Psilocybin and MDMA for the treatment of trauma-related psychopathology

This review (2021) investigates the therapeutic rationale behind the use of psilocybin and MDMA in the treatment of PTSD and depression. Both compounds and the possible treatment modalities (the combination with talk therapy) are discussed. A combination of first MDMA-assisted therapy, followed by psilocybin-assisted therapy is also presented.

Abstract

“This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological 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 paper reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.”

Authors: Catherine I. V. Bird, Nadav L. Modlin & James J. H. Rucker

Summary

This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. Psilocybin and MDMA have been used to treat trauma-related MDD and PTSD, and have received Food and Drug Administration ‘breakthrough therapy’ designation.

Drug-assisted psychotherapy: psilocybin and 3,4-methylenedioxymethamphetamine (MDMA)

Psychedelic drugs are agonists at serotonin receptors, and have been used by different human societies for thousands of years. In the early 1970s, thousands of patients were treated with psychedelics in clinical settings, with mixed results.

The Controlled Substance Act of 1970 and the Misuse of Drugs Act of 1971 prohibited all routine clinical use of psychedelics.

Psilocybin has shown encouraging preliminary safety and efficacy data in pilot and feasibility trials for anxiety, depression, OCD, alcohol dependence, tobacco addiction, major depression, and treatment-resistant depression.

The drug development process with psilocybin is now accelerating, and a large randomized placebo-controlled phase 1 trial has concluded that psilocybin is safe and well-tolerated when given to up to 6 healthy volunteers, simultaneously, in a controlled setting.

Numerous phase 2 multi-site clinical trials with psilocybin are now ongoing in Europe and North America for the treatment of major depressive disorder and treatment-resistant depression.

MDMA was first synthesized by Merck in 1912 and was used as an adjunct for both individual and couples psychotherapy between 1977 and 1985. It was placed in Schedule 1 of the CSA in 1985 and remains in this most restrictive category today. Since 2000, MDMA-assisted psychotherapy has been investigated for the treatment of PTSD, social anxiety in autistic adults and alcohol use disorder. Results show that participants receiving MDMA experienced significantly greater reductions in PTSD symptoms.

MDMA is well-tolerated in modern clinical trials and has mild physical effects such as increased heart rate and blood pressure. The majority of deaths following recreational MDMA use have been linked either to polydrug use or to drug use plus risky behaviours and environment.

MDMA and psilocybin assisted psychotherapy take place in a comfortable, quiet, neutrally furnished room, with relaxing music and a supportive relationship with at least one therapist. Inner focus and psychological support are crucial to both approaches.

Clinical studies of MDMA or psilocybin-assisted psychotherapy have shown encouraging results, but larger, multi-site, placebo-controlled RCTs are needed to further address questions of efficacy. Expectancy effects may be exacerbated within research with psilocybin and MDMA as a result.

Both psilocybin and MDMA have received breakthrough therapy designation from the FDA, and phase 3 trials are underway to assess the safety and efficacy of MDMA-assisted psychotherapy in participants with PTSD.

PTSD and MDD are likely to be treated with licenced MDMA or psilocybin outside of a research setting, given the position of psilocybin and MDMA in the drug development process, and the potential mechanisms by which they may exert their therapeutic effects.

Trauma & psychopathology

Exposure to traumatic events is a universal risk factor in the development of psychopathology. Most people can manage their stress response to regain optimal functioning.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) includes Posttraumatic Stress Disorder (PTSD) and Acute Stress Disorder (ASD). PTSD is characterized by recurring symptoms of depressive and negative thoughts and feelings, hyperarousal, re-experiencing, and avoidance of distressing memories, feelings, thoughts or external reminders of the event. The International Classification of Disease, 11th Revision (ICD-11) includes complex posttraumatic stress disorder (CPTSD), which includes symptoms of PTSD and additional problems such as affect regulation, beliefs about oneself and difficulties in sustaining relationships.

Trauma exposure has been linked to the development and severity of various psychiatric conditions including major depressive disorder (MDD), dysthymia, bipolar disorder, substance abuse disorders and anxiety disorders. There is an overlapping cluster of symptoms shared between MDD and PTSD diagnoses.

The severity and impact of a stress reaction, and the lasting psychoneurobiological changes, are risk factors contributing to adverse outcomes following trauma exposure, including the subsequent development and/or diagnosis of a psychiatric condition.

PTSD and MDD: comorbidity and treatment

It is estimated that 62-92% of PTSD cases demonstrate comorbidity, with MDD being the most common co-morbid condition. Furthermore, the disorders share associated risk factors, symptoms and treatments.

PTSD and MDD co-occurring individuals have higher burden, greater functional impairment, and increased suicidal behaviours compared to individuals with MDD-only or PTSD-only diagnoses.

MDD and PTSD are heterogeneous and aetiologically complex conditions, with anhedonia, concentration difficulties/memory impairment, sleep disturbances, guilt and distorted cognition being central to the condition. Comorbidity of these two conditions may indicate an underlying degree of risk for psychopathology following trauma.

The neurobiology of the trauma response

PTSD symptoms are likely to reflect changes in neurobiological and endocrine functions in response to stress, and may include alterations to the limbic system, the hypothalamic-pituitary-adrenal (HPA) axis and key monoamine neurotransmitter systems associated with traumatic experience(s).

The limbic system

The limbic system receives sensory input via the thalamus, and the prefrontal cortex and anterior cingulate cortex filter out irrelevant information and inhibit responses to sensory stimuli. Trauma exposure can lead to decreased volumes in these areas, which can impair extinction of fear responses.

The amygdala is a key limbic structure involved in the mediation of fear responses and emotional processing. In PTSD, the amygdala displays a heightened response to neutral and emotional stimuli, contributing to irritability, aggression and overall hypervigilance, and in MDD, increased amygdala activity has also been observed.

The hippocampus is involved in fear conditioning, stress response and contextual aspects of fear. Trauma-exposed people have a reduced hippocampal volume, which may underlie avoidance, numbing, memory loss and dissociation experiences.

The HPA axis

The HPA axis is a neuroendocrine stress response system, and it is activated by acute stress. The hypothalamus secretes corticotropin-releasing hormone, which stimulates the release of glucocorticoids from the adrenal cortex.

Although uniform changes to cortisol levels in PTSD have not been observed, a dysregulation of the negative feedback loop between HPA axis and cortisol production may contribute to abnormal stress encoding and fear processing.

The mechanisms discussed most probably influence monoaminergic neurotransmitter turnover and subsequent neuromodulation. Current pharmacological treatments for PTSD are all antidepressants that specifically target the serotonin transporter (SERT), but these treatments are insufficient.

MDMA, a SERT inhibitor, stimulates the release of serotonin into the synaptic cleft, which leads to a clinical state of interpersonal tenderness, empathy and warmth, which may facilitate positive reappraisal of trauma-related material during psychotherapy.

MDD and PTSD: current treatments

PTSD can be treated with antidepressant drugs such as sertraline and paroxetine. However, only 20 – 30% of patients achieve remission with SSRI treatment, and benzodiazepines are not recommended as a first-line pharmacological treatment. Current UK treatment guidelines recommend psychological interventions as the first-line therapy for the treatment of PTSD, although the comparative efficacy of psychological and pharmacological treatments for PTSD is not yet established.

NICE recommends trauma-focused, exposure-based psychotherapies for PTSD, including cognitive processing therapy (CPT), cognitive therapy for PTSD (t-CBT), narrative exposure therapy (NET), prolonged exposure therapy (PET), and Eye Movement Desensitisation and Reprocessing (EMDR). However, nonresponse to initial treatment with pharmacological and psychological treatments is high with PTSD.

Depression

MDD treatment varies in intensity depending on the severity of the depression and the individual’s history with depression. Psychological therapies are favoured for milder forms of depression, with antidepressants and combination treatments recommended for moderate to severe forms of depression.

Treatment-resistant depression (TRD) develops in approximately 1/3 of those with a diagnosis of depression. Patients with TRD are more likely to require hospitalization and less likely to respond to subsequent treatments.

Novel treatment approaches

Despite the treatment gaps in MDD and PTSD, esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been licensed as a treatment for MDD given in combination with an SSRI, and has also been investigated for the treatment of PTSD.

The development of esketamine, an old drug with a new indication, reflects a slow yet steady resurgence of research into the antidepressant and anxiolytic properties of psilocybin and methylenedioxymethamphetamine (MDMA).

Mood effects and emotional processing

Both psilocybin and MDMA can alter the processing of affective information. Psilocybin reduces recognition of negative facial expression and enhances positive mood, while MDMA reduces the recognition of negative emotional stimuli.

Psilocybin attenuates amygdala reactivity to negative and neutral stimuli, and increases positive mood states following psilocybin administration. However, psilocybin increases amygdala reactivity to fearful faces.

Psilocybin has been shown to facilitate the processing of negative memories/experiences acutely, and to decrease functional connectivity between the ventromedial prefrontal cortex and the amygdala. This may explain the decreased threat sensitivity observed in participants with TRD following psilocybin treatment.

Psilocybin may inhibit fear responses during the revisiting of traumatic material, which may have therapeutic utility in addressing negative cognitive and emotional biases seen in depression.

There has been historic use of psychedelics in the treatment of ‘concentration camp syndrome’, but no clinical research into the utility of psilocybin for the treatment of PTSD has been conducted since. Ayahuasca has been suggested as a possible treatment for PTSD.

Similar to psilocybin, MDMA modulates circuitry that can become dysregulated following trauma. In healthy volunteers, perceptions of favourite and worst autobiographical memories were changed following 100 mg of MDMA.

These findings support the idea that MDMA modulates emotional processing and memory, and reduces the identification of negative emotions.

MDMA has been theorized to have antidepressant properties, but no human trials have directly investigated the use of MDMA for the treatment of MDD.

MDMA induces a rapid, dose-dependent release of monoamines from pre-synaptic vesicles (5-HT), but it also competes with synaptic monoamines for reuptake into the neuron, leading to a relative surge in 5-HT concentration. This mechanism suggests MDMA may be a suitable candidate for antidepressant treatment.

MDMA-assisted psychotherapy for alcohol use disorder (AUD) and chronic PTSD demonstrated significant decreases in depressive symptoms, with the 125 mg group demonstrating a larger average drop from baseline compared to the 30 mg group. A pooled analysis of four phase 2 RCTs investigating MDMA for PTSD demonstrated that improvement in depression symptoms was greatest for the active group compared to the control group. Although depressive symptoms may be part of the therapeutic process, qualitative analyses may be useful in capturing subtle changes in quality. Additionally, it is worth noting that the self-report BDI scale is not a blinded outcome measure thus expectancy effects are more likely to have contributed to findings.

MDMA has been shown to increase emotional empathy, subjective ratings of closeness to others and feelings of trust. Oxytocin levels increase as a result of 5-HT efflux, following MDMA, which may contribute to subjective increases in feelings of trust.

Oxytocin modulates neural circuitry related to the neurobiological response to trauma, and may be a potential underlying mechanism of the attenuation of amygdala activity observed. It may also be a potential adjunct to psychotherapy.

Psilocybin has been shown to increase emotional empathy, decrease feelings of social exclusion and rejection processing, and improve patient-therapist relationships. It may also help improve psychotherapeutic efficacy by supporting the development of a strong therapeutic alliance.

Conclusion

Evidence suggests that psilocybin- and MDMA-assisted psychotherapy can be used to treat comorbid and non-comorbid PTSD and depression, especially in those who have not responded to available treatments. A potential treatment course could include administering MDMA-assisted psychotherapy in the first instance and then offering psilocybin-assisted psychotherapy in those for whom depressive symptoms still persist.

Professor Allan Young at King’s College London receives grant funding from COMPASS Pathways PLC to undertake phase 1 and phase 2 trials with psilocybin. James Rucker has undertaken paid consultancy work for Beckley PsyTech and Clerkenwell Health.