March 26, 2024 -- If you think of LSD as a dangerous illegal drug without any legitimate medical uses, think again.
LSD is still illegal, but recent studies show that this powerful compound is not usually dangerous if taken under controlled circumstances and that it has the potential to help some people with serious mental conditions.
The FDA recently designated a form of LSD as a breakthrough therapy to treat generalized anxiety disorder. This decision was based partly on a rigorously designed drug trial in which about half of the patients on the drug got significant relief from the condition.
The FDA’s breakthrough therapy designation speeds up the development and review of drugs intended to treat a serious condition where early evidence indicates the drug may be better than available therapies. The acceleration of this process may well lead to FDA approval of LSD for treating generalized anxiety disorder within the next few years. That approval would automatically legalize the clinical use of LSD.
Moreover, two other psychedelic drugs, psilocybin (found in certain mushrooms) and MDMA (better known as the club drug “ecstasy”), have also received breakthrough therapy designation from the FDA and are further along the road to approval for treatment-resistant depression and posttraumatic stress disorder (PTSD), respectively.
In the LSD trial conducted by a company called MindMed, the 194 volunteers, who ranged in age from 18 to 74, ingested a purified, stable version of the compound in one of four different doses or received a placebo. The single LSD experience resulted in clinically meaningful improvements on the Hamilton Anxiety Rating Scale -- a scale that is commonly used in clinical trials to evaluate the effectiveness of anxiety medications and treatments -- at week 4. At week 12, 48% of the people who received 100 micrograms of LSD saw “remission” of their anxiety, and 65% of the people in the study responded clinically to the drug. The average reduction in anxiety shifted the 100-microgram group from “markedly ill” to “borderline ill” on a different rating scale.
How could this be? Scientists still don’t understand exactly how, but an extensive body of research on psychedelic drugs suggests that patients who take them undergo a kind of mental “reset” that is often accompanied by mystical feelings.
In Michael Pollan’s book How to Change Your Mind, he cites researchers who believe that the people who have the most to gain from psychedelic drugs are those who have the kinds of disorders characterized by mental rigidity, such as alcohol and tobacco addiction, depression, and obsession. Somehow, the experience of opening themselves up to drug-induced perceptual shifts and a loss of ego helps them break loose of these mental restraints.
The Research Is Progressing
Collin Reiff, MD, a clinical assistant professor of psychiatry at NYU Grossman School of Medicine, welcomed the FDA’s breakthrough designation for LSD.
“It’s very exciting,” he said. “For one, it draws people’s attention to the efficacy of these compounds, which will get people more interested in the research. Hopefully, it will lead to more grants being approved by the NIH and other government organizations. The designation is essentially a catalyst that facilitates the research to help us understand a new compound, and it may be a new treatment for generalized anxiety disorder.”
MindMed’s next step is to conduct what is known as a phase III trial to demonstrate LSD’s safety and effectiveness for GAD, using a larger group of patients. That study is set to begin later this year, said Daniel Karlin, MD, assistant professor of psychiatry at Tufts University School of Medicine and chief medical officer of MindMed.
Meanwhile, Reiff noted, the companies seeking FDA approval for psilocybin and MDMA have made progress since getting their breakthrough therapy nods a few years ago. MDMA for PTSD has been tested in two positive phase III trials, and a new drug application has been submitted to the FDA. Compass Pathways, the firm studying psilocybin for depression, also has two phase III trials going, and the results from one of them are expected this summer, he said.
“The challenge isn’t necessarily in the research,” Reiff said. “The challenge is that, if the results continue to be positive, how do you make these compounds available in a safe manner on a wide scale? How do you ensure that providers are well trained, that there’s equitable access to care? Are insurers going to reimburse this? There are a lot of things to figure out.”
Psychedelics in Psychotherapy
One of the biggest questions, Reiff stated, is whether and to what degree psychedelic drugs can be used to complement traditional psychotherapy. Since the revival of this kind of research in recent years, and going back to earlier clinical studies, the standard protocol has been to involve trained psychotherapists in the intervention. The three-part approach includes patient education and preparation for the psychedelic treatment, the intervention itself, in which the therapist may be present, and a post-trip “integrative” session in which the patient and the therapist discuss what the person has learned about himself or herself from the experience.
In contrast, the MindMed trial dispensed with psychotherapists after they had referred patients to the study. Noting that other studies have not rigorously tested the value of using psychotherapists in psychedelic interventions, Karlin said that his company set out to test the “drug-only effect.”
Patients in the trail received education before their treatment. When they took the LSD, a pair of non-therapist monitors were in the room with them to provide support and assistance if they had difficulties during their trip. Afterward, Karlin said, “the patients came back to the clinical site for assessments, and as a component of that process, they were able to ask questions about their session.”
Karlin said that the phase III trial will be similarly designed, and he stressed that the drug company wants to find out whether therapists are really needed to get significant benefits. If LSD is approved by the FDA for general anxiety disorder, he said, MindMed intends to make the drug available to both psychotherapists and non-therapists “who want to be able to use this outside the context of psychotherapy.”
Reiff said more research is needed to determine whether psychedelic interventions can have better results if psychotherapists are involved in the treatment. Nevertheless, he stressed the importance of proper training for the guides of patients who receive psychedelic drugs.
“The more training, the better. If someone has a panic attack or a challenging experience, that can be turned into a positive outcome, or we can learn a lot from it. But you need someone there who is comfortable guiding the patient through that.”
Why the Environment Must Be Controlled
One point on which Reiff and Karlin agree is that for psychedelic drugs to benefit patients’ mental health, they must be taken in a highly controlled environment.
In the clinics where these experiments are conducted, patients normally lie down on a couch, and they may wear dark eye shades and listen to carefully programmed music on headphones. The idea is to let them focus on exploring their inner geography rather than having to deal with the external environment, which can seem frightening or bizarre.
“Mostly what people describe doing in these sessions is a self-exploration process, and they look at their relationship to their anxiety,” Karlin said. “So the point of being in a comfortable place is not to have anything that distracts from that internal process. We want people to know that they’re safe because LSD can be unnerving and confusing, and we want to have trained monitors there, and we want them to be comfortable.”
Will the FDA Open a Pandora’s Box?
One reason why much less research has been done on LSD than on psilocybin or MDMA is the baggage that LSD carries from its brief but notorious period of widespread usage in the 1960s. But before the drug became illegal in 1968, there had been many studies of its potential clinical uses in the 1950s and early ‘60s. Among other things, researchers had documented the benefits of LSD and psilocybin in treating alcoholism, anxiety, and depression.
American society turned against LSD after Timothy Leary, a Harvard University professor who conducted psychedelic experiments and was fired after offering LSD to his students, began proselytizing about the supposed benefits of “acid” to young people at large, recalls Pollan in his book. Bad trips, psychotic breaks, flashbacks, and suicides by acid trippers got a lot of publicity, and the scientific establishment turned against psychedelics. Nevertheless, a small underground carried on psychedelic research, which led to the studies being conducted today.
The checkered history of psychedelics raises the question of what might happen in the larger society if the FDA approves LSD for treating specific mental health conditions. Already, a number of unregulated clinics are offering psychedelics as part of clinical trials or a form of ketamine that is FDA approved. And there are still people using psychedelic drugs illegally.
Karlin said he isn’t worried about the potential for abuse, partly because the kind of people who seek help with their anxiety and depression are not those who would seek illegal “street” drugs. Moreover, he noted, people cannot become addicted to LSD.
“While there’s always the potential for substance misuse or abuse, this drug does not induce the kind of usage patterns that are associated with other drugs that create a dependence.”
Reiff views LSD, psilocybin, and MDMA as new tools for psychiatrists and psychotherapists to use. “If we can make it available to people for whom other treatments aren’t working, that’s a wonderful thing.”
But he cautions that things could get out of control, as they did before.
“We will want to make sure that practitioners are well trained, so there are no adverse outcomes. And we want to make sure that we don’t get this wrong. We got it wrong in the 1960s. The drugs hit the mainstream well before they hit clinics. All it takes is some bad headlines, and that will crush the whole thing. So let’s take it slowly in little steps.”