More than 60 years ago, Bill Wilson, the architect of the largest sobriety program in history, experimented with LSD and began publicly advocating for the psychedelic substance as a path to recovery from alcoholism. Today, an increasing body of research suggests that the insight of the co-founder of Alcoholics Anonymous may hold merit.
The therapeutic potential of these highly stigmatized hallucinogenic drugs has generated widespread interest, extending beyond substance abuse disorders. Studies indicate that psychedelic therapy could potentially alleviate the debilitating effects of conditions such as depression, anxiety, eating disorders, and post-traumatic stress disorder (PTSD).
But how does it function? How does therapy involving mind-altering “trips” or hours of hallucination fundamentally alter an individual’s brain?
But how exactly does it operate? How does therapy involving mind-altering “trips” or hours of hallucination fundamentally alter an individual’s brain?
Much of what researchers “know” remains theoretical, primarily based on basic science like hers, according to Jamie Peters, PhD, a neuroscientist with a primary appointment in the University of Colorado School of Medicine’s anesthesiology department and a secondary appointment in pharmacology at the CU Anschutz Medical Campus.
However, Peters is hopeful that a resurgence in attention will lead to regulatory acceptance of research and that more definitive answers are on the horizon. “This is a really exciting time to be working in this area,” Peters said. “I think of it as a renaissance of interest in this class of drugs that have been under-researched for decades.”
How the Remodeling Unfolds
Psychedelics cross the blood-brain barrier either directly, like LSD, or indirectly, like psilocin, a converted active metabolite of psilocybin – the psychedelic component of “magic mushrooms.” Once inside the brain, the drugs target serotonin receptors (specifically 2A and 2C), enhancing sensory input and creating the hallucinations and strong sense of connection many users report.
“In some cases, you may cross senses,” Peters said of patients experiencing a phenomenon called synesthesia. “You may see sounds or hear colors.”
Hallucinogens are psychoplastogens, fast-acting compounds that support structural and functional neural plasticity, meaning brain cells and pathways can be reshaped and, in some cases, restored after insult or injury. “The root of the term literally means mind-molding,” Peters said.
Like a tree given a miracle food that spurs rapid branch growth, neurons (brain cells) supplied with a psychedelic boost sprout dendrites. The resulting branch-like network allows for novel connections (synapses) with other neurons. “This new formation of synapses between neurons happens at least in vitro, and there is some evidence this happens in vivo as well,” Peters said.
Finding Ground Zero
Called synaptogenesis, the increased numbers of synaptic contacts serve as points of communication between neurons. Research suggests the process rebuilds critical pathways lost to mental health disorders. It’s thought that when this remodeling takes place in the brain’s cerebral cortex, therapeutic benefits occur, Peters said.
“We understand that the prefrontal cortex, the foremost part of the cortex, plays a crucial role in decision-making, inhibitory control over impulses, and flexible behavior,” Peters explained. “And all of these functions are often compromised by neuronal atrophy in neuropsychiatric disorders, such as PTSD, depression, and substance abuse disorders,” she continued. “So, while we haven’t definitively proven that the prefrontal cortex is the primary site for psychedelic-induced therapy, it remains one of our main objectives.”
To trip or not to trip?
Another focus of Peters’ research revolves around a scientific debate that could significantly influence the future of psychedelics as a therapeutic treatment. The contention centers on whether experiencing the hallucinogenic effects of these drugs is essential for therapeutic benefits.
“There are two schools of thought on this matter. Some believe that the stronger the ‘trip’ or mystical-like experience, the more effective the therapy. However, there’s another camp that contends hallucinations may not be necessary for the therapeutic effects of psychedelics. I tend to lean toward the latter view.”
Her inclination stems from basic research conducted with University of California Davis medicinal chemist David Olson and other scientists. “David has been converting numerous psychedelic scaffolds into non-hallucinogenic variants of those compounds. We’ve been able to test some of these in our animal models.”
Opening new avenues
In their studies, rodents are conditioned to respond to light and sound cues indicating the availability of heroin for self-administration by pressing a lever. Heroin, a highly addictive opioid responsible for the majority of over 100,000 U.S. overdoses annually, is chosen for self-administration nearly every time, much like in humans.
In a subsequent phase examining relapse, the animal models are withdrawn from the opioid for a period. Upon reintroduction of the cues, the previously weaned rodents promptly resume lever pressing, indicating relapse. According to Peters, “When administered a single dose of tabernanthalog (TBG), a non-hallucinogenic version of the psychedelic drug ibogaine modified by Olson, relapse rates in the animal models decreased. The heroin cues no longer triggered relapse for up to two weeks, a significant period considering the lifespan of rodents.”
TBG, derived from the psychedelic compound ibogaine, has been clinically used in Europe for its anti-addictive properties. “Patients reported long-term reductions in cravings after a single dose, followed by years of abstinence,” Peters noted. However, ibogaine was eventually withdrawn from the European market due to toxicity and cardiac issues.
In their multi-institutional study published in the journal Nature, the non-toxic TBG variant was found to promote structural neural plasticity, reduce alcohol and heroin-seeking behavior, and produce antidepressant-like effects. “This illustrates the potential of novel psychedelic-derived compounds and their therapeutic benefits,” Peters remarked.
Quick, effective, long-lasting
Peters highlights the low-dose, long-lasting potential of psychedelic drugs and their derivatives as one of the most exciting aspects of psychedelic therapy. “This differs significantly from our current first-line therapies for depression and substance use disorder, such as SSRIs or methadone, which often require chronic administration over weeks, months, or even a lifetime.”
SSRIs, commonly prescribed for depression, also target serotonin receptors. “However, SSRIs achieve this indirectly, and it takes time for them to take effect,” Peters explained. “SSRIs inhibit serotonin reuptake, gradually increasing serotonin levels in the synapses that can bind to receptors. Psychedelics, on the other hand, bind directly to the receptors, producing a relatively immediate effect.”
Eliminating hallucinations, breaking barriers?
If non-hallucinogenic compounds prove effective in upcoming human clinical trials, they could overcome significant hurdles to psychedelic therapy, Peters suggested. “The main drawback of classical psychedelics with hallucinogenic properties is their liability, making it unlikely that they would be prescribed for outpatient use,” she noted. “This limits accessibility and increases the associated costs of therapy.”
Chemically altering drugs to eliminate hallucinations could potentially enable outpatient prescription, she added. “They could be taken home and stored in medicine cabinets like other first-line therapies for depression or addiction.”
Proceed with caution
While Peters advocates for ongoing psychedelic-related research and appreciates the university’s support for such studies, she advises against self-use.
“This is particularly important when obtaining these agents ‘on the street.’ Nowadays, almost any street drug can be contaminated with fentanyl, a highly potent and often lethal opioid,” Peters cautioned. “Moving toward legalization and regulation of these agents at the federal level sooner rather than later would improve quality control.”
“I understand that many people are enthusiastic about the potential of psychedelics as therapy, but I hope they temper that enthusiasm with a healthy dose of caution when considering recreational or non-medical use,” she concluded. “There is still much we don’t know.”
