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The Resurgence of Psychedelics in Mental Healthcare

written by breanne e. pirino phd Feb 19, 2024

Psychedelic drugs have been used across cultures and contexts for millennia. The indigenous peoples of the Amazon have long used ayahuasca for shamanic rituals, and some Native American groups have used peyote for thousands of years in religious ceremonies. Psychedelic drugs became of significant, though controversial, scientific interest for their therapeutic potential in the 1950s and 1960s, but interest eventually waned over the decades. As the psychedelic era of the 1960s and 1970s came to a close and the Drug Enforcement Administration’s classification of psychedelics as Schedule I drugs made them illegal (except in some religious contexts), interest waned in the therapeutic potential of psychedelic drugs.

Over the past several years, however, there has been a resurgence of interest in these drugs for the treatment of a variety of mental health conditions, such as treatment-resistant depression, anxiety, and post-traumatic stress disorder (PTSD). Currently, there are 475 clinical trials registered on ClinicalTrials.gov that claim to investigate the use of psychedelics, and a bill was recently passed in December 2023 by the United States Congress to fund further research into the use of psychedelics and other hallucinogenic drugs for the treatment of mental health disorders in military personnel. Some have even referred to this renewed interest as the “psychedelic renaissance.”

What are psychedelic drugs?

There is often some confusion regarding what drugs are classified as psychedelics, and people sometimes (incorrectly) use the terms “hallucinogen” or “psychoactive drug” interchangeably with “psychedelic.” It is important to note that psychedelics and hallucinogens are both types of psychoactive drugs. However, psychedelics are a specific subset of hallucinogenic drugs. That is, both of these drug classes can alter an individual’s mental processes, such as mood, perception, and cognition, but while hallucinogens are characterized by their ability to alter perception, or generate hallucinations, psychedelics are characterized by the specific receptors they target in the brain. Thus, while all psychedelic drugs are psychoactive, hallucinogenic drugs, only some hallucinogenic drugs are psychedelics.

Various drugs commonly referred to as psychedelics do not meet the criteria necessary to be classified as such. Here, we list some drugs that arepsychedelics and some that are not:

1. Psychedelics – Lysergic acid diethylamide (LSD), mescaline (peyote), dimethyltryptamine (DMT, an active ingredient in ayahuasca), psilocybin (magic mushrooms)

2. Other hallucinogens that are NOT psychedelics – Ketamine, salvia, atropine

3. Other psychoactive drugs that are NOT psychedelics or hallucinogens – 3,4-methylene-dioxymethamphetamine (MDMA, commonly known as  ecstasy)

How do psychedelic drugs work?

In the brain, psychedelic drugs exert their effects on the serotonin system, a neurochemical system that is involved in a wide variety of processes, including mood. Many people may be familiar with serotonin because this is the brain system targeted by a common class of antidepressant medications called selective serotonin reuptake inhibitors (SSRIs). While this class of medications works by increasing serotonin activity in the brain and improving depression symptoms in approximately 20% of individuals, the popular idea that depression is the result of too little serotonin is not universally supported by clinical evidence. Moreover, while these serotonin-boosting medications can be effective for some people, they generally take several weeks to improve symptoms and can have unpleasant side effects, due to the broad role of serotonin in the brain and body. 

Psychedelic drugs work a bit differently, though. Instead of broadly boosting serotonin signaling, they activate one particular type of serotonin receptor (there are many!), called 5-HT2A, and, interestingly, some antipsychotic drugs do the opposite and block this receptor. You can think of a receptor as a lock and the drugs that interact with them as a key. Psychedelics, for example, can act as the “key” that fits perfectly into the 5-HT2A ”lock,” allowing the key to turn the lock and open the door, which in this case refers to the alteration of cellular processes. On the other hand, antipsychotic drugs that block this receptor are like a key that does not quite fit. In this case, the key can go into the lock, but it cannot turn to unlock the door. Thus, antipsychotic drugs block the 5-HT2A receptors and prevent the right key (serotonin) from going into the lock and opening that door. However, unlike SSRIs, psychedelics only increase the activity of one very particular “lock,” the 5-HT2A.

After the psychedelic drug binds to the 5-HT2A receptor, a complex cascade of processes occurs, ultimately leading to enhanced neurochemical activity, structural changes in brain cells, similar to those associated with antidepressant effects, and changes in gene expression. Importantly, the receptors to which these drugs bind also exist outside of the brain, such as in the gastrointestinal tract, which can cause side effects commonly associated with psychedelic use, like nausea and vomiting.

Are there health risks associated with psychedelic use?

Psychedelics can also bind to other receptors, such as dopamine receptors and other serotonin receptors (5-HT2B and 5-HT2C), which can cause unfortunate and even dangerous side effects. For example, drugs that act at the 5-HT2C receptor have been found to suppress appetite, and those that act at 5-HT2B can cause life-threatening heart disease. Moreover, some of these drugs can interact poorly with certain medications. This raises serious concerns about the use of psychedelic drugs due to these risks.

 What are the clinical applications of psychedelics?

Studies have been conducted into the potential use of psychedelics for the treatment of depression, anxiety, cluster headaches, and anorexia. Many of the completed studies are early-stage investigations focused on safety and examining the effects in healthy individuals. There are, however, hundreds of clinical trials actively running or recruiting participants to study the possible application of psychedelics in anxiety, depression, bipolar disorder, autism spectrum disorder, post-traumatic stress disorder, and substance use disorders, among others. One completed trial, conducted by the Ross Laboratory at New York University found that psilocybin treatment reduced depression and anxiety in individuals with life-threatening cancers, and these reductions were found to be sustained almost 5 years later. At Yale University, the Bassir Nia Laboratory has registered a study to examine the potential therapeutic effects of DMT in individuals with alcohol use disorder. Interestingly, another study in Switzerland is investigating the use of LSD in the treatment of cluster headaches, indicating the broad range of disorders being targeted by psychedelic treatment. 

Conclusion

Investigating the therapeutic potential of psychedelic drugs, such as psilocybin, LSD, and DMT, is once more an active and exciting area of research. Early studies suggest that psychedelics may have profound effects on some mental health conditions,  and this renewed interest may inform the development of new, more effective medications.

 

Written by Breanne E. Pirino, PhD. 

Edited by Hash Brown Taha.

 

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