Complexities of psychedelics for therapeutic use in obesity and eating disorders

An editorial discusses the potential for psychedelic drugs to treat obesity and eating disorders, highlighting that 5-HT2A receptor agonism boosts neuroplasticity in the prefrontal cortex, a region involved in inhibitory control that is altered in obesity. However, rodent studies show conflicting results on weight loss after psilocybin. A key concern is cardiac valvulopathy from off-target 5-HT2B receptor agonism, especially for individuals with underlying cardiac issues from obesity or eating disorders. Next-generation psychedelics with lower 5-HT2B affinity may reduce these risks. Weight-adjusted dosing and specialized psychotherapy are also important considerations.

Study at a glance

Abstract

In an interesting and timely editorial, Borgland and Neyens provide a snap­ shot of preclinical research that could support the development of psyche­ delic drugs as part of a therapeutic regimen in individuals with obesity or eating disorders (EDs), including an­ orexia nervosa (AN) and binge eating disorder (BED).1 The role of the sero­ tonergic system in appetite was key in the development of the 5­HT2C recep­ tor agonist lorcaserin as a treatment for obesity. The editorial highlights studies in rodents showing that 5­HT2A receptor agonism augments neuroplasticity in the prefrontal cortex — a critical brain region for inhibitory control and decision­making, which has been shown to be functionally altered in individuals with obesity and may instigate mal­ adaptive eating behaviours. However, recent rodent obesity­model studies have shown conflicting results regard­ ing weight loss following psilocybin treatment.2,3 The high comorbidity of EDs and obesity with mood disorders may contribute to the etiology of these conditions at the psychological and neuro biological levels,4 often leading to the prescription of selective serotonin reuptake inhibitor antidepressants. However, the caveats and concerns associated with psychedelic therapy trials described in the editorial are less representative of the complexities of contemporary psychedelic drug de­ velopment under stringent clinical/ laboratory practice guidelines. More­ over, as therapeutic indications, obesity and EDs have complex neuropsychi­ atric and physiologic components. A central concern in the develop­ ment of novel, or third­generation, psychedelic drugs for therapeutic use or prolonged microdosing paradigms (if shown to be therapeutically effica­ cious) is the potential for cardiac valvu­ lopathy and toxicity due to off­target 5­HT2B receptor agonism.5–7 While this is of less concern for physically healthy individuals who may undergo 1 or 2 psychedelic treatment sessions, under­ lying cardiac issues may contraindicate the use of chronic “microdoses” of psyche delics in individuals with EDs and obesity. Cardiovascular issues in these populations may be caused by the chronic use of appetite suppressants, electrolyte abnormalities from purging can cause arrhythmias, and high adi­ posity can precipitate heart disease. Cardiac failure has been observed with the recreational use of 3,4­methylene­ dioxy­methamphetamine (MDMA),8 currently in phase 2 trials for AN­ restrictive subtype and BED (where par­ ticipants were ineligible if they were classified as AN­purging subtype). Dur­ ing the development of next­generation psychedelics, the progression of com­ pounds with lower agonist affinity at the 5­HT2B receptor is a key workflow element to reduce cardiac risks, and rigorous cardiac screening, monitoring and reporting of adverse events is a requirement in clinical trials. Determining the appropriate dosage of psychedelic compounds may also be complicated in individuals with high and low body weights. Weight­ adjusted dosing of psilocybin has been reported in individuals with a body mass index between 17.5 and 35.6,9 but may be less appropriate for individ­ uals with severe obesity or EDs, as complex interactions between sero­ tonergic function, drug effects and body weight have been reported.10 Moreover, psychotherapy is a critical component of psychedelic treatment programs to support the patient with integration into meaningful behav­ ioural and psychological changes to fa­ cilitate long­term recovery. It is likely that specialized psychotherapy pro­ grams focusing on eating behaviours will be required for people with obes­ ity or EDs as therapeutic indications. Psychedelic drug development is an exciting field with potential to provide vital pharmaceutical tools. Further­ more, the development of next­ generation psychedelic compounds with lower 5­HT2B affinity than classic psychedelics presents enhanced safety for individuals with EDs and obesity.