Reviewing the potential of psychedelics for the treatment of PTSD

This review (2020) discusses the potential of MDMA, ketamine, classical psychedelics, and cannabinoids as potential treatments for PTSD.

Abstract

“There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search for and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, 2 psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses 4 types of compounds: 3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide), and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.”

Authors: Erwin Krediet, Tijmen Bostoen, Joost Breeksema, Annette van Schagen, Torsten Passie & Eric Vermetten

Summary

Reviewing the Potential of Psychedelics for the Treatment of PTSD

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD), and the search for new mechanisms of action has stalled. A promising new approach involves the use of psychedelic drugs, which have received breakthrough designations for psychiatric indications.

Introduction

Posttraumatic stress disorder (PTSD) is a complex disorder with limited efficacy of current treatments. The search for new drugs with new mechanisms of action has stalled, and exposure-based psychotherapy remains the first line treatment for PTSD.

Pharmacological targeting of 1 specific neurotransmitter system is insufficient for the treatment of PTSD and may benefit from pharmacologically induced changes in the capacity to engage with traumatic material in psychotherapy.

Most currently used psychotherapies for the treatment of PTSD are exposure-based therapies, which rely on imaginal visualization of the traumatic events and exposure to trauma-related cues that trigger fear responses. However, 40 – 60% of patients do not respond adequately to psychotherapy.

Psychoactive substances such as psychedelics may be used to treat mental health issues by increasing capacity for emotional and cognitive processing, strengthening therapeutic alliance, and targeting fear extinction and memory consolidation.

Psychedelics are increasingly being studied for the treatment of a range of psychiatric indications, including PTSD. MDMA, ketamine, classical psychedelics, and some cannabinoids are being investigated for the treatment of PTSD.

Psychedelic Drugs in the Treatment of PTSD

Psychedelic drugs are a category of compounds that can induce a wide range of psychological, cognitive, emotional, and physical effects. They have been used for treating disorders ranging from depression to substance use disorders and PTSD.

Psychedelic drugs are increasingly being studied for the treatment of PTSD, but well-designed clinical studies are still scarce.

Background

MDMA was first synthesized in 1912 as an intermediate substance in the synthesis of a hemostatic drug. It has been investigated for the treatment of PTSD, alcohol use disorder, and social anxiety in autistic adults since 2000.

Therapeutic Rationale

MDMA reduces fear response to anxiety-provoking stimuli, enhances introspection, and increases interpersonal trust, which can benefit the therapeutic alliance. MDMA does not alter cognition or produce a clouding of consciousness.

Several papers have been published on the therapeutic mechanisms of MDMA-assisted psychotherapy, including evidence that increases in the trait of openness play a moderating role between treatment with MDMA-assisted psychotherapy and reductions in PTSD symptoms.

MDMA attenuates amygdala activity while activating the frontal cortex, and increases oxytocin levels, which may be a contributing factor to the prosocial effects of MDMA and its therapeutic potential for the treatment of PTSD.

Setting

MDMA-assisted psychotherapy for PTSD is usually embedded within a psychotherapeutic treatment, with several non-drug preparatory sessions preceding and multiple integrative therapy sessions following each MDMA session. The therapy sessions last 5 to 8 hours and are accompanied by 2 therapists.

Administration

MDMA is administered orally in doses ranging from 75 to 125 mg. The effects typically last 4 to 6 hours, with some lingering effects in the hours afterwards.

Evidence in the Treatment of PTSD

In 2000-2002, a clinical trial was conducted in Spain with 6 women with chronic PTSD secondary to sexual assault. The study found that MDMA was both physically and psychologically safe.

MDMA-assisted psychotherapy for PTSD was first tested on 12 treatment-resistant patients in 2010 and showed significant reductions in PTSD symptom scores compared with placebo. MDMA-assisted psychotherapy was granted a breakthrough therapy designation by the FDA in 2019.

Safety and Potential Side Effects

MDMA can cause anxiety, tight jaw, headache, and fatigue. It is known to increase heart rate and blood pressure in a dose-dependent manner, and can cause slight hyperthermia, but these effects have not been reported in medically supervised use of MDMA.

Background

Ketamine is a noncompetitive N-methyl-D-aspartate-receptor antagonist that was first synthesized in 1962 and approved as an anesthetic in 1970. It has been used in the treatment of alcoholism and heroin addiction based on an aversion approach, and is increasingly studied for the treatment of PTSD.

Therapeutic Rationale

Ketamine has been shown to have rapid effects in the treatment of depression, and several neurobiological mechanisms have been proposed for its use in the treatment of PTSD. Ketamine may also enhance the receptiveness to psychotherapeutic interventions.

Ketamine could be used as an augmentation strategy for trauma-focused psychotherapy, and could result in long-term remission of PTSD symptoms. Ketamine has been used in the treatment of alcohol and heroin addiction, and in some other indications.

Setting

Ketamine is typically not used in a substance-assisted psychotherapy framework, and is usually administered in clinical hospital rooms without the use of music or much time spent on psychological preparation and integration of ketamine experiences.

Administration

Ketamine is typically administered intravenously in doses of 0.5 mg/kg over a period of 40 minutes to treat psychiatric indications, and can also be administered intramuscularly, intranasally, or orally. It can be used for different treatment approaches, depending on the therapeutic approach.

Evidence in the Treatment of PTSD

Ketamine infusion led to a significant and rapid reduction of PTSD symptom severity in 41 patients with chronic PTSD and associated depressive symptoms, and the effects lasted up to 7 days after the single infusion. Ketamine may also enhance the effects of depression treatment with repeated infusions.

To our knowledge, the only published study that has attempted to treat PTSD with ketamine has used an approach that is somewhat comparable with substance-assisted psychotherapy. The study used a single i.v. dose of 0.5 mg/kg ketamine over 40 minutes, combined with 2 cycles of a mindfulness exercise.

Safety and Potential Side Effects

Ketamine can cause drowsiness, dizziness, nausea, visual and perceptual alterations, and dose-dependent dissociative effects. It can also induce short-lived anxiety, but supportive clinical settings can minimize these effects.

Background

Classical psychedelics include psilocybin, LSD, and DMT, and share a common mechanism of action, mainly by agonistic action at the 5-HT2A receptor. Several trials are currently being conducted with psilocybin- and LSD-assisted psychotherapy for the treatment of depression and anxiety in patients with life-threatening diagnoses.

Therapeutic Rationale

Studies suggest that classical psychedelics may be useful for the treatment of PTSD. These substances induce several neurobiological changes and may decrease amygdala reactivity, which may help patients with PTSD to process traumatic memories.

Psychedelics have been shown to increase emotional empathy, creative divergent thinking, enhanced mindfulness-related capacities, increased insightfulness, reduced avoidance and increased acceptance and connectedness, and long-term increases in the personality trait of openness. They are also known to induce mystical-type experiences, which may mediate therapeutic effects in other mental disorders.

Setting

Psychedelics are administered in a comfortable and aesthetically pleasant setting under the guidance of a female/male therapist team. The approach is nondirective, and interaction with the therapists or guides is often kept to a minimum, especially during the first few hours of the experience.

Administration

Psilocybin and LSD are administered orally at the beginning of a treatment session in doses ranging from 10 to 25 mg psilocybin or 50 to 200 g LSD.

Evidence in the Treatment of PTSD

Before PTSD was introduced as a psychiatric diagnosis in 1980, LSD and psilocybin were used in the Netherlands to treat traumatized patients. In a long-term follow-up study, all but 1 patient reported moderate to strong improvements after treatment with this method.

Since then, no studies have investigated the potential of a classical psychedelic for the treatment of PTSD. However, the DMT-containing plant concoction ayahuasca recently has been proposed as a candidate for its treatment.

Safety and Potential Side Effects

Classical psychedelics can cause nausea, vomiting, physical discomfort, and psychologically challenging experiences. They are not toxic to the human organism and do not cause dependence or serious after effects when used in medically supervised settings.

Background

Cannabis has been used in Asia and the Middle East for thousands of years for medicinal, spiritual, and other purposes. Since the 1990s, scientific studies into medicinal applications have been increasing again, and the World Health Organization has proposed rescheduling cannabis to allow for medical applications.

Therapeutic Rationale

Cannabis contains more than 100 different cannabinoids, including tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on the endocannabinoid system, which plays a central role in emotional memories and the hypothalamic-pituitary-adrenal response under stress.

Cannabis and synthetic cannabinoids are used for the temporary relief of PTSD symptoms. They might hold potential for use within a substance-assisted psychotherapy model as well, as they can increase fear extinction and disrupt fear memory reconsolidation.

Setting

Medical cannabis and synthetic cannabinoids are used to reduce PTSD symptoms and might benefit from a substance-assisted psychotherapy model.

Administration

Cannabinoids can be administered by several routes, including oral, sublingual, and inhalation. The duration of effects depends on the route of administration and the particular cannabinoid or cannabis strain used.

Evidence in the Treatment of PTSD

Several studies have investigated the use of cannabinoids for the treatment of PTSD. A placebo-controlled trial with nabilone showed significantly stronger improvements on several PTSD symptoms, nightmares, and sleeping problems compared to a placebo.

Safety and Potential Side Effects

Cannabinoids have several side effects, including dry mouth, dizziness, fatigue, anxiety, and cognitive deficits. They might also be an additional risk factor for the development of psychotic disorders in susceptible individuals.

Discussion

Exposure-based psychotherapy is unequivocally designated as a first-line treatment for PTSD, yet there is an urgent need for novel interventions that can increase the efficacy of PTSD treatments.

MDMA may help patients with PTSD experience reduced fear and shame, and increased feelings of trust and safety, which allows them to more easily revisit and process traumatic memories and gain openness and trust.

Ketamine has shown to reduce symptoms of PTSD in some people, but multiple infusions over the course of several weeks may extend therapeutic effects. Moreover, the proper integration of ketamine within a substance-assisted psychotherapy framework might hold promise for long-term effects.

Although psilocybin and LSD have shown promising results for the treatment of a variety of psychiatric indications, clinical trials focusing on the treatment of PTSD are still lacking. Their partially unpredictable psychological effects might not make them the best candidates compared with other substances reviewed here.

For these reasons, classical psychedelics might have less potential for the treatment of PTSD than MDMA. However, patients might be more easily handled after they have previously experienced MDMA.

Cannabinoids have been used for the symptomatic treatment of PTSD. However, larger RCTs are necessary to determine the safety and efficacy of cannabinoids in PTSD, and to determine the long-term risks and side effects.

PTSD has been associated with increased risk for developing cannabis use disorder, and extensive use of cannabis may have negative effects on PTSD symptoms. Although monitored prescription of medical cannabis in controlled dosages cannot be compared with excessive unsupervised use of cannabis from unknown sources, close monitoring is advised.

Psychedelic compounds may increase engagement with and effectiveness of psychotherapies through a variety of psychological and neurobiological effects, such as increased insightfulness and introspection, and strengthened therapeutic alliance.

The quest for optimization of psychedelic treatment methods opens new areas for clinical and scientific exploration. Cognitive processing therapy, prolonged exposure, and Eye Movement Desensitization and Reprocessing may be used in such sessions.

Depending on the dose of ketamine or classical psychedelics used, the most appropriate therapeutic approach might be nondirective, while the timing of the psychotherapeutic intervention relative to the administration of the psychedelic drug might be more flexible.

A pilot study added 2 MDMA sessions to cognitive behavioral conjoint therapy for PTSD, during which the patient took the drug together with their partner. The results suggest that this approach is promising.

Third-wave therapies are increasingly being explored for the use in combination with psychedelic drugs, including acceptance commitment therapy. These therapies are informed by concepts and practices that are rooted in contemplative spiritual practices.

To increase our understanding of the use of psychedelic drugs in the treatment of PTSD, we need to generate more data regarding the safety and efficacy of these drugs, identify patients for whom these treatments might be indicated and effective, and understand the diverse psychological states they can induce. Substance-assisted psychotherapy can be expensive, so research on cost-effectiveness is required. It is also important to consider where in the treatment trajectory these therapies might potentially be indicated and whether they should only be considered for treatment-resistant patients or also as first-line treatments.

When properly applied, new models of substance-assisted psychotherapy may offer valuable contributions to the spectrum of existing pharmacological and psychotherapeutic treatments for PTSD. If successfully implemented, many patients with PTSD could potentially recover.

Study details

Topics studied
PTSD

Study characteristics
Literature Review

Authors

Authors associated with this publication with profiles on Blossom

Erwin Krediet
Erwin Krediet is a PhD candidate at Leiden University Medical Center and Psychologist/Researcher at ARQ National Psychotrauma Centre. He also volunteers on the program team of ICPR.

Joost Breeksema
Joost J. Breeksema is a researcher (PhD candidate) and director of ICPR and the OPEN Foundation. He is one of the central connectors in the (European) psychedelic space.

Torsten Passie
Torsten Passie has done work on the psychedelic experience (altered states of consciousness) and the pharmacology of hallucinogenic drugs. He is currently a visiting professor at Harvard Medical School.

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