Psychedelic drugs to treat post-traumatic stress disorder (PTSD)

Sarah Bunn; Stephen Naulls

Overview skip to link
What is PTSD? skip to link
Existing treatments for PTSD skip to link
Psychedelic-assisted psychotherapy for treating PTSD skip to link
MDMA (3,4-methylenedioxymethamphetamine, ‘ecstasy’) skip to link
Ketamine skip to link
‘Classical Psychedelics’ skip to link
Regulation of psychedelic drugs used in medicine skip to link

Overview

POST has published briefings focussed on the use of psychedelics to treat depressive disorders, anxiety disorders and eating disorders. This is part of our wider work on the use of psychedelics to treat mental health conditions. POST will publish a major briefing on the theme later in 2024. This briefing discusses post-traumatic stress disorder (PTSD) and covers:

an overview of PTSD and the main symptoms
existing treatments for PTSD, namely drug treatments and talking therapies
emerging psychedelic-assisted psychotherapy for PTSD, including MDMA, ketamine, psilocybin and LSD
future and ongoing research.

What is PTSD?

PTSD is a complex anxiety disorder caused after exposure to one or more traumatic events. This involves ingrained traumatic memories in the brain. In international medical diagnostic criteria the main symptoms are:

Re-experiencing trauma: people may relive the traumatic event through vivid memories, flashbacks or nightmares. These experiences can feel intense and overwhelming, often accompanied by strong emotions like fear or horror, and may include physical sensations. People can also describe periods of dissociation.
Avoidance behaviour: individuals may try to avoid thinking about or discussing the traumatic event. They may also steer clear of places, activities or people that remind them of the trauma.
Mood dysregulation: people may experience negative changes in thoughts and/or mood related to the traumatic event. It is common for a person to be diagnosed with other mental health conditions, such as depressive or substance use disorders. People may also describe emotional blunting. Some people with PTSD also describe negative self-perceptions, including feeling worthless, leading to suicidal thoughts in some cases.
Heightened sense of danger (hyper-arousal): people may constantly feel on edge, and may think and behave as if they are in danger. This could be exhibited as being easily startled by loud noises, always being on guard, or feeling hyper-aware of potential threats in their surroundings.
Interpersonal difficulties: individuals experiencing symptoms of PTSD may encounter difficulties with friends, family or colleagues, that may lead to a state of social alienation and disconnection.

These symptoms persist for several weeks or longer and significantly impact various aspects of life, such as personal relationships, work and social activities.

PTSD is caused by myriad traumatic experiences. These can be single, repeated or multiple events, including but not limited to:

serious accidents
physical or sexual assault
neglect or abuse, including during childhood or domestic abuse
work-related trauma
trauma related to serious health problems
war and conflict
severe violation of personal rights and torture

This means that, in evaluating the effectiveness of the treatments for PTSD, it is important to consider the nature and extent of symptoms, as well as the origin of the trauma.

Existing treatments for PTSD

Often, psychological interventions can be used shortly after traumatic experiences to try to prevent the onset of PTSD. Both medication and talking therapies can help to treat people who have already developed PTSD. Overall, such treatments are successful in about 35-40% of patients.

Pharmacological treatments

Pharmacological (drug) treatment is not currently recommended by NICE to prevent PTSD in individuals experiencing acute stress following a traumatic event/s. However, it has a role for individuals who have already developed PTSD and who may have a preference for drug treatment, or if other treatments have failed. These include:

Selective serotonin reuptake inhibitors (SSRIs) increase serotonin (a chemical transmitter) levels in the brain, contributing to mood stabilisation. For example, sertraline can be taken if an individual has a preference for drug treatment.
Selective noradrenaline reuptake inhibitors (SNRIs) act on both serotonin and another transmitter system (norepinephrine), providing a dual mechanism of action. For example, venlafaxine can be taken if an individual has a preference for drug treatment.
Antipsychotic drugs can be used for severe psychological symptoms such as hyperarousal or psychotic symptoms that have not responded to other treatments.

All of the treatments above were considered ‘off-label’ as of 2018 when this guidance was last reviewed by NICE. This means the use of an approved drug for an unapproved indication or in an unapproved age group, dosage, or route of administration.

Psychological treatments (psychotherapy)

These include:

Individual trauma-focused cognitive behavioural therapy(CBT), which can include cognitive processing therapy, narrative exposure therapy, or prolonged exposure therapy. CBT interventions can be targeted towards specific symptoms, such as sleep disturbance or anger.
Eye-Movement Desensitisation and Reprocessing (EMDR) therapy, which involves using side-to-side eye movement alongside talking therapy in a structured format to process the negative images and emotions associated with traumatic memories.

Psychedelic-assisted psychotherapy for treating PTSD

Research into the use of psychedelic-assisted psychotherapy for PTSD has been conducted using MDMA, ketamine, and the four ‘classical psychedelics’ (psilocybin, LSD, mescaline and DMT). These are described in POST’s rapid response article on depression.

Generally, this approach involves ‘non-trip’ sessions with a medical professional to ensure safety, prepare the patient and build a relationship, and a minimum of one ‘trip’ session where the patient undergoes a form of talking therapy after administration of a psychedelic compound.

Evidence from studies conducted in hundreds of participants suggests that psychedelic-assisted psychotherapy may be an effective treatment for PTSD. However, to date, there is not enough information from large clinical trials with sufficient participants comparing psychedelic-assisted psychotherapy directly to existing treatments.

MDMA (3,4-methylenedioxymethamphetamine, ‘ecstasy’)

MDMA is thought to increase social behaviour and emotional empathy, and subjective judgements of openness and trust. MDMA-assisted psychotherapy for PTSD was first studied in a clinical trial of six women with PTSD resulting from sexual assault. The number of participants was very small, but the study demonstrated the possible safety (both physically and mentally) of using such a treatment in this patient cohort. Since then, more robust trials have been published:

The first randomised-controlled trial using MDMA-assisted psychotherapy was conducted in 20 patients with treatment-resistant PTSD.
Twelve participants received two MDMA-assisted psychotherapy sessions. 83% of participants receiving the treatment no longer met the criteria for PTSD diagnosis, versus 25% in the control group that received psychotherapy alone.
These participants were followed up for between 17 to 74 months. The researchers found that the majority of those who had received MDMA-assisted psychotherapy – a group previously considered treatment-resistant – continued to report symptomatic relief.
MDMA-assisted psychotherapy at three doses (30mg, 75mg and 120mg) was tested in 26 military veterans, fire officers and first responders. The groups that received the two higher doses reported significantly higher reductions in PTSD symptoms compared to the group receiving the lowest dose. For those receiving the highest dose, the effects were still present at a 12-month follow-up.

A 2019 ‘pooled analysis’ of these results combined the results of the above trials and others, for 72 participants receiving MDMA-assisted psychotherapy. After two sessions, more than double the number of patients in the group receiving MDMA-assisted psychotherapy no longer met the diagnostic criteria for PTSD than those receiving psychotherapy alone. This study outlined a possible protocol for a phase 3 clinical trial.

In 2023, results from a multi-site randomised, double-blinded phase 3 study for MDMA-assisted psychotherapy for PTSD were published. Of 104 participants, 53 received MDMA-assisted psychotherapy and 51 were given a placebo alongside therapy. At 18 weeks, the participants receiving the MDMA-assisted psychotherapy reported ongoing significantly improved PTSD symptoms and functioning compared with those receiving a placebo and therapy.

Ketamine

Ketamine is of increased interest to researchers since the early 2000s due to its antidepressant properties. POST has published evidence on its use in treatment-resistant depression. Ketamine is sometimes referred to as a ‘dissociative psychedelic’, which underpins the interest in its use as an adjunct to therapy, and as a treatment on its own. One form of ketamine, esketamine (as a nasal spray), is approved by the US Food and Drug Administration (FDA) to treat depression.

Ketamine-alone for PTSD

In contrast to the other drugs included in this briefing, ketamine has been studied for its possible use as a treatment in isolation (without psychotherapy) in some research. Researchers believe this may be possible due to short-term changes to some connections in the brain:

41 patients with chronic PTSD had an intravenous infusion (into a vein) of ketamine. This significantly reduced the severity of PTSD symptoms, and the effects lasted for seven days when participants were followed up.
Further research indicated these short-term effects could be prolonged through additional infusions. 15 military veterans with treatment-resistant depression received six doses of intravenous ketamine over 12 days. Follow up showed that the median time to relapse was 41 days and overall, 80% of participants entered remission for PTSD.
Similarly to the above research on MDMA, a larger study had 158 participants allocated to receive low, moderate or high doses of ketamine. However, although it found reductions in depression symptoms among people with co-existing depression at the start of the study, the study found no effect of ketamine on PTSD symptoms at any dose.

Ketamine-assisted psychotherapy for PTSD

Ketamine-assisted psychotherapy was used in a study combining an infusion of ketamine with a form of mindfulness-based cognitive therapy (MBCT) in 20 participants. This study reported comparatively longer duration of the improvement of symptoms in individuals given ketamine with MBCT than those receiving MBCT alone (34 days versus 11 days).

A comprehensive review article focussed on ketamine for PTSD was published in 2023. This review collated the results of several studies and reported a pooled analysis of the published data on ketamine. It found that overall there was evidence of reductions in PTSD symptoms with ketamine treatment, but significant variation between individual studies. This is likely due to the various outcome measures used by researchers to determine whether an intervention is beneficial, in addition to three papers using ketamine alone and only two using ketamine-assisted psychotherapy.

‘Classical Psychedelics’

The research focussed on classical psychedelics to treat PTSD is comparatively limited.

Psilocybin-assisted group therapy was studied in 18 men who were long-term AIDS survivors. It found that symptoms in keeping with PTSD declined following treatment and was sustained at three months. However, this study predominantly focussed on ‘demoralisation’ among participants and only three of eighteen participants met PTSD diagnostic criteria.

Some other studies focussed on depression and anxiety as their primary outcomes have indicated a possible promise for the treatment of PTSD, but they have not explicitly studied psilocybin in response to this.

Some researchers have used survey data or animal studies to focus on Ayahuasca/DMT and mescaline, but no comprehensive experimental data for humans has been published to date. This limited research is not included in this briefing but is summarised in another review article focussed on psilocybin and other classical psychedelics.

Regulation of psychedelic drugs used in medicine

Regulations vary for each psychedelic compound, and between the various jurisdictions where research is taking place.

In 2017, the FDA granted MDMA ‘breakthrough therapy’ status for the treatment of PTSD and is expected to make a decision regarding possible licensing in the near future. In June 2023, the FDA published guidance for clinical investigations regarding the use of psychedelic drugs. Organisations have placed official requests for MDMA to be licensed in the USA for the treatment of PTSD, and it is approved for use as a PTSD treatment in Australia.

Acknowledgements

POST is grateful to Dr Stephen Naulls, Clinical Research Fellow at POST, for researching this briefing.

POST would like to thank Basant Pradhan MD, Anthony Rostain MD, and Professor Irving Wainer, Cooper University Hospital, Camden, New Jersey, USA, who acted as external peer reviewers in preparation of this article.