Oxford scientists propose that psychedelics could rewire brain circuits behind compulsive eating, offering a bold new strategy to treat obesity, if future trials confirm their potential.
Review: The compulsive eating paradigm: can psychedelics help in treating obesity? Image Credit: Eskymaks / Shutterstock
Psychedelics, a class of hallucinogenic drugs, may serve as a potential therapeutic intervention for some obese people who experience addictive-like overeating behaviors, recent research suggests. Researchers at the University of Oxford published a review article in the Journal of Eating Disorders to depict the potential utility and proposed mode of action of psychedelics in treating overeating and obesity. However, they emphasize that human trials are still lacking, with no direct evidence yet in obese populations, and findings are largely based on preclinical or addiction-related studies.
Background
Obesity is a chronic metabolic condition characterized by excessive accumulation of fat in the body due to an imbalance between energy consumption and expenditure. With rapidly increasing prevalence, obesity has become a major public health crisis worldwide.
Emerging research suggests that in some individuals, obesity might have a connection with addictive behavior, where obese people feel the urge to eat more in response to food-related stimuli despite its adverse health consequences. However, the authors note that this compulsive eating model does not apply to all obese patients, as factors like genetics, socioeconomic status, and metabolic needs also play significant roles.
In a subset of obese people, compromised reward pathways have been observed, which can potentially increase their response to palatable foods. Repetitive eating behaviour may become increasingly habitual in these people, making it harder for them to control overeating. This behavior in some obese people resembles compulsive substance use in addicted people.
Compulsive eating behaviour may also make it harder for obese people to allow dietary change and develop healthy eating habits, highlighting the idea that obesity is a multifactorial disease that requires a multi-segment treatment regimen that also addresses potential behavioral mechanisms. The researchers propose that patient stratification—for example, identifying those with high scores on the Yale Food Addiction Scale—could improve treatment targeting.
Psychedelics and Compulsive Behaviors
Recent research suggests the long-term potential of psychedelics in treating disorders of compulsive behaviors. LSD, psilocybin, and ayahuasca are considered classical psychedelics that predominantly serve as serotonin 2A receptor (5-HT2A) agonists but also interact with other receptors, such as dopamine D2 and TrkB, which may contribute to their therapeutic effects. These drugs induce non-ordinary mental states characterized by alterations in mood, perception, thought, and sense of self.
In patients with alcohol-use disorder, psychedelics have been found to increase the efficacy of cognitive behavioral therapy in achieving significant long-term improvements in addictive behaviors. Similarly, preclinical studies suggest that in obese people, psychedelics might show promising outcomes in terms of increasing ‘cognitive flexibility’ that could make patients more amenable to psychotherapy.
Potential Mode of Action of Psychedelics-Assisted Therapy
Compulsive eating behaviors are triggered when food-related stimuli strongly predict reward and induce motivation for overeating. The “relaxed-beliefs-under-psychedelics” model (REBUS) suggests that psychedelics temporarily relax, rather than suppress, this stimulus-reward association, allowing people to become more open to new insights that may be offered in a therapeutic context.
In this context, evidence indicates that psychedelics-mediated increased excitability of deep-layer pyramidal cells is crucial for stimulus-reward desynchronization. These pyramidal neurons play important roles in encoding expectations about sensory experience, potentially including the stimulus-reward predictions that might drive compulsive eating behaviour.
It has also been observed that ‘microdosing’ LSD (a classical psychedelic drug) is associated with improved reward processing and reduced addictive behaviors in healthy adults in preliminary studies. This effect can be justified by the scientific evidence showing the potential influence of psychedelics on the mesolimbic pathway, a classical reward processing pathway.
Regarding behavioral flexibility, evidence indicates that psychedelics-assisted psychotherapy can induce neuroplasticity and promote beneficial psychological changes even in the state of cognitive rigidity.
Psychedelics-mediated psychological flexibility might help compulsive eating disorder patients alter their perceptions and meaning of food-related stimuli, allowing them to develop healthy eating behaviors.
Epigenetic Modulations by Psychedelics
Epigenetic modulations (DNA methylation and histone acetylation) are known to associate with altered gene expressions in pathways involved in energy balance, appetite control, reward processing, and stress responses.
Psychedelics have been found to increase gene expression related to neurogenesis and synaptic plasticity by influencing the epigenetic landscape. Histone-acetylating properties of psychedelics are responsible for their beneficial effects on synaptic plasticity.
Changes in neuronal activity can also indirectly remodel chromatin states, which in turn can induce transcriptional changes leading to increased dendritic plasticity.
Epigenetic changes, such as neuronal plasticity gene hypermethylation, might reduce adaptability in brain networks that regulate reward processing and self-control. Psychedelics can reverse these changes and increase plasticity in important brain regions, leading to the restoration of normal eating behavior.
These plausible modes of action of psychedelics suggest that the “psychedelic epigenome” can serve as an exciting new avenue in psychiatry.
Impact of Psychedelics on the Gut-Brain Axis in Obesity
A disrupted gut-brain axis is a major hallmark of obesity. Gut dysbiosis, characterized by altered gut microbial composition and diversity, increases intestinal permeability and induces low-grade systemic inflammation by releasing lipopolysaccharides.
This chronic low-grade inflammation can impair brain networks responsible for satiety and reward processing.
Another major hallmark of obesity is overactivation of the kynurenine pathway through inflammation-driven induction of indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO).
Since the kynurenine pathway is a major metabolic route for tryptophan, its overactivation leads to diversion of tryptophan from serotonin synthesis and generation of neurotoxic metabolites that promote neuroinflammation and impair neurotransmission. This prolongs gut-brain axis dysfunction and metabolic dysregulation.
Acting as non-competitive IDO inhibitors, psychedelics can reduce kynurenine production and subsequently restore intestinal barrier function. These actions highlight the anti-inflammatory properties of psychedelics. Preliminary and sometimes conflicting entero-protective properties of psychedelics, especially LSD, have also been observed in animal studies and preclinical models.
Clinical and Practical Considerations
In clinics, psychedelic-assisted therapy sessions may help patients focus on their internal experiences and identify novel thoughts and feelings. The therapy may also help patients develop profound personal insights that could strengthen their commitment to change.
Since psychedelic-assisted therapy makes patients more open to adopting new behaviors, it can be integrated into lifestyle coaching to support sustainable changes in diet and physical activity.
However, the researchers caution that psychedelics carry risks, including cardiovascular strain (e.g., increased heart rate and blood pressure) and psychological distress in vulnerable individuals. To date, no clinical trials have tested psychedelics specifically for obesity, and all proposed mechanisms remain theoretical. They also emphasize the need for rigorous human trials to validate preclinical findings and address ethical and logistical challenges in therapy development.