Psychedelics have gained massive media attention in recent years and their reputation is in the midst of a dramatic renaissance. Psychedelic compounds, such as LSD (lysergic acid diethylamide), first came into the spotlight in the 1940s and quickly became an important subject of extensive research for their potential in treating a multitude of neuropsychiatric diseases. However, an enormous collection of published research studies conducted during the 1940s and 1950s quickly fell under a shadow when abuse of psychedelics escalated and social stigmas surrounding them became increasingly prevalent in the 1960s. The social turmoil threatened by psychedelics proved too much, resulting in all hallucinogens becoming categorized as Schedule I controlled substances by the U.S. Food and Drug Administration (FDA) with high abuse liability and no approved medical use in 1970, halting the majority of research on these drugs. After decades of stifling by stigma and drug laws, the patient work of researchers committed to revealing the medicinal potential of psychedelics has begun to re-open the doors to this field. With advancements in technology and improvements in clinical research design, researchers have not only been able to confirm their therapeutic utility in neuropsychiatric and peripheral diseases but also begin to understand how psychedelics work on a cellular and molecular level. These scientific advances have allowed researchers to start identifying potential compounds with comparable therapeutic benefits of psychedelics and reduced side effects for improved success in the clinic. Those attending the annual ASPET meeting at Experimental Biology 2019 had the opportunity to hear about some of the most recent and cutting-edge studies on psychedelics at the session entitled “Maximizing the Therapeutic Value of Psychedelics: Recent Preclinical Studies”. In this session, researchers from across the country highlighted the incredibly versatile role of psychedelics for the treatment of both neuropsychiatric and peripheral diseases while addressing important hurdles that psychedelics research must overcome to provide promising therapeutic options. Drs. Clint Canal (Mercer University) and Peter Hendricks (University of Alabama Birmingham; UAB) led this session.

Recent clinical studies have shown the potential of psychedelics to be more effective in treating diseases such as post-traumatic stress disorder (PTSD), depression, smoking and alcohol use disorder, than currently available treatment options. The promise of psychedelics across such a wide range of ailments may foreshadow their ability to help individuals with treatment-resistant mental illness (those that persist after two or more treatment approaches). One extensive and ongoing study found that treatment with the psychedelic psilocybin helped approximately 65% of participants stop smoking for over a year following the study. Currently available treatments to stop smoking only yield on average a 30-35% abstinence rate; highlighting psilocybin as a promising therapeutic for helping smokers quit. Additionally, Dr. Sara Lappan (UAB) highlighted a number of emerging studies showing success of psilocybin in treating individuals with alcohol and cocaine use disorders. Together, these findings suggest a powerful, multifaceted role of psilocybin for treatment of neuropsychiatric disorders, such as substance use disorders.

Despite the groundbreaking results of psychedelics in clinical studies, they do not come without side effects and liabilities that may limit their utility as a therapeutic agent. Therefore, it is critical for researchers to understand how psychedelics produce therapeutic effects in order to develop new medications that maintain the therapeutic benefits without the psychedelic effects themselves. One researcher working towards this goal, Dr. Kevin Murnane (Mercer University), digged into the mechanisms involved in the therapeutic actions of psychedelics with a focus on targeting the serotonin (5-HT) 2A receptor (5-HT2AR) pathway. Psychedelics stimulate 5-HT2ARs, which are highly expressed in brain regions implicated in behaviors such as emotion, cognition and reward, resulting in activation of intracellular signaling cascades unique from those elicited by serotonin and responsible for their psychoactive effects. The Murnane lab and collaborators at the Mercer University Center for Drug Design utilize a cutting-edge approach called pharmacophore modeling to pinpoint new compounds targeting the 5-HT2AR system. Through these efforts, they have been able to identify a number of promising 5-HT2AR-activating targets that may elicit comparable therapeutic effects observed with compounds such as psilocybin and MDMA (3,4-Methylenedioxymethamphetamine) while diminishing the psychedelic effects. Another researcher working towards identifying safer effective alternatives to psychedelics, Dr. William Fantegrossi (University of Arkansas for Medical Research) explains that metabolism of MDMA results in products that cause adverse side effects such as increased body temperature and heart rate. By altering the chemical structure of MDMA, its metabolism can be altered to produce fewer of these toxic metabolites. Dr. Fantegrossi shares ongoing research from his lab that focuses on an altered formulation of MDMA that shows decreased cardiovascular side effects while maintaining therapeutic efficacy; thus, highlighting the potential for safer, effective alternatives to traditional psychedelics that have the capability of harnessing their beneficial therapeutic effects.

Although much of the recent attention on psychedelics has been focused on their potential utility in treating neuropsychiatric disorders, a wealth of research suggests that psychedelics have immense potential as treatments for peripheral conditions as well. Dr. Charles Nichols (LSU Health Sciences Center) expanded on important work from his laboratory showing that activation of 5-HT2AR with psychedelics produces powerful anti-inflammatory activity in tissues of the blood vessels and gut. With about 60% of the adult population suffering from some form of inflammatory disorder (e.g., asthma, cardiovascular disease, and metabolic disorder), the development of psychedelics to treat peripheral inflammation at sub-behavioral levels has immense potential to improve human health in various disease states.

Through patient and dedicated work of countless researchers, like those featured in this session, the medicinal potential of psychedelics has recently begun to gain traction on a larger scale. The FDA has recently designated MDMA as a "breakthrough therapy" for PTSD, a status that may lead to faster approval. In sum, the future for psychedelics is promising but many questions remain unanswered. The field of psychedelics research will continue working tirelessly to shed light on the medicinal benefits of psychedelics while finding new ways to improve their safety.

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