Why Psychedelic Drugs May Become a Key Treatment for PTSD and Depression

While it has been referenced throughout history, notably in World War I, post-traumatic stress disorder (PTSD) as we know it today was first described as a distinct diagnosis after World War II among individuals who had survived Nazi concentration camps. The patients came home experiencing anxiety, depression and nightmares. They were frequently startled. In a paper synthesizing some of these early observations in 1963, psychiatrist Paul Chodoff wrote, “Perhaps the most nearly universal and most characteristic symptom was an obsessive rumination state in which the patient was more or less constantly preoccupied with recollections of, and ruminations about, his experiences during persecution, and about family who had died or been killed.” Psychiatrists tested a variety of treatments from drugs to exposure therapy for what Chodoff referred to as “concentration camp syndrome.”

More than 70 years after the initial observations, patients diagnosed with PTSD today still have few treatment options; most likely they will be prescribed a combination of therapy and antidepressant drugs. For some patients, these treatments make a positive difference in their quality of life, but many others continue for years without relief from nightmares, flashbacks, severe guilt and anxiety that can come with the condition. According to the U.S. Department of Veterans Affairs, about 6 percent of Americans will be diagnosed with PTSD at some point in their lives, whether they served in the military or not. While PTSD is often associated with traumas from war, it can also refer to symptoms after other traumatic experiences such as being involved in a serious accident, witnessing death or injury or being a victim of sexual assault.

Patients and scientists have longed for more options. “How many drugs are registered [in the U.S. and Europe] for PTSD?” asks Eric Vermetten, a psychiatrist at the University of Leiden in the Netherlands and a military veteran himself. “The answer is two. And when were they registered? 21 years ago. That’s 21 years, we haven’t had any new drugs registered for PTSD.”

But maybe the path forward is one that was abandoned decades ago. In the 1960s, psychiatrist Jan Bastiaans, also at the University of Leiden, treated concentration camp syndrome with the psychedelic drugs LSD and psilocybin (an active ingredient in magic mushrooms) because he thought that in their minds, these patients were still in the camps. He believed “the LSD or psilocybin opened them up to the extent that they can liberate themselves,” explains Vermetten. Other psychiatrists and regulators believed the therapy was too dangerous, even if it did have therapeutic potential. Despite the criticisms, Bastiaans continued treating patients with the drugs until his retirement in 1985, but by that time, he was nearly alone in his opinion of their therapeutic value.

Outside of the Netherlands, resistance was even stronger. In 1968, the United States outlawed LSD possession, categorizing the hallucinogen as a Schedule 1 drug. Two years later, it prohibited possession of psilocybin. MDMA (also known as ecstasy or Molly) lasted a bit longer, having been synthesized as a potential therapeutic in 1912. In the 1970s, some psychiatrists had started studying it as a potential therapy again, but it was simultaneously being used as a party drug and was banned by the U.S. in 1985.

Now, the drugs are gaining acceptance again as patients and doctors have expressed frustration with current treatment options.

Over the past few years, studies have suggested that just a few doses psilocybin or MDMA combined with therapy may help patients with PTSD or other mental illnesses. The results have been promising enough that the U.S. Food and Drug Administration (FDA) has designated both treatments as breakthrough therapies—a priority status given to promising drugs designed for an unmet need. The company developing the drug receives ongoing support from the FDA throughout the clinical trial process and priority review when the data is available. MDMA has received breakthrough status for treating PTSD while psilocybin has received the designation for treating treatment resistant depression.

“When I started [researching psilocybin] the idea that you could give a single dose of a drug and people would feel better almost immediately, and then feel better for months on end. I wouldn't have thought that was possible,” says Joshua Woolley, a psychiatrist at the University of California San Francisco who studies psilocybin. “But now it’s exploding…there’s a lot of momentum.”

How It’s Thought to Work

The common category of antidepressants often used to treat PTSD now are Selective Serotonin Reuptake Inhibitors (SSRIs). These drugs work by increasing the amount of serotonin available to bind to serotonin receptors in the brain. Serotonin is a neurotransmitter that helps regulate your mood. When more serotonin binds to specialized receptors, it may help patients feel more stable and content.

Psilocybin also acts on serotonin receptors, but scientists say the drug’s impact reaches far beyond serotonin. They believe that the drug actually alters the way neurons connect to one another. “We're talking about a different mechanism of action that these drugs have compared to the old serotonergic compounds,” says Vermetten “The mechanism action doesn't rely on one molecule.”

Many patients prescribed antidepressants experience a range of side effects from upset stomach to insomnia. One of the reasons that psychedelic therapies are so appealing is that they’re thought to work with only a few doses—limiting the risk of side effects.

Woolley explains that the psychedelic drugs seem to induce a state of plasticity that can make it easier for people to rewire neuronal circuits and learn new things, like they did when they were kids, for example. That provides the opportunity for therapy to be especially effective. Patients are more likely to embrace new connections and ways of thinking during their treatment.

Additionally, Rakesh Jetly, chief medical officer of Mydecine, a company developing psychedelic medicines, and a veteran of the Canadian army, says, brain imaging studies have shown that the drugs can induce changes in a network of cells that normally helps us understand who we are and where we are in time and space, called the default mode network. The disruption of this circuit may be behind the symptoms of many PTSD patients who experienced trauma in war. When an individual feels scared, this is the part of the brain that tells them, “Hey, man, you’re okay. You’re not [at war] in Rwanda anymore. You’re not [fighting] in Afghanistan,” explains Jetly. However, if the default mode network isn’t working properly, the person may have difficulty recognizing that they’re no longer in danger.

What the Experience is Like

Despite experimenting with different doses and treatment plans, most psychedelic treatment programs operate similarly. Prior to receiving any doses, a patient will meet with one or two therapists or guides—not necessarily doctors or psychiatrists—trained to help them through the experience. These experts will explain how the treatment sessions will work and take time to discuss the individual’s struggles and goals prior to treatment.

Psychedelics usually take 20 to 40 minutes to kick in, then the medicine lasts around six hours. During that time some patients listen to music or talk to the therapists. They may feel introspective and relaxed. They also might hallucinate. Some patients may experience a “bad trip” or frightening hallucinations. Therapists are trained to help patients manage any fear or paranoia that arises. A treatment regimen may include one or several days of dosing, but it doesn’t end there. “What’s really unusual about these treatments in particular is that it’s not just giving people the drug,” says Woolley. “Millions and millions of people use psilocybin or magic mushrooms and all those people don’t get better.”

“And so what most people think is that well, that probably means that it’s something about how it’s given.” Woolley explains that setting matters. Patients mentally prepare for the experience and go through it in a calm and familiar environment, with therapists they trust, rather than surrounded by concert-goers they haven’t previously met, for example.

That practice is different from the treatment most patients are likely to be familiar with—cognitive behavioral therapy (CBT)—a type of therapy designed to help people identify and change negative thought and behavior patterns. “Anybody trained to be a therapist from like 1980 on has been taught to do this very directive psychotherapy, a CBT approach. ‘We will talk about this. We're going to learn this skill. How did it go? When you go home, we want you to do this homework,’” says Jetly. But some scientists think that approach doesn’t make the most sense with psychedelic treatments. Jetly believes the therapy should be directed more by the patient than the therapist, leaving the individual free to make associations between different experiences they may not have previously recognized.

In addition to a variety of doses and formulations, different trials are testing different therapeutic approaches. For example, the therapist’s main goal could just be to guide the experience and keep the patients safe since patients could experience psychoses or behave erratically. Jetly believes therapists should help guide patients as they discuss whatever comes to mind, but not insist on focusing on specific goals like they might during CBT. “There’s no right and wrong, but you’re hoping that with the medicine, and after the experience, that they’ll be able to bring up stuff that was otherwise painful and maybe make some connections.” That could help them better understand themselves and make sense of their experiences. The most important part, says Vermetten, is that therapy continues after the psychedelic treatment. “The drug is the catalyst. The therapy is not [done] when you're done with the two sessions of psilocybin,” he says. At first, they’ll process what they felt during the treatments, but Vermetten says many patients will continue to see their therapists to discuss both the experiences during the treatment and any continuing effects from their trauma.

Still, Woolley says, determining the best type of therapy and who is most qualified to provide it is an important challenge in the field. While the drugs aren’t considered addictive and most known side effects wear off within hours, being under their influence can make people especially vulnerable. “How is this going to be regulated?” he asks. “If you give a drug that may enhance suggestibility, it's a pretty profound power that could be used for nefarious purposes or inadvertently used for nefarious purposes.” A therapist might be able to convince someone to do something they wouldn’t otherwise do. For example, a STAT investigation suggests that one therapist exploited an elderly Holocaust survivor to the tune of $4,000,000 as he underwent psychedelic treatment. The therapist, with whom he was romantically involved, may also have offered to help him end his life after he expressed suicidal thoughts, according to the article.

Both psilocybin and MDMA remain illegal in the U.S. at the federal level, though several cities have moved to decriminalize psilocybin and Oregon has taken to building its own set of regulations around the drug’s use. Over 200 clinical trials are registered on clinicaltrials.gov to test the effects of psilocybin or MDMA on conditions like PTSD, major depressive disorder and alcohol use disorder, but experts emphasize that it’ll still take time before the medicines are widely available. “We want the FDA to recognize these as safe and effective treatments,” says Jetly. “So we're going to demonstrate the safety and efficacy of these treatments.”