The Psychopathology of Trauma: Psilocybin and MDMA

This article looks at similar psycho-neurobiological alterations and how trauma affects psychiatric morbidity. Post-Traumatic Stress Disorder (PTSD) requires trauma, but trauma history is strongly connected with a number of psychiatric disorders. According to some data, Major Depressive Disorder (MDD) is the psychiatric disorder that develops most frequently after trauma.

• About 50% of PTSD cases also have MDD as a co-morbid condition. The argument over whether these phenomena are the product of faulty nosology or whether comorbid MDD + PTSD is a unique phenotype of trauma-related psychopathology is based on overlapping symptomatology and neurobiology between these illnesses.

Nevertheless, comparable therapeutic strategies have been used in the past with various degrees of effectiveness. Psychiatry is actively testing a unique treatment strategy called drug-assisted psychotherapy, which combines pharmacological and psychological techniques.

The Food and Drug Administration has designated psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy as “breakthrough therapies” for the treatment of refractory MDD and PTSD, respectively. The therapeutic benefits of psilocybin and MDMA for treating PTSD and MDD associated with trauma are discussed in this article.

Introduction

Phosphoryloxy-N,N-dimethyltryptamine (psilocybin), dimethyltryptamine (DMT), d-lysergic acid diethylamide (LSD), and mescaline are examples of traditional psychedelic drugs. The subjective psychoactive effects are due to partial agonism of the type 2 A serotonin receptor, which is mostly expressed on layer V pyramidal neurons in the prefrontal cortex.

They are agonists at serotonin receptors. Different, geographically isolated human groups have been seen to use plant-based psychedelics for recreational, medical, and religious purposes throughout history. Although this time frame is still disputed, some reports place the beginning of this use in the thousands of years ago.

From 1950 through the beginning of the 1970s, more than 1,000 clinical publications about the use of psychedelics in the treatment of thousands of patients were published after the accidental discovery and marketing of LSD in the Western world. Although these trials were far from ideal in many ways, a recent analysis of the pre-1970s literature concluded that they were likely to be safe when conducted in medically monitored settings and merited additional study with the aid of contemporary trial design paradigms.

Discussion

The use of psychedelics in research was severely constrained and all normal clinical usage was outlawed by the Controlled Substance Act (CSA) of 1970 in the US (and the broadly equivalent Misuse of Drugs Act, 1971, and related legislation in the UK). However, an agreement between the FDA and the National Institute on Drug Abuse in 1992 made it possible to resume clinical research with traditional psychedelics.

• Since then, psilocybin’s use as a treatment for anxiety and depression in end-of-life care, alcoholism, tobacco addiction, severe depression, and treatment-resistant depression has shown positive early safety and efficacy findings.
• Psilocybin drug development is currently accelerating. More recently, 89 healthy volunteers participated in a sizable, randomized, placebo-controlled phase 1 trial that assessed the safety profiles of a single dose of a placebo, 10 mg, and 25 mg of psilocybin. No significant adverse events were noted, and no adverse events necessitated study withdrawal.

The majority of “mood altered” adverse events were found to be positive (post hoc), and the adverse event profile was of the expected “psychedelic” kind. This study found that administering psilocybin to up to six healthy volunteers simultaneously in a controlled environment was safe and well-tolerated. It should be emphasized that a peer-reviewed journal has not yet published the trial’s findings.

The use of psilocybin in several phase 2 multi-site clinical trials for the treatment of major depressive disorder (MDD) and treatment-resistant depression (TRD) is also now being conducted (listed down below). The largest of them, conducted in Europe and North America, is a major multicenter randomized controlled phase 2b trial of single doses of psilocybin administered to patients with treatment-resistant depression.

MDMA: History

Merck created MDMA for the first time in 1912. Between 1977 and 1985, an estimated 4000 psychiatrists and psychologists utilized MDMA as an adjuvant for both individual and couple psychotherapy when its psychedelic effects were discovered. A restricted substance, MDMA (sometimes known as “ecstasy”) was added to Schedule 1 of the Controlled Substances Act (CSA) in 1985, just like psilocybin and the other traditional psychedelics.

It still falls under this strictest classification today. MDMA, an amphetamine derivative, stimulates the release of hormones (cortisol, oxytocin), monoamines (serotonin, dopamine, norepinephrine), and downstream signaling molecules (including brain-derived neurotrophic factor, or BDNF), which may act to modulate neural circuitry involved in processing traumatic memories, among other things.

MDMA: Psychological and Physiological Effects

Wide-ranging subjective effects of MDMA include heightened empathetic, affiliated, and interpersonal trust sensations. The term “entactogen” (literally, “to cause touch within”) is frequently used to describe MDMA. Since 2000, clinical research has been conducted on the use of MDMA-assisted psychotherapy to treat PTSD, social anxiety in individuals with autism, and alcohol use disorder.

• The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) was used to measure PTSD symptoms in a pooled analysis of six randomized, double-blind controlled clinical trials investigating MDMA-assisted psychotherapy for the treatment of PTSD. The results demonstrated clinically significant reductions in PTSD symptoms. After two drug therapy sessions using either active doses of MDMA (75-125 mg) or placebo/control doses (0-40 mg), 54.2% of participants in the active group and 22.6% in the control groups no longer satisfied the CAPS-IV diagnostic scores for PTSD.

Treatment Models

Both psilocybin and MDMA are utilized in the same treatment approaches for assisted psychotherapy, with the goal of promoting positive psychological development in an environment that is secure, comfortable, trusting, and free from judgment. In order to ‘deepen’ the therapeutic process, MDMA and psilocybin dosage sessions take place in a cozy, peaceful, neutrally decorated room with calming music and a supportive relationship with at least one therapist.

Dosing is approached in a supportive, non-directive manner in psychotherapy. Drug-dosing sessions are preceded by “preparation” sessions and followed by “integration” sessions. Inner attention and conversation both take place during sessions with MDMA. Both treatments require inner focus and psychological support, but psilocybin therapy fosters continuous attention to internal processes with the goal of discussing the experience with others.

The FDA has designated psilocybin and MDMA-assisted psychotherapy as “breakthrough therapies,” giving them precedence in the regulatory drug development process. This classification was given to MDMA in 2017 for its use in PTSD psychotherapy.

One of two phase 3 randomized, double-blind, placebo-controlled, multi-site clinical trials that The Multidisciplinary Association for Psychedelic Studies (MAPS) had planned to conduct to evaluate the security and effectiveness of MDMA-assisted psychotherapy in patients with PTSD is now complete as of September 2020. For both the treatment of Major Depressive Disorder and Treatment Resistant Depression, psilocybin therapy has been deemed a “breakthrough.

PTSD and MDD are probably the first mental diseases to be treated with licensed MDMA or psilocybin outside of a research setting, given the state of current research and drug development initiatives. The current research reviews the contribution of trauma to psychiatric illness and associated neurobiological alterations in PTSD and MDD. Although PTSD and MDD are separate diseases, they frequently co-occur and show a substantial amount of clinical overlap. Furthermore, these illnesses share a common underlying cause in the form of trauma exposure. The probable mechanisms by which psilocybin and MDMA may exert their therapeutic benefits in both trauma-related MDD and PTSD are addressed in light of their places in the drug development process. Whether psilocybin should be taken before MDMA is a practical question of interest.

Trauma & Psychotherapy

A common risk factor for the development of psychopathology is exposure to traumatic experiences, such as severe accidents, physical or sexual abuse, war-related catastrophes, and life-threatening illnesses (for oneself or loved ones). According to the World Mental Health (WMH) Survey conducted by the World Health Organization, 70.4% of respondents had endured traumas throughout their lifetime.

• Low mood, worry, weariness, dissociation, increased physical arousal, agitation, and numbness are a few of the reactions to traumatic situations. Most people can control this stress reaction to return to their ideal state of functioning, and not everyone who has a traumatic event will go on to meet the requirements for a mental health disorder.

Post-traumatic Stress Disorder (PTSD) and Acute Stress Disorder are two of the “Trauma- and Stressor-Related Disorders” listed in The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (ASD). Both mention trauma as a crucial diagnostic need. PTSD is the diagnosis that is most likely to indicate a chronic or lifelong disease because ASD requires symptoms to disappear within one month of the incident, and lifetime diagnoses of PTSD affect about 4% of the world’s population.

• PTSD is characterized by recurrent symptoms of intrusive upsetting memories, flashbacks, nightmares, and avoidance of distressing memories, feelings, thoughts, or external reminders of the event. These symptoms include depressive and negative thoughts and feelings (self-blame, isolation), hyperarousal (irritability, aggression, elevated startle response), and re-experiencing.

A dissociative subtype of PTSD recognised by the DSM-5 includes depersonalization, derealization, and disconnected feelings. The degree of functional impairment brought on by these symptoms, which may raise the risk of suicidality, is another way to measure severity.

• Complex posttraumatic stress disorder (CPTSD), which includes all diagnostic criteria for PTSD as well as additional issues like affect regulation, self-image issues (self-blame, worthlessness), and relationship maintenance challenges, is included in the International Classification of Diseases, 11th Revision. Compared to PTSD, the concept of trauma under CPTSD is a little less categorical and refers to upsetting situations that are typically lengthy or repetitive in character and from which escape is either difficult or impossible (prolonged domestic abuse, childhood sexual or physical abuse, discrimination, torture, slavery).

Other psychiatric illnesses such as major depressive disorder (MDD), dysthymia, bipolar disorder, substance addiction disorders, and anxiety disorders when trauma presents as an external risk factor have also been connected to the development and severity of trauma exposure.

The most prevalent disorder that develops after trauma may be MDD, and PTSD and MDD share a similar set of symptoms. Given that both depression and exposure to trauma are inherited qualities, the link between trauma exposure and MDD is complicated and poorly understood. Although it has been shown that childhood adversity, such as physical and sexual abuse, family violence, and neglect, increases vulnerability to negative adult mental health outcomes like PTSD, MDD, and anxiety.

• The intensity and impact of a stress reaction, as well as the long-lasting psycho-neurobiological changes, are risk factors that might lead to unfavorable consequences, such as the later development and/or identification of a mental health problem.

The results of trauma exposure are influenced by underlying genetic vulnerabilities. Additionally, a wide range of variables affect how traumatic events turn out. The occurrence and presentation of the resultant psychopathology can be influenced by the type and degree of the trauma (e.g., assaultive vs. non-assaultive). Some of the elements that can enhance the likelihood of trauma exposure include gender, race, sexual orientation, and prior trauma exposure.

Trauma & Psychotherapy: Continued

The aforementioned information summarizes the evidence that may support the use of psilocybin- and MDMA-assisted psychotherapy for the treatment of trauma-related symptomatology and depressive symptomatology, respectively. Although depression is a complicated psychosocial disorder with many potential causes, there is strong evidence that it can stem from traumatic events, especially those that occur early in life.

A diverse approach to treatment is necessary when comorbid with PTSD. Drug-assisted psychotherapy models’ integration of psychotherapy and medication appears to be an effective strategy for treating both depression and PTSD, particularly in patients who have not responded to previous therapies. The infrequent recurrence of depressed symptoms after MDMA use could be an artifact or a crucial mechanism in the processing of traumatic memories.

• Negative social interactions are caused by a lack of empathy and social cognition, which also affects how we receive and process socially significant information. The essential assumptions underlying the expected social processing benefits following both MDMA and psilocybin-assisted treatment include improved therapeutic relationship and emotional empathy.

Psilocybin has been demonstrated to lessen emotions of social exclusion and rejection processing in the anterior cingulate cortex as well as to promote emotional empathy without compromising cognitive empathy. These outcomes might enhance patient-therapist interactions and lessen social disengagement. Following psilocybin-assisted psychotherapy, participants with depression reported greater experiences of connection (to self, others, and the world) and decreased feelings of avoidance.

Summation

Giving MDMA-assisted psychotherapy in the beginning and then psilocybin-assisted psychotherapy to individuals whose depressive symptoms still persist could be a possible course of treatment. After experiencing more “present” altered states of consciousness while under the influence of MDMA, it has been hypothesized that this course may help the patient become more used to the heightened arousal felt when under the influence of psilocybin.

The therapeutic connection may be strengthened by MDMA’s “trust increasing” properties in the beginning, allowing for a “deeper” subsequent acute psilocybin experience. Direct investigation of the potential transdiagnostic applications of psilocybin and MDMA assisted psychotherapy for comorbid and non-comorbid PTSD and depression requires proof of concept research.