(editorial and research assistance provided by Amanda J. Lee)

With the resurgence of scientific interest into the healing properties of psychedelics, current studies are investigating potential therapeutic breakthroughs in the treatment of substance use and mental health disorders. The landscape of addiction treatment faces new challenges, as evidenced during the Covid pandemic.[1] With dual-diagnoses on the rise, promising new treatment modalities are needed more than ever.

Psychedelics include plant-based hallucinogens such as ayahuasca (a South American psychoactive brewed drink used both socially, ceremonially, or as shamanic spiritual medicine among the indigenous peoples of the Amazon basin), psilocybin (more commonly known as “magic” mushrooms) and mescaline (present in certain cacti), as well synthetics such as MDMA, ketamine and LSD (lysergic acid diethylamide, made from a substance found in ergot, a fungus that infects rye grain).

A consortium of UCSF researchers—headed by psychiatrist and researcher Dr. Joshua Woolley—have recently launched the Translational Psychedelic Research Program (TrPR, pronounced “tripper”) to conduct clinical studies in Psychedelic-Assisted Therapy (PAT)—a therapeutic practice that involves ingestion of a psychedelic drug.[2] Clinical trials have shown that when carefully selected patients take a prescribed psychedelic in a monitored setting, they can have a medically safe experience, which can create profound, durable psychological and behavioral change.[3]

Researchers nationwide join UCSF in diligently working to advance medical knowledge about psychedelics as a treatment method for such conditions as eating disorders, bipolar depression, chronic back pain, anxiety, PTSD, SUD, and end-of-life distress.

Beginning in the 1960s, psychedelics became the drug of choice for the non-conformist, anti-authority counterculture youth. “Turn on, tune in, drop out” was the rallying cry spoken in 1967 by psychedelic poster child, Dr. Timothy Leary at the Human Be-In, a musical festival of 30,000 hippies in Golden Gate Park in San Francisco. Leary—psychologist, scientist, professor, and avid LSD user—was also an early pioneer of advocating LSD for therapeutic use in psychiatry. His deceptively simple phrase urged people to reject the status quo and seek a spiritual path through psychedelics.

In 1970, President Nixon signed the Controlled Substances Act into law, classifying all psychedelics as Schedule I drugs with no accepted medical use. This designation effectively prohibited research for decades. Yet prior to this, in the 1950s, many clinical studies with psychedelics had been conducted.

Though the road to legalization is a byzantine maze, some psychedelics have been made legal: in 2023, Oregon became the first state to decriminalize psilocybin for use as a treatment option for mental health conditions at licensed service centers under a therapist’s supervision. According to the Psychedelic Medicine Association, psychedelics that will be most readily available as medicines now or soon include ketamine—widely legal for medicinal purposes; MDMA (“ecstasy”)—recently completing Phase III Trials and awaiting FDA approval; and psilocybin—currently in Phase III Trials, having been granted “Breakthrough Designation” from the FDA.[4]

When Albert Hofmann discovered LSD in 1943 while attempting to synthesize a derivative of ergotamine for migraine headaches, little was known about its chemistry or neurobiological effects on the brain. But recent scientific advances allow us to better understand how this drug group works and serve as tools for the study of the brain directly applicable to SUDs and mental health problems.

Psychedelics such as psilocybin, dimethyltryptamine (DMT) found in ayahuasca, and mescaline have an ancient history of medicinal use in indigenous cultures.[5] However, the understanding of their mechanism of action is quite recent. Those psychedelics share a structural similarity to the LSD molecule and act as agonists at the 5-HT2A serotonin receptors, cellular proteins that play a role in cognitive flexibility.[6] These receptors have an activating effect on subcortical neurons, producing an increase in neuroplasticity mediated by Brain Derived Neurotrophic Factor (BDNF) in the ventral tegmental area (VTA.)[7]

Subcortical structures are a group of diverse neural formations deep within the brain which include the diencephalon, pituitary gland, limbic structures and the basal ganglia, and are involved in complex activities such as memory, emotion, pleasure, and hormone production.[8] This discovery of the effects of LSD on the brain’s serotonin receptors triggered the modern era of psychopharmacology.

Studies indicate that administration of 5-HT2A receptor agonists through psychedelics can be used as effective therapy to treat SUDs and comorbid mental health disorders through their stimulation of BDNF, which assists with the regrowth of atrophied neurons seen with such chronic disorders.

A recent placebo-controlled study in Brazil showed that ayahuasca regulates the stress response in patients—particularly at higher dosages with rapid drops in depression. During the study, ayahuasca stimulated an increase in BDNF-blood levels, with lower increases in cortisol. This increase in neurotrophic factors helps to grow atrophied subcortical dendrites and readjust the stress response, reducing brain inflammation. Higher levels of BDNF brought about a better clinical response. Large reductions in such neuro-inflammation were related to lower depressive symptoms with no evidence of toxicity after the acute dose of ayahuasca.[9] In another study involving patients suffering from life-threatening cancer, using plant-based psilocybin mushrooms provided substantial relief and sustained decreases in depression.[10]

Misusing psychoactive drugs, such as methamphetamines and heroin, can impair a person’s subcortical learning mechanisms. Continued misuse can produce an abnormal augmentation in the representative, emotional information related to aversion.

At times, those who suffer from addiction and PTSD can experience free-floating fears that arise even in the absence of triggering external environmental factors. Mood disorders also can develop, such as depression, and/or non-contextual fears, leading to a repeat of the addiction cycle.

Psychedelic studies of trauma have shown that trauma can affect 5-HT2A receptors through inhibition, allowing the brain to bury the emotion in its subcortical regions. This leads to the traumas being repressed within the primitive areas of brain—referred to by therapists as the “Trauma Cone.” This Trauma Cone leaks stress hormones which cause emotional distress and cravings, triggering a relapse to SUDs in genetically predisposed individuals. For the person with an SUD, the craving response, neurochemical in nature, serves as a signal to use an addicting drug, initiating the classic cycle of intoxication, withdrawal, and craving. Since psychedelics have the power to dysregulate the brain,[11] this disruption in the relapse cycle—particularly with individuals who are prone to return to use and have high psychiatric comorbidity—allows for the creation of healthier neural connections, replacing old patterns with new pathways in brain circuitry—a key to obtaining therapeutic results.[12]

Fundamental to the therapeutic benefits when using psychedelics include the creation of the appropriate “set and setting.” “Set” refers to a person’s mindset when taking the psychedelic, whereas “setting” refers to the physical environment. Within their psychedelic program, UCSF researchers found that a traditional white hospital room proved inhospitable to the mind-altering effects of the drugs. The sterile environment was not conducive for the brain’s healing experience, so they created a more supportive space for study participants that was colorful and cozy.[13]

As part of a carefully curated atmosphere, music plays a significant role in psychedelic therapy, as it enhances the physiological benefits of psychedelic treatment. Neurobiological studies have found that psychedelics alters the brain’s perceptions of music by activating neuronal channels, making music more soothing. This in turn relaxes the patient, deepening their experience, thereby creating long-lasting effects. Research has also indicated that playing different forms of music during the psychedelic experience helps facilitate hallucinatory visions that are beneficial in dealing with a range of pathologies including PTSD and depression.[14]

Psychedelic therapy remains controversial in 12-step support programs such as Narcotics Anonymous (NA) and Alcoholic Anonymous (AA), even though studies have demonstrated the efficacy of psychedelics in reducing drinking in people with alcohol use disorder.[15]. In 1950, Bill Wilson, cofounder of AA, took LSD for treatment of his serious depression, finding positive results for decades.[16] While Wilson rigorously maintained his commitment to alcohol sobriety in the program, he found that LSD produced a spiritual experience that helped him cope with his disease. This spiritual experience is a key component of AA’s 12-step recovery process.

But when Wilson proposed his psychedelic therapy method to the AA General Services board, they vigorously opposed it, as the use of any mood or mind-altering substance challenged their idea of sobriety. That attitude might be shifting today as newer, younger members of AA have started Spiritual Awakening groups to integrate and destigmatize the use of psilocybin as an adjunct to traditional support programs.

As a current member of AA, I believe, along with other like-minded doctors, that being able to access your spiritual side (whatever you deem that to be) is an essential part of recovery from SUDs.

The use of psychedelics has evolved from a countercultural phenomenon to a potential for mental health and SUD treatment. However, there is still much research to be done and the legal status of psychedelics remains a complex issue. As potential treatment for a number of chronic diseases, psychedelics should no longer be burdened with a Schedule 1 classification.

In addition, the medical and scientific communities need to continue their rigorous approach to data collection and methodologies. Studies should employ careful screening for participants, standardized preparation and administration of substances, curated settings, and supervision by trained professional monitors. Potential harms to the participant exist with sessions led by non-professionals or within unsupervised sessions such as those found in so-called psychedelic wellness spas.

As a practicing addiction medicine specialist for over five decades and as a person in recovery, I am cautiously optimistic about the use of this valuable drug group. In the right hands, they are powerful tools for addressing the ongoing SUDs and mental health issues facing the world.

About David E. Smith, MD, DFASAM 

Dr. Smith’s work with psychedelics began at UCSF as a medical student and continued when he became involved in caring for the marginalized and disenfranchised youth during the Summer of Love by founding the Haight Ashbury Free Clinic in San Francisco, inaugurating the principle of “Health Care is a right, not a Privilege." He is still practicing as an addiction medicine specialist in the Bay Area. Dr. Smith is a Diplomate of the American Board of Addiction Medicine, a past President of the American Society of Addiction Medicine (ASAM) and the California Society of Addiction Medicine (CSAM). He is the Founding Editor of the Journal of Psychoactive Drugs and co-author of “Unchain Your Brain: 10 Steps to Breaking the Addictions that Steal Your Life.” He is currently working on his memoir, covering his early years, through the Summer of Love, and up to today.