Reviewing the Potential of Psychedelics for the Treatment of PTSD

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

International Journal of Neuropsychopharmacology, 2020, 23, (6), 385–400

doi : 10.1093/ijnp/pyaa018

https://pubmed.ncbi.nlm.nih.gov/32170326/

 

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.

Key words : PTSD, psychedelics, MDMA, ketamine, cannabinoids

 

Introduction

Posttraumatic stress disorder (PTSD) is a complex disorder with a host of neurobiological alterations (see Yehuda et al., 2015; Vermetten et al., 2018). During the last 2 decades, only 2 medications (i.e., paroxetine and sertraline) have been approved for the treatment of PTSD, both of which have demonstrated limited efficacy (Hoskins et al., 2015; Cipriani et al., 2018). Meanwhile, the search for and development of drugs with new mechanisms of action has stalled (Krystal et al., 2017b). Because of the limited efficacy of pharmacotherapeutic interventions, PTSD treatment guidelines (Department of Veterans Affairs and Department of Defense, 2017; National Institute for Health and Care Excellence,
2018) have unequivocally designated exposure-based psychotherapy as a first line treatment for PTSD. Yet, even after multiple modalities of psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity (Steenkamp et al., 2015; Bryant et al., 2016; Kitchiner et al., 2019). Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD.

The complexity of PTSD makes pharmacological targeting of 1 specific neurotransmitter system (e.g., targeting stress reactivity with selective serotonin reuptake inhibitors or hyperarousal with beta-blockers) insufficient. The treatment of PTSD may require more than pharmacologically targeting dysregulated molecules and pathways associated with developing and sustaining PTSD symptom severity and may benefit from pharmacologically induced changes in the capacity to engage with traumatic material in psychotherapy (DePierro et al, 2019). This may imply an approach to therapy that is conceptually different from the currently available treatments.

Most of the currently used psychotherapies for the treatment of PTSD are exposure-based therapies, which rely on imaginal visualization of the traumatic events and exposure to traumarelated
cues that trigger fear responses. The goal is to extinguish conditioned fear to cues associated with trauma by desensitization to fearful stimuli and learn that the trauma is not reenacted in real time. The approach is directive, and the role of the therapist is to instruct the patient to relive the trauma and to provide
a cognitive framework for change (Resick et al., 2016). Many patients experience a reduction in PTSD symptoms after psychotherapy. However, 40–60% of patients do not respond adequately (Haagen et al., 2015; Steenkamp et al., 2017; Watkins et al., 2018). The processing of traumatic memories typically can be an emotionally challenging experience for PTSD patients. For some patients, emotional detachment, fragmentation of trauma memories, or an inability to complete sessions due to the inability to tolerate reexperiencing traumatic memories can lead to nonresponse and treatment dropout (Mott et al., 2014; Goetter et al., 2015). Engagement in psychotrauma-focused therapy may be difficult for some patients in particular, especially those with extreme affect dysregulation or with shame or guilt associated with the recall of traumatic memories.

The integration of the targeted use of certain psychoactive substances within a psychotherapeutic treatment may have the potential to address some of these challenges. The psychoactive properties of psychedelic drugs may be of particular interest within such a substance-assisted psychotherapy approach. The rationale behind this approach is that these drugs can catalyze the psychotherapeutic process, for example, by increasing the capacity for emotional and cognitive processing through pharmacologically diminishing fear and arousal, by strengthening therapeutic alliance through increased trust and rapport, or by targeting processes of fear extinction and memory consolidation.

After a several decades hiatus, psychedelics are increasingly being studied for the treatment of a range of psychiatric indications (Mithoefer et al., 2016; Kyzar et al., 2017). Within the past 2 years, the US Food and Drug Administration (FDA) has recommended 2 compounds (3,4 methylene-dioxy-meth-amphetamine and psilocybin), which are still on the US Drug Enforcement Administration’s most restrictive schedule, a breakthrough therapy designation, and approved esketamine for treatment resistant depression. Currently, several psychedelics are being investigated for the treatment of PTSD. In this article, we review the potential of 4 types of psychedelic compounds: 3,4-methylenedioxy-methamphetamine (MDMA), ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide [LSD]), and some cannabinoids.

Psychedelic Drugs in the Treatment of PTSD

The use of psychedelics as medicines has recently been called a new emerging paradigm (Nichols et al., 2017). Although many questions remain about the mechanisms of action and efficacy, psychedelic drugs have seen a renaissance in research on their therapeutic potential, ranging from the treatment of depression to substance use disorders and PTSD (Kyzar et al., 2017; Curran et al., 2018). Psychedelic drugs (sometimes referred to as hallucinogens or entactogens) refer to a category of compounds that
can induce a wide range of psychological, cognitive, emotional, and physical effects (Nichols, 2004; Vollenweider and Kometer, 2010). For this review, we use a broad definition of psychedelic drugs, which includes substances such as MDMA, ketamine, and cannabis, whose pharmacological profiles differ substantially from the serotonergic “classical” psychedelics (such as psilocybin and LSD) but which all share the capacity for inducing an altered or opening of the sense of self.

Although psychedelic drugs are increasingly being studied for the treatment of PTSD, well-designed clinical studies are still scarce. In the following sections, we will summarize the available evidence for 4 types of psychedelics, providing background information and addressing the therapeutic rationale for each substance, the setting in which they are administered, and the current state of evidence for the treatment of PTSD. For an overview, see Table 1.

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