Can Psychedelics Help Treat PTSD?

Older generations may remember that, in the early 1960s, psychedelics like LSD were legal in the US. But in 1970, the U.S. Drug Enforcement Agency made most psychedelics illegal under federal law when the agency categorized them as Schedule 1 drugs. These are drugs defined as not having any accepted medical use and having a high risk of being abused.

But times are changing. Since the 1990s, researchers have been allowed to once again investigate psychedelic drugs’ potential for treating serious mental health disorders like post-traumatic stress disorder (PTSD).

The most commonly studied psychedelic drugs are psilocybins, known as magic mushrooms, and MDMA (3,4-methylenedioxymethamphetamine), commonly known as ecstasy or molly. These two types work differently. MDMA stops serotonin (5-HT), dopamine (the “feel good” hormone) and norepinephrine from being reabsorbed into the brain, leaving someone with higher levels. It doesn’t alter the brain, but it promotes the good feelings. Psilocybins, however, work by disrupting how different regions of the brain communicate, altering perception.

The drug ketamine is often grouped with psilocybin and MDMA, but it doesn’t fall under the psychedelic umbrella. “Ketamine is a dissociative,” said Manoj Doss, PhD, a research fellow in the Department of Psychiatry and Behavioral Sciences at Dell Medical School, University of Texas at Austin. “Its hallucinogenic effects have a similar mechanism of action as PCP, nitrous oxide and dextromethorphan.” Dissociative drugs affect the brain differently than psychedelics.

Psychedelics vs. Antidepressants

Why are people considering psychedelics—or researching the drugs—today? Currently, antidepressants—such as sertraline (Zoloft), paroxetine (Paxil) or venlafaxine (Effexor)—are often prescribed to treat PTSD. The first two are SSRIs (selective serotonin reuptake inhibitors). Venlafaxine is an SNRI (serotonin-norepinephrine reuptake inhibitor). But these medications are not ideal for everyone. Typically, they only help about half of those who need them, and it can take weeks before there are signs of improvement for those they do help. They can also cause disturbing side effects, and it can be difficult to stop using them.

It might take only a single dose of psilocybin to treat PTSD, with the effectiveness lasting for several years.

Jennifer Mitchell, PhD, professor of neurology in the School of Medicine at the University of California, San Francisco, and deputy associate chief of staff for research and development at the San Francisco VA, explained that medications like SSRIs and SNRIs were developed to treat depression and anxiety—and they don’t always work well for people with PTSD. The idea behind using them is that a lot of people with PTSD also have depression and anxiety. So, for some of these individuals, the medications may improve their quality of life, but they don’t have an impact on the PTSD. The antidepressants blunt the emotional part, but the cause of the PTSD itself has not gone away.

A 2023 study led by Dr. Mitchell found that over 85% of participants who had MDMA-assisted therapy for moderate-to-severe PTSD had a significant improvement in their symptoms, compared with those who didn’t have the treatment (placebo group). By the end of the study, over 70% of those with PTSD no longer met the criteria for having the disorder, compared with 47% in the placebo group.

Dr. Mitchell also pointed out that someone can be on antidepressants for years but that with a psychedelic, “it can be one and done.” It might take only a single dose of psilocybin to treat PTSD, with the effectiveness lasting for several years.

Your Brain on Psychedelics

The best way to explain how psychedelics work is to compare them to antidepressants and show you how both affect the multiple different types of serotonin receptors in the brain. Serotonin is a chemical that sends messages between nerve cells. It’s responsible for many body functions at different types of receptors, ranging from mood and sleep to digestion and sexual desire.

When you take an SSRI or SNRI, the available serotonin increases, which is why these drugs can help manage depression. But because they aren’t targeted to any particular serotonin receptor, this increase can result in side effects, such as vomiting, diarrhea, insomnia, sexual dysfunction and weight changes. These effects can be so uncomfortable that people may stop taking the medication.

Though the exact ways psychedelics work to treat trauma are not yet fully defined, research has highlighted some important mechanisms. Psychedelics also work on serotonin, but in different ways, so they may avoid some of the bothersome SSRI-related side effects.

“MDMA is an indirect agonist that leads to greater release of serotonin and blocks its re-uptake,” said Brandon Weiss, PhD, assistant professor at the Center for Psychedelic & Consciousness Research at Johns Hopkins University in Baltimore. MDMA broadly acts on serotonin in certain brain areas while avoiding effects at other receptors that drive bothersome side effects, such as 5-HT3 receptors, which could cause nausea, and 5-HT1A receptors, which could result in tremors, delusions and other psychiatric symptoms.

“Classic psychedelics such as psilocybin and LSD directly activate specific serotonin receptors, most notably serotonin 2A,” Dr. Weiss said. “This is what’s associated with the iconic classic psychedelic experience.”

In addition to the serotonin, the drugs also promote a greater global connectivity in the brain—how different parts of the brain talk to each other in a system called the default mode network. The default mode network is a group of interconnected brain regions that is most active during rest, self-reflection and internally focused thought, and daydreaming.

But the default mode network is just that: It tends to operate by default. According to a 2024 study, psilocybin rewires this communication, allowing parts of the brain that don’t usually communicate to start talking to each other.

This change in operations can also foster change in thinking, resulting in more flexibility and adaptability in how patients think about major life events. This can decrease negative moods and change how the brain responds to different stressful situations.

And, importantly, these changes can last for weeks because of the effects of neuroplasticity: The psychedelic may prompt the brain to form new and different connections over the weeks that follow treatment. Some have theorized that this period of heightened plasticity can “reopen” critical periods of brain development, allowing for easier learning of new, healthier patterns.

These effects differ from antidepressants. “Historically, many have suggested that [taking a psychedelic] can be a sort of a foray into the dark side of your mind, into your memories and the impact that previous experiences have had on your life,” Dr. Mitchell explained. “That foray helps you acknowledge and then potentially let go of some of the previous trauma.”

After the treatment, many people say they feel a weight has been lifted. “I think this is why it’s garnering so much attention from [military] veteran groups,” Dr. Mitchell said.

“For example, you’re not just medicating somebody so that they can sleep. You’re helping them address whatever it is—the fear, the shame, the anxiety—and that’s allowing them to have much higher quality of life,” she explained.

“Historically, many have suggested that [taking a psychedelic] can be a sort of a foray into the dark side of your mind. … That foray helps you acknowledge and then potentially let go of some of the previous trauma.”

Dr. Mitchell compared this to stirring a pot: “You’ve got a bunch of stuff hidden in the corners and crevices of that pot, and [the psychedelics are] just giving it a good stir. So it brings all this subject matter up that perhaps was sort of tamped down and hidden.”

Don’t Take Psychedelics Without a Doctor or Therapist

There have been quite a few articles about psychedelics in the news over the past few years. Americans, including war veterans, sometimes travel to other countries where they can legally try the therapy—or they may try it at home after buying the drugs from street dealers.

But using psychedelics to manage a mental health issue is not a do-it-yourself project. It can be very dangerous without appropriate supervision. In the clinical environment, people have access to safe and reliable dosing. There is quality assurance, so individuals know they’re getting the exact drug. The number of doses is limited, and there is medical support before, during and after treatment, such as preparation for the treatment, medical monitoring of vital signs during treatment and emergency intervention if needed, and critical therapies following the treatment to maximize potential benefits during the period of increased neuroplasticity.

Perhaps most importantly, there is a connection and trust that patients have with their doctor or therapist. In an unsupervised setting, friends and family generally don’t have training in what to do if something goes wrong. Dr. Mitchell remembers hearing stories in the 1970s about people who used these drugs and thought they could fly, jumping out of windows. While this isn’t common, bystanders aren’t usually equipped to deal with these situations if they do happen.

Dr. Doss also pointed out that while most people who take these drugs don’t react negatively, there are those for whom psychedelics aren’t safe, including people with a history of schizophrenia or bipolar disorder.

The drugs are not safe for people with heart issues either—and some people may not know ahead of time that they have a heart problem. Before Dr. Doss’ team gives study participants psychedelics, “we do tests like an EKG to check if there’s anything abnormal going on with their hearts,” he said.

Long-term negative effects from psychedelics aren’t common, but they can happen. People might experience continued mood fluctuations and symptoms of depression that don’t go away, for example. The rate of these effects seems to be higher when the drugs are taken in an unsupervised setting. A 2023 study found that of 2,300 people who took psilocybin in an unsupervised setting, 11% reported serious and lasting negative effects. However, according to Dr. Weiss, the number is lower in laboratory and clinical settings, more like 0% for healthy participants and 4% for participants with previous psychiatric disorders, as reported in a 2024 study from the Johns Hopkins University Center for Psychedelic and Consciousness Research.

Another thing to consider when taking psychedelics for mental health issues is that they’re usually not a standalone treatment. They are more effective if combined with psychotherapy so that the person is supported when they feel intense emotions or memories. One study showed that psilocybin can help patients feel closer to their therapists. The improved relationship is known to lead to better results in therapy.

Dr. Mitchell explained further, saying that the psychedelic drug trials involve preparatory psychotherapy work to help participants get ready. “Then after you get the psychedelic, there’s the integrative work, more psychotherapy. It sort of bookends the psychedelic experience. It’s really important that the participant knows how safe they are and how well-attended to they are.”

More Research Needed

In August 2024, the U.S. Food and Drug Administration (FDA) rejected an application to approve MDMA to treat PTSD that has not responded to other treatments. The agency’s reasoning was there was insufficient information about the drug’s safety and efficacy. But researchers haven’t given up. They’re working on new, more robust clinical trials to show how psychedelics can be effective in the right circumstances. Right now, psychedelics can only be obtained legally in the U.S. through research programs.

Other researchers are looking in a different direction, working to develop compounds that mimic the results of psychedelics. Dr. Doss explained that researchers led by David E. Olson, PhD, at the University of California, Davis, are working on novel compounds that produce therapeutic effects comparable to first-generation psychedelics but without the subjective hallucinogenic effects. Other researchers are looking at tabernanthalog (TBG), which may have therapeutic potential.

Visit ClinicalTrials.gov if you are interested in clinical trials with psychedelics.