships. The trauma definition under CPTSD is slightly less categorical than that of PTSD, defining distressing events that are usually prolonged or repetitive in nature and where escape is difficult or impossible (prolonged domestic abuse, childhood sexual or physical abuse, discrimination, torture, slavery).
Trauma exposure has also been linked to the development and severity of various other psychiatric conditions including major depressive disorder (MDD), dysthymia, bipolar disorder, substance abuse disorders and anxiety disorders where trauma presents as an external risk factor. MDD may be the most common condition following trauma and there is an overlapping cluster of symptoms shared between MDD and PTSD diagnoses. The relationship between trauma exposure and MDD is complex and not well understood, where both depression and trauma exposure are heritable traits. However, robust correlations between childhood adversity (e.g., physical and sexual abuse, family violence and neglect) and increased vulnerabilities to adverse adult mental health outcomes, including PTSD, MDD and anxiety have been demonstrated.
The severity and impact of a stress reaction, and the lasting psycho-neurobiological changes, represent risk factors contributing to adverse outcomes, including the subsequent development and/or diagnosis of a psychiatric condition. Underlying genetic vulnerabilities affect outcomes following trauma exposure. Furthermore, there are a variety of factors that influence outcomes following traumatic experiences. The nature and severity of the trauma (e.g., assaultive vs. non-assaultive) can influence the occurrence and presentation of resulting psychopathology. Gender, race, sexual orientation and previous exposure to trauma are some of the factors that can increase the incidence of trauma exposure.
MDMA and Psilocybin-Assisted Psychotherapy: Transdiagnostic Uses
Existing evidence that may support the use of psilocybin-assisted psychotherapy for the treatment of trauma-related symptomatology, and MDMA-assisted psychotherapy for the treatment of depressive symptomatology, has been outlined above. Whilst depression is a complex psychosocial condition with a multitude of triggers, there is robust evidence to suggest that it can arise as a result of traumatic experiences, particularly in early life. When comorbid with PTSD, a multifaceted approach to treatment is required. The combination of psychotherapy and pharmacology as is presented in drug-assisted psychotherapy models seems to be a valuable approach in treating both depression and PTSD, especially in those who have not responded to available treatments. The occasional persistence of depressive symptoms following MDMA may be an artefact or a key mechanism in the processing of traumatic memories.
- Impaired social cognition and empathic abilities contribute to negative social interactions and impact the ability to perceive and process socially relevant information. Improved therapeutic alliance and emotional empathy are outcomes central to the hypothesized social processing improvements following both MDMA and psilocybin-assisted therapy.
- Psilocybin has been shown to increase emotional empathy, without affecting cognitive empathy, as well as decrease feelings of social exclusion and rejection processing in the anterior cingulate cortex. These effects may contribute to improved patient-therapist relationships and reduce social withdrawal. In depression, participants reported increased feelings of connection (from self, others and the world) and reduced feelings of avoidance following psilocybin-assisted psychotherapy.
A potential treatment course could be to administer MDMA-assisted psychotherapy in the first instance and then offer psilocybin-assisted psychotherapy in those for whom depressive symptoms still persist. It has been suggested that this course may allow the patient to be more accustomed to the heightened arousal experienced under psilocybin after experiencing more ‘present’ altered states of consciousness under MDMA. The ‘trust enhancing’ qualities of MDMA may prove useful in strengthening therapeutic alliance in the first instance to allow for a ‘deeper’ subsequent acute psilocybin experience. Proof of concept studies is required in order to directly investigate the potential transdiagnostic uses of psilocybin- and MDMA-assisted psychotherapy for comorbid and non-comorbid PTSD and depression.