Psychedelic and Dissociative Drugs as Medicines

Two dissociative drugs are currently FDA-approved: ketamine, which is approved as an anesthetic, and its derivative, esketamine, for treatment resistant depression.¹ The FDA has also granted “breakthrough therapy” designation for two formulations of psilocybin being studied for safety and efficacy as a medical treatment for depression. The FDA also designated MDMA a breakthrough therapy to expedite research for it as a treatment for post-traumatic stress disorder.²

Technology such as brain imaging expanded scientists’ capacity to study psychedelic and dissociative drugs in the laboratory, stimulating a new wave of research in the early 1990s.³ Today, they are studying many of these substances to determine their potential therapeutic effects, along with appropriate dosages and the best way to deliver corresponding treatments, such as talk therapy.⁴ Areas of research include: 

Substance Use Disorders 

Researchers are studying psilocybin as a potential therapeutic for treating alcohol use disorder and for quitting smoking.^5,6 NIDA is also funding trials investigating ketamine-assisted therapy for cocaine and methamphetamine addiction. Another trial is investigating whether administering subanesthetic doses of ketamine during emergency care might help reduce drug use and suicide risk among people with opioid use disorder. 

Depression and Anxiety 

A number of studies are focusing on whether psilocybin may be an effective treatment for depression and anxiety.^7,8 Several studies have shown that ketamine can significantly improve symptoms in patients with treatment-resistant depression.¹

Post-traumatic stress disorder (PTSD) 

Researchers are studying MDMA-assisted therapy for people with severe PTSD.⁹

Anxiety Related to End-of-Life 

Studies are looking at whether psychedelics can reduce anxiety and depression in people with cancer and can promote well-being and quality of life.^10,11

Chronic Pain 

A few studies have indicated that the psychedelics psilocybin and LSD may have the potential to ease symptoms of chronic pain conditions such as cluster headaches, lower back pain, cancer-related pain and phantom limb pain.¹²

Psychedelic-assisted therapy—or ketamine-assisted therapy, if that substance is used—is when the use of psychedelic or dissociative drugs is integrated with other treatments, mainly talk therapy. Though more research is needed, scientists theorize that these substances promote brain changes that have the potential to promote healthy thought patterns,¹³ potentially supporting the effectiveness of talk therapy.

For example, some of these substances have mood effects that may boost the success of talk therapy. They may promote trust, sociability, and openness to suggestion; lessen anxiety; and reduce a person’s worrying or self-talk. These effects may also help people to work through challenging emotions or experiences with their therapist. Changing the patterns of a person’s brain activity may also disrupt habitual and potentially negative paths of thought and behavior,^3,14 helping people adopt new and more positive ways of thinking.^3,15 For more information, see “How do psychedelic and dissociative drugs work in the brain?”

A typical approach is to administer these drugs in one to three sessions, combined with counseling, in a relaxing setting designed to help the patient be receptive to new perceptions, thoughts, and feelings, including mystical-type experiences. However, only esketamine is FDA approved for therapeutic use to date.

Some people who use psychedelic or dissociative drugs report having a mystical experience, a change in perception that may include feeling a strong sense of awe and of unity with everything that exists. This new and potentially meaningful experience may inspire brain changes that may affect a person’s emotions, outlook and behavior.

Researchers are still unclear if it’s necessary to have a mystical experience—which also carries the risk of side-effects such as fear—for the drugs to work.¹⁶ Research in psilocybin-assisted therapy suggests that there is a correlation of mystical experience with positive outcomes for smoking, alcohol, end-of-life anxiety, and depression. But some laboratory research suggests that it is possible for psilocybin to have antidepressant effects without causing changes in consciousness or perception.¹⁷ Scientists are also researching substances that may be chemically similar to psychedelics that may have the same therapeutic benefits without these mind-altering effects.^18,19

Yes. More long-term, large-scale research is needed, but evidence so far suggests minimal negative health effects from supervised use of these substances, such as in clinical trials.²⁰ However, participants in these trials commonly report feeling fear, confusion or anxiety, and have had side effects such as nausea, vomiting, headache, fatigue, and high blood pressure.⁴ Further, psychedelic and dissociative substances can cause serious negative side-effects when used outside of a clinical setting. For more information, see “Are psychedelic and dissociative drugs safe?”

Some people report “microdosing” psychedelic drugs, typically LSD or psilocybin. Microdosing refers to regularly taking these drugs in very small amounts, typically one tenth to one twentieth of a typical recreational dose. People report that they microdose to lessen mental health symptoms such as depression and stress, improve productivity, and ease pain. However, research to date has not established whether microdosing is safe or effective.^21,22

Additional research on the safety, efficacy, and mechanisms of action of psychedelic or dissociative substances is critical. However, there are multiple challenges to conducting this research, including:

Establishing Research Controls 

A person’s personality and expectations of the experience before taking a psychedelic drug—called the mindset or “set”—and the surrounding people and environment—called the “setting”—play a role in how they respond to it.^2,3 Scientists are trying to establish the best clinical trial protocols for testing how these drugs work in people. They must assess the role of set and setting and the importance of the psychedelic or mystical experience that may accompany use of the drugs. They must also figure out how to measure and control placebo effects, which is when a person’s expectations of how a drug will work influences their response to it.²³ Because the effects a psychedelic or dissociative drug are so distinctive, it is difficult to find another substance to mimic its effects in a controlled clinical trial.

Challenging Experiences for Participants 

Some people who take these drugs have mind-altering experiences that may cause fear, anxiety or paranoia. In one study of high-dose psilocybin effects in 18 adults, 94% reported a long-lasting and meaningful experience up to a year later, but 39% also reported extreme fear during the treatment session.²⁴

Mental Health Issues 

There is some evidence that psychedelic drugs might bring about or trigger schizophrenia-like illness in people with predisposing factors, but little evidence that they cause long-term psychiatric problems for most people.²⁵ As a precaution, participants with previously diagnosed psychosis or bipolar disorder, and sometimes other mental illnesses, are excluded from participation, but this may limit knowledge on the drugs’ real-world effects and safety. For more information, see “What is the Relationship Between Psychedelic and Dissociative Drugs and Mental Illness?”

• NIDA conducts and supports pre-clinical (laboratory) research to better understand how psychedelic and dissociative drugs affect cells and activity among different regions of the brain, and how any brain changes affect people’s health, mood, and perception.
• NIDA also supports clinical research on these substances’ therapeutic potential, particularly for tobacco cessation and substance use disorders, as well as studies on their use and health effects in real-world settings.
• The Institute is also supporting research into substances that are chemically similar to psychedelic and dissociative drugs and that may have therapeutic effects, but without side effects like hallucinations, altered perception, physical discomfort, or other negative health effects.