The compulsive eating paradigm: can psychedelics help in treating obesity?

Abstract

Obesity is a multifactorial disorder involving a behavioural aetiology in subsets of patients that traditional therapeutic approaches have failed to address. Drawing parallels with addiction, the rewarding aspects of a chronic energy-dense diet can compromise dopaminergic reward circuits, eventually causing individuals to become habitually responsive to food-related stimuli despite adverse health consequences. The maladaptive prediction of reward and motivational salience that becomes associated with food-related stimuli can exert top-down influence on perception and attention, promoting compulsive eating behaviour. Emerging research suggests that psychedelics, e.g., psilocybin and LSD, induce non-ordinary mental states where the influence of such behaviours could potentially be reduced and modified. Based on current evidence, mechanisms have been proposed which suggest that psychedelics might relax the top-down influence of high-level predictions encoded within neuronal hierarchies and sensitise them to bottom-up information flow. Additionally, psychedelics are thought to open a window of psychological flexibility, allowing people to potentially become open to new cognitive and behavioural strategies that can be offered via assisted psychotherapy. Therefore, psychedelics-assisted psychotherapy may encourage beneficial changes to eating behaviour, in those with maladaptive eating habits. While promising in theory, new research is needed to assess the potential efficacy of psychedelics-assisted psychotherapy in treating compulsive eating behaviour.

Plain language summary

Obesity is a complex condition, and for some people, it involves patterns of overeating that resemble addictive behaviours. Eating too much energy-dense food, such as junk food, can affect the brain's reward system, making it harder to resist food (similar to addiction), even when it leads to negative health effects like weight gain and disease. This behaviour can become compulsive, meaning that people keep eating in response to food cues, even if they don’t feel hungry.Recent research suggests that psychedelics, like psilocybin (found in “magic mushrooms”) and LSD, might help people break these habits. These substances can alter the way the brain processes information and make people more open to change. Combined with psychotherapy, psychedelics might help people with compulsive eating behaviour by weakening the strong mental associations they have with food and instead adopt healthier habits. Although this idea shows promise, more research is needed to determine how effective psychedelics-assisted therapy could be in treating overeating and obesity.

Introduction

The prevalence of global obesity over the past 50 years presents a significant health challenge, as it constitutes a major risk factor in conditions such as cardiovascular disease, cancer and diabetes [1]. Fundamentally, obesity is driven by a chronic imbalance between consumed and expended calories, causing excessive body fat accumulation. However, its underlying cause is typically multifactorial, encompassing behavioural, genetic and metabolic influences, which might together contribute to the low long-term adherence to dieting and exercise among obese patients. After repeated failure of calorie-restricting diets in achieving weight-loss [2, 3] obese patients might opt to augment these with pharmacological or surgical interventions, which also vary in long-term effectiveness and pose their own physical risks and financial challenges. Given these limitations of current obesity treatments and the ever-rising burden of obesity, alternative strategies are worth exploring.

With increased interest in the interactions of the brain within an obesogenic environment, there is growing support for the idea that obesity might be understood within the same neurobiological framework as addiction, where patients feel the urge to eat in response to food-related stimuli despite its potentially catastrophic consequences [4]. In subsets of patients, obesity has been associated with compromised reward pathways, which enhances the response to palatable food. With repetition, eating behaviour may become increasingly habitual and thus harder for the individual to control, mirroring compulsive substance use in addicted individuals. Compulsive eating behaviour may also underlie the difficulty in inducing dietary change in these individuals, stressing the notion that obesity as a multifactorial disease requires a multi-pronged treatment regimen that also addresses potential behavioural mechanisms.

There remain limitations in the efficacy of therapies addressing disorders of compulsive behaviour. For example, small effect sizes (even smaller at 12-month follow-up) were often reported by studies assessing the efficacy of cognitive behavioural therapy (CBT) for addiction, with minorities of patients experiencing high relapse rates [5, 6]. While CBT appears effective in the short term for treating eating disorders, its long-term effectiveness remains uncertain [7], and the efficacy of pharmacotherapeutic strategies varies [8]. However, recent research has demonstrated long-lasting therapeutic potential of psychedelics in compulsivity-associated disorders such as addiction [9, 10]. Classical psychedelics including LSD, psilocybin and ayahuasca, are predominantly 5-HT2A receptor agonists which induce non-ordinary mental states characterised by alterations in mood, perception, thought, and sense of self [10]. While much of the focus has been on the 5-HT2A receptor-mediated consciousness-altering effects, psychedelics exhibit complex polypharmacology by interacting with multiple receptors. For instance, they engage the dopaminergic system, which is altered in obesity and influences food-related reward behaviours (discussed in more detail later). Additionally, TrkB activation, binding with brain-derived neurotrophic factor (BDNF), may enhance neuroplasticity, while 5-HT1A receptor interactions could affect mood and stress responses, both of which are relevant in obesogenic environments [11]. These combined effects make it challenging to isolate the specific role of each receptor in behaviour. Consequently, the general scope and mentioned studies in this review focus on network-level effects, which offer a more holistic understanding of how psychedelics influence self-perception, motivation, and reward in the context of compulsivity.

In the context of addiction, psychedelics-assisted psychotherapy (PAT), involving high doses of psilocybin combined with CBT in participants with alcohol-use disorder led to > 80% reduction in the frequency of heavy drinking days at 32-weeks follow-up, whereas the improvement in the placebo-assisted CBT group was significantly lower (~ 60%) [12]. Therefore, psychedelics seem to enhance the efficacy of psychotherapy to achieve remarkable long-lasting improvements for addiction. Theories drawn from current evidence which explain the action of psychedelics propose that psychedelics open a window of neural plasticity and cognitive flexibility, within which the influence of prior behaviours can be reduced [13]. This potentially explains the efficacy of PAT in treating addiction, where behaviours that drive compulsive drug-seeking are modified. The same mechanisms were proposed to explain the therapeutic potential of PAT in treating eating disorders some of which involve binge eating behaviours, a behaviour in common with a proportion of individuals with obesity. Rigid beliefs and habitual maladaptive behaviours regarding eating, body weight and shape may be amenable to change under psychedelics, potentially allowing disordered eating behaviour to be improved [14–16].

Similarly, there have been previous discussion regarding the use of psychedelics to treat obesity through disrupting ‘hardwired’ obesogenic circuits and enhancing ‘cognitive flexibility’ which might make patients more amenable to psychotherapy [17, 18]. Data from a drug use survey (2005–2014) found that individuals who had used classic psychedelics had lower odds of heart disease, diabetes, hypertension, obesity, and being overweight, suggesting an association with improved cardiometabolic health [19]. Borgland et al. highlight that the cognitive and neurostructural flexibility induced by psychedelics contributes to therapeutic effects in depression and could benefit obesity treatment, given the strong association between depression and obesity. Although this paper lacks detail in how psychedelics might target the primary neuropathophysiological processes that precipitate compulsive eating behaviour, it acknowledges that psychedelics-induced acute changes such as in functional connectivity between 5-HT-associated networks might lead to long-lasting changes in brain regions which control food intake (this will be explained in more detail later) [18]. Similarly, Fadahunsi et al. discussed that psychedelics’ ability to enhance ‘neuroplasticity’ through BDNF-driven mechanisms could target addiction-related behaviours, arguing that this could be applied to obesity [17]. However, the authors did not suggest specific mechanisms by which processes which perpetuate compulsive eating behaviour can be targeted by psychedelics.

This review aims to bridge these gaps by proposing the steps by which chronic intake of energy-dense foods can lead to compulsive eating behaviour, and based on current evidence from psychedelic research suggest how PAT could be used to target these obesogenic neuropsychological processes. The influence of psychedelics on the epigenetic landscape and the gut-brain-axis will also be explored as additional mechanisms underpinning the long-lasting therapeutic effects of PAT.

Rationale for the compulsive eating model in obesity subsets

The evolutionary function of storing fat is to safeguard against periods of food scarcity. The food availability hypothesis contextualises obesity within the modern food environment, where readily accessible energy-dense palatable foods, alongside sociocultural influences and marketing strategies, contribute to excessive caloric intake [20]. The resultant neurobiological effects of a chronic energy-dense diet (EDD) seem to strongly parallel disturbances seen in addiction.

Energy-dense food availability in inducing reward-related deficits

The rewarding aspects of food consumption reinforce feeding decisions and motivate the pursuit of palatable foods via dopaminergic (DA) activity within the striatum and associated mesolimbic structures [21]. The repeated stimulation of DA reward pathways via excessive consumption of readily accessible palatable foods is believed to trigger neurobiological adaptations that may lead to the loss of control over eating behaviour [4]^*. The effects of food availability on the responsiveness of brain reward systems were measured in rats given extended, restricted or no access to a 40-day ‘cafeteria diet’ (high in fat and sugar) consisting of palatable energy-dense food. Extended access rats most excessively gained weight, which was closely associated with a worsening deficit in brain reward responsivity, reflected by their progressively elevated threshold to obtain rewarding electrical self-stimulation through indwelling electrodes [22]^*. Palatable food-intake was insensitive to punishment via shock-paired cue light only in extended access rats, indicating compulsivity (see next section). This was also reported in rats with extended access to intravenous cocaine self-administration, suggesting parallels with addiction-like symptoms [23]. In terms of dopaminergic circuitry, striatal dopamine D2 receptor (D2R) levels, which are often downregulated in addicted individuals [24], were inversely correlated with body weight, with extended-access rats displaying the lowest D2R levels.

This finding resonates with a PET study involving morbidly obese individuals, where striatal D2R availability was negatively correlated with BMI [25], mirroring the striatal deficit in the extended access rats. Stice et al. used fMRI to show that BMI is negatively correlated with striatal (caudate) activation in response to consuming milkshake, which was amplified in those with the Taq1A1 allele, who as a result have a variation in the D2R gene and thus display reduced striatal D2R function compared to those without the allele [26]. This suggests that striatal dopamine release to palatable food intake is reduced with weight gain, which could be associated with reduced D2R density. Therefore, a greater intake of palatable food would be required to compensate for the hypofunctioning reward system. However, there remains a question of causality as it’s possible that individuals who are predisposed to striatal D2R alteration are more likely to gain weight. Interestingly, in a 6-month prospective fMRI study in overweight/obese women, the striatal response to milkshake was shown to be reduced compared to pre-study baseline only in those who gained weight, but not stable-weights [27]. Therefore, weight gain could perturb striatal systems, similarly to the extended access rats, however, the exact contribution of an EDD to this perturbation is unclear in this study.

The response to negative reinforcers may also be blunted which was indicated in a group of obese individuals who underwent a conditioned-cue preference test, where presented abstract patterns were probabilistically associated with a reward or punishment. Compared to healthy weights, obese individuals were less able to avoid choosing the pattern associated with negative outcomes [28]. Negative consequences (e.g., weight gain, satiety) may therefore fail to deter unhealthy eating behaviour in these individuals due to altered negative outcome learning [29]. Additionally, executive control over incentive salience is essential to maintain goal-directed behaviour. However, in a food-specific go/no-go task, where participants ranging from lean to obese must withhold responding to palatable food images, high BMI was associated with increased erroneous responsivity to the images and reduced activation of prefrontal regions implicated in inhibitory control (e.g., ventrolateral and medial prefrontal cortex) [30]. This apparent lack of inhibitory control can drive the elevated sensitivity to food-cues seen in individuals with compulsive eating behaviour [31], potentially facilitated by their increased attentional bias to food-related cues [32]. Therefore, the reinforcing nature of a chronic EDD can promote an individual to impulsively respond to and gradually overconsume highly palatable food.

Habitual overeating: a switch to compulsivity

Over time, hedonically motivated responses can devolve into compulsive habit-driven responses, as seen in addicted individuals. If an eating response is repeatedly reinforced, neurons stop firing during food delivery and instead fire when exposed to stimuli that predict food reward. Hence, cues that predict palatable food intake can promote automatic overeating, independent of the resultant hedonic value [33]. The extent to which an eating response is habitual can be determined by its sensitivity to outcome devaluation, e.g., via satiation, which normally reduced the hedonic value of food. However, obese men displayed minimal behavioural adaptation in responding to devalued food compared to lean men [34], suggesting that their control of food-seeking behaviour was not consistent with reward value, indicating habit-driven eating behaviour. In a similar devaluation study in healthy weights who were additionally trained to associate a cue with food delivery, the devaluation effect was abolished when the food-cue was introduced [35]. Therefore, food-associated stimuli (conditioned reinforcers) which are more abundant in day-to-day than the food itself, may override satiety signals and robustly enhance the desire to eat.

The relevance of this compulsive eating paradigm is still debated as it does not consider that the rewarding properties of food are also tied to the body's physiological need for energy and nutrients, making its hedonic value more complicated than addictive substances. Additionally, genetic predispositions, social factors such as socioeconomic status (affecting access to healthy food options) and cultural norms can significantly influence eating habits, highlighting that the compulsive eating paradigm might not universally apply to all obese patients. Therefore, patient stratification may be required to identify those who display a compulsive eating phenotype (perhaps using standardised measures such as the Yale Food Addiction Scale), thus informing their treatment strategy.

Potential therapeutic mechanisms of psychedelics-assisted therapy

As discussed earlier, maladaptive eating habits form when food-related stimuli strongly predict reward and produce motivational salience as they are repeatedly reinforced by reward prediction errors. This stimulus-reward association can drive compulsive eating behaviour as strongly weighted predictions are thought to elicit top-down control that biases perception and attention towards responding to food-related cues. The “relaxed-beliefs-under-psychedelics” model (REBUS) suggests that psychedelics temporarily loosen these maladaptive predictions, allowing people to become more open to new insights that may be offered in a therapeutic context (e.g., via CBT) [13]. This framework can explain the therapeutic effects of PAT for conditions like depression and addiction, which may also be useful in patients displaying compulsive eating behaviour.

Neural correlates of the psychedelic experience

Carhart-Harris et al. analysed the transition from normal waking consciousness to the psilocybin-induced psychedelic state using fMRI in healthy subjects [36]. Correlated with its subjective effects, psilocybin-infusion led to decreased activity and disrupted resting-state functional connectivity (RSFC) of cortical hub regions, such as the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). Within these cortical regions, psilocybin has been shown to decrease the oscillatory power of broad frequency ranges using MEG recordings, implying a general disorganisation of cortical network-level rhythmic activity [37]^*. Via dynamic causal modelling in the PCC, a psilocybin-dependent increase in the excitability of deep-layer pyramidal cells was determined as the most likely synaptic mechanism underlying this network desynchronisation. This is consistent with the dense expression of 5-HT2ARs in deep-layer pyramidal neurons [38] and the finding that stimulation of the 5-HT2ARs enhances spontaneous EPSPs in rat neocortical layer-5 pyramidal cells by reducing outward potassium currents [39]. These selective effects of psychedelics on deep-layer cortical neurons are important in the context of predictive coding as these pyramidal populations are thought to encode expectations about sensory experience [40], potentially including the stimulus-reward predictions that might drive compulsive eating behaviour.

However, psychedelics seem to modulate network level activity of multiple hub regions and it is currently unclear whether these same regions impose top-down predictions regarding stimuli during decision-making. Interestingly, in a study requiring patients to identify either a face or house amongst randomly intermixed reduced-contrast images, fMRI revealed that the goal of identifying faces led to greater activation of the mPFC [41], which is modulated by psychedelics as mentioned earlier. When identifying faces, dynamic causal modelling (DCM—infers directional connectivity) indicated that the mPFC exerts feedforward effective connectivity with face-responsive regions (e.g., amygdala, fusiform face area). The mPFC might therefore maintain and impose predictive face information especially considering that it has been demonstrated to learn associations between context and corresponding adaptive responses to mediate decision-making [42]. Thus, the mPFC might also encode and impose predictions regarding food-related stimuli, although this is only a potential theory that requires further investigation.

Heightened excitability can render the deep-layer pyramidal neurons selectively more sensitive to external bottom-up input, potentially allowing modulation of prior predictions regarding food-related stimuli via the release of prediction error within neuronal hierarchies. The REBUS model proposes that increased bottom-up information flow is the precise neuromodulatory change induced by psychedelics that might reduce the top-down influence of these predictions, which may be useful in patients with compulsive eating behaviour [13]. Similar therapeutic mechanisms were proposed for the use of PAT in eating disorder patients who experience a distorted body image and altered reward processing towards food (e.g., decreased bias towards food in AN, increased bias in BED), formed by maladaptive beliefs and negative thought patterns about one’s own body (e.g., “My body isn’t thin enough”). In an appropriate therapeutic setting, enabling bottom-up signals to disrupt maladaptive priors could help people with EDs reevaluate and reinstate healthier beliefs about their body and food [14]. The notion of normalised reward processing perhaps links to finding that ‘microdosing’ LSD led to increases in metrics of reward responses and reward-based reinforcement learning in a small group of healthy adults [43], however they might not represent the state of disrupted reward-based learning seen in obesity subsets.

Of note, psychedelics have been observed to act on the mesolimbic pathway, classically associated with reward, which might be relevant to this idea of “improved reward processing” and the reduction in addictive behaviours observed in patients [44]. Linking back to the compulsive eating model, the dopaminergic mesolimbic circuitry is believed to primarily mediate binging behaviours and initial establishment of maladaptive changes that ultimately affect other brain networks [45], so these effects are worth considering. LSD displays agonist and partial agonist activity at D2 and D1 receptors, respectively [46], while psychedelics such as psilocybin enhance endogenous dopamine release via upstream effects on 5-HT2A/1A receptors [47]. Although 5-HT2A receptors are present in mesolimbic structures such as the ventral tegmental area and nucleus accumbens, the role of serotonergic neurotransmission in the mesolimbic pathway is somewhat complicated by variations in response based on serotonin receptor subtypes, so further research is needed to more carefully dissect how the different neural targets of psychedelics function to produce the observed behavioural results in patients [47].

Relaxation of prior predictions via increased bottom-up information flow

Increased bottom-up information flow, as proposed by the REBUS model, may be facilitated by changes in effective connectivity measured during LSD-induced consciousness by Preller et al. using fMRI and DCM. LSD increased effective connectivity from the thalamus to cortical areas (PCC), indicating a disinhibition of thalamocortical gating of information flow [48]. However, correlations between connectivity parameters and subjective effects could not be calculated in this study, thus, the subjective experiences that might be associated with reduced thalamocortical gating are unclear. Interestingly, subjective LSD-induced effects such as visual hallucinations have been attributed to increased thalamocortical connectivity [49]. Also, individuals more vividly experience perceptual scenarios and emotions under psychedelics compared to normal consciousness which might also link to this idea of increased bottom-up information flow [50].

Preller also observed that the effective connectivity from the ventral striatum (VS) to the thalamus and cortical areas was attenuated under LSD [48]. The VS is involved in encoding the incentive value of stimuli, potentially facilitating approach behaviours to food-cues, and heightened VS activity in response to food-cues seems to predict habitual overeating and obesity [26]. Therefore, reduced VS-thalamus connectivity might diminish the influence of reward-information regarding food-related stimuli that might promote hyperresponsivity to food-cues in individuals with compulsive eating disorders. However, the relaxation of such high-level predictions under psychedelics has not yet been measured behaviourally, although lower-level perceptual alterations might be linked to this notion. For example, perceiving Kanisza triangles involves a perceptual illusion requiring object completion using prior expectations which interpolate the existence of a triangle based on indirect object boundaries (Fig. 1). Under psilocybin, object completion to perceive Kanisza triangles was reduced, indicating diminished influence of prior predictions [51].

Fig. 1.

Kanisza triangle [51]

Psychedelics-induced behavioural flexibility

Although the function of the brain serotonergic system is enigmatic, recent evidence suggests that enhanced 5-HT2AR signalling produces a neuroplastic state which facilitates behavioural flexibility [52]. For example, PAT administered to patients with treatment-resistant depression, characterised by cognitive rigidity, produced a sustained ~ 40% reduction in the mean depression score (QIDS-SR16) 5 weeks post-treatment [53]^*. Although depression involves different cognitive mechanisms to compulsive eating, this is still an important finding as it suggests that PAT can induce neuroplasticity and promote beneficial psychological changes even in states of cognitive rigidity. This study also indicated that connectivity measures ‘reset’ post-treatment from the acute psilocybin-induced disruption of resting-state networks (see earlier). Therefore, psychedelics might enhance cognitive flexibility acutely such that behaviours can be altered before reintegration of normal functioning, meaning that 5-HT2AR signalling might have an “annealing” function, for which the appropriate therapeutic influence via psychotherapy is presumably important. This potentially explains how acute brain effects of PAT might translate into long-lasting therapeutic effects on attitude, mood and behaviour.

Changes in behaviour and lifestyle may be facilitated by the capacity of psychedelics to increase creative divergent thinking, which was measured in ayahuasca-using participants given ayahuasca tea followed by a picture concept task that asks them to find associations between presented pictures [54]. Increased divergent thinking under psychedelics might allow individuals to generate new effective cognitive, emotional, and behavioural strategies which can help them to adapt interpretations regarding stimuli. Revisions of prior cognitive biases can also be driven by increased insight into one’s own emotions, beliefs, memories, and relationships, which was measured to be significantly increased in participants under psilocybin [55]. Additionally, acute insight experienced during treatment with psilocybin for treatment-resistant depression was predictive of positive long-term clinical outcomes [53]. Applying this to the idea of compulsive eating behaviour, increased awareness of one’s own habitual patterns through psychedelics-induced insight may enable individuals to recognise and disengage from automatic responses to food-related stimuli, reducing their predictive influence on behaviour.

Psychological flexibility under psychedelics might also alter subjective perceptions and meanings of stimuli, which are likely encoded by internal models [56]. In a multi-modal imaging study with LSD, decreased RSFC between the parahippocampus-retrospenial cortex (PH-RSC) seed and the rest of the brain, measured by fMRI, correlated with visual-analogue-scale ratings of “altered meaning”, indicating that participants perceive stimuli differently [57]. Considering how PH-RSC networks are important in the encoding and retrieval of associative memories, psychedelics seem to reduce the functional connectivity of the brain with memory systems, potentially weakening prior stimulus-related associations. Applying this to patients with a compulsive eating phenotype, the significance associated with food-related cues might change as they may become less predictive of reward. However, the single subjective measure of “altered meaning” is broad and can apply to various types of stimuli. In future studies, selective effects on the meaning of food-related stimuli could perhaps be tested in individuals displaying compulsive eating behaviour. A specific visual-analogue-scale can be used to measure subjective ratings of the perceived meaning/significance of food-related cues before and after a period of psychedelics- vs placebo-assisted psychotherapy.

Psychedelics might act through epigenetic modulation

The effects described so far are at the network and behaviour-level, which might in-part be explained by changes at the molecular level. Psychedelics may influence neuronal activity by modulating the chromatin landscape. Epigenetic changes, e.g., through DNA methylation and histone acetylation, are significant contributors to diseases including the perpetuation of obesity, affecting gene expression in pathways involved in energy balance, appetite control, reward processing and stress responses [58]. For example, stress and psychosocial trauma increase DNA methylation in CpG islands of genes regulating neuronal plasticity, such as the BDNF gene, potentially reducing the capacity for plasticity [59]. This can have lasting effects on gene expression in stress-susceptible areas such as the PFC and hippocampus, ultimately affecting behaviour.

Interestingly, psychedelics have been shown to influence the epigenetic landscape, enhancing gene expression relating to neurogenesis and synaptic plasticity [59]. Epigenetic changes elicited by a repeated LSD regimen in mice PFC resemble those observed during critical periods of neurodevelopment, affecting gene signalling pathways related to neurogenesis, nervous development, axonal guidance, and learning [60]. Additionally, psychedelics such as LSD and DOI also have histone-acetylating properties. A single dose of DOI in mice enhanced fear extinction and increased dendritic spine density in the frontal cortex. This occurred with sustained modulation of the acetylation level of the transcriptional enhancer histone H3K27 PFC neurons which correlated with neurotrophic-related transcriptional shifts associated with enhanced synaptic plasticity and antidepressant-like activity [61]. Such changes suggest that psychedelics may promote neural adaptation by reshaping chromatin states, particularly in enhancer regions of genes involved in synapse organisation and assembly. Neuronal activity changes could also indirectly remodel chromatin states as depolarisation induces CaMKII-dependent release of a methyl-binding protein at the BDNF promoter III which may drive transcriptional changes that lead to dendritic plasticity [62].

These findings suggest a plausible mechanism by which psychedelics could target the epigenetic underpinnings of obesity which might precipitate compulsive eating behaviours, to produce long-lasting therapeutic outcomes. Epigenetic changes, such as hypermethylation of neuronal plasticity genes, might reduce adaptability in circuits regulating reward processing and self-control. By reversing these changes and enhancing plasticity in key brain regions like the PFC, psychedelics may help restore normal eating behaviour. Given that the different mechanisms modulating DNA accessibility may interact with one another and many of these studies fail to distinguish effects across neuronal cell types, delineating the “psychedelic epigenome” marks an exciting new avenue in psychiatry.

Psychedelics might influence the gut-brain-axis in obesity

In obesity, the gut-brain axis (GBA) is disrupted, reinforcing obesogenic mechanisms. Dysbiosis, marked by reduced microbial diversity and a shift toward pro-inflammatory species, increases gut permeability and promotes systemic inflammation through the release of lipopolysaccharides. This low-grade inflammation impairs hypothalamic and brainstem circuits responsible for satiety and reward processing. Additionally, disrupted secretion of gut hormones such as GLP-1, ghrelin, and peptide YY further dysregulates appetite control and energy homeostasis [63].

The kynurenine pathway (KP), a major metabolic route for tryptophan, is overactivated in obesity due to inflammation-driven induction of indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). This overactivation diverts tryptophan from serotonin synthesis and generates neurotoxic metabolites such as quinolinic acid, which exacerbate neuroinflammation and impair neurotransmission [64]. This perpetuates GBA dysfunction and metabolic dysregulation.

Interestingly, psychedelic compounds such as DMT and tryptamines (LSD, psilocybin) act as non-competitive IDO inhibitors, reducing kynurenine production and potentially restoring gut barrier function [65]. In mice, repeated LSD administration was associated with a significant decrease in the kynurenine/5-HT ratio in the hippocampus, suggesting anti-inflammatory effects of LSD [66]. Potentially contributing to gut health, psilocybin was shown to reduce inflammation in the inflamed human 3D intestinal tissue [67]. Repeated LSD administration significantly decreased the gut microbiome Shannon alpha diversity, but prevented a decrease in Firmicutes:Bacteroidetes (often-used marker of broad microbiome disruption) suggesting enteroprotective effects [66]. Although various preclinical studies suggest that psychedelics may alter gut microbial composition, these effects appear dose-dependent and highly variable. Future studies could investigate if psychedelics affect microbiota-produced metabolites such as short-chain fatty acids which influence the inflammatory state precipitated by GBA dysregulation.

Psychedelics-assisted psychotherapy in the clinic

Psychedelic-assisted therapy begins with preparatory sessions where facilitators build trust and discuss the patient's goals and intentions for therapy. The psychedelic experience involves a relaxing environment which helps patient focus on their internal experiences followed by discussion with the facilitators to identify novel thoughts and feelings that arose during the session. This post-session reflection aids in reframing destructive behaviours and solidifying new perspectives into daily life, which hopefully has long-lasting effects unlike current weight-loss strategies.

Patients undergoing PAT may develop profound personal insights that could strengthen their commitment to change. Expressive therapies, such as art or narrative-based techniques, could help patients process and articulate these insights in a structured way. Additionally, practitioners could facilitate meaning-making sessions, where patients are encouraged contextualise their insights and relate them to their treatment goals. During the heightened mental flexibility induced by psychedelics, practitioners trained in guiding these sessions can help patients explore new perspectives on food, self-control, and exercise. PAT might also incorporate exercises that target flexible thinking, such as reflective journaling, mindfulness practices, or personal goal-setting. Since patients may feel more open to adopting new behaviours, PAT could be paired with lifestyle coaching to support sustainable changes in diet and physical activity.

Conclusions and caveats

In line with previous discussion in this field [18], there is rationale to suggest compulsive eating behaviour might be caused by maladaptive associations regarding food-related stimuli, which could potentially be dissolved and altered through PAT. However, there are general caveats to the presented framework. For example, many of the conclusions from studies investigating the action of psychedelics are based on correlations between neuroimaging findings and subjective effects in small cohorts which are often influenced by context, personal beliefs and prior expectations. Therefore, the correlations may not always accurately reflect the underlying neurobiological mechanisms, although this variance could be reduced by using a larger cohort. These studies are also limited by their single-blind design, which is an effective compromise as participants quickly become “unblinded” to the acute psychoactive effects of the drug, thus diminishing the value of blinding. Perhaps for future studies a multiple-dose design (e.g., 1, 10, 25 mg psilocybin) could standardise the expectancy effect since all participants would expect to receive the active drug. Additionally, the costs associated with drug development and the provision of assisted psychotherapy has financial implications that must be considered. However, if effective in individuals with compulsive eating tendencies, PAT might reduce the financial burden associated with conventional obesity treatment strategies.

Although psychedelics show an acceptable cardiovascular safety profile in healthy individuals [68], it is important to note that psychedelics can pose a risk to one’s health if they have predisposing conditions. In addition to being contraindicated for individuals who are predisposed to psychosis or have a history of psychotic disorders, the implications of increased risk of cardiovascular disease in obese patients must also be considered [18, 69]. One concern is the potential for cardiac valvulopathy and toxicity due to off-target 5-HT2B receptor agonism, which was seen in serotonergic drugs that had to be pulled from the market (e.g., Phen/fen, methysergide) [70]. This warrants rigorous cardiac screening, monitoring and reporting of adverse events in clinical trials, as well as developing next-gen psychedelics compounds with reduced 5-HT2B agonism [71, 72]. There is also potential for adverse events, such as serotonin syndrome, which may occur when psychedelics are taken alongside serotonergic medications used to treat comorbid depression (as is often seen in obese patients). However, PAT could transdiagnostically address comorbidities like depression, meaning that additional serotonergic medication might not be needed. Given the potential risks, it may be optimal to combine PAT with pharmacotherapies like GLP-1 receptor agonists (once their safety in combination with psychedelics is established). In this approach, psychedelics would only need to be used periodically to help reset behavioural patterns and support adherence to long-term lifestyle change and pharmacotherapy, rather than as a continuous treatment.

The use of psychedelics to treat obesity has not yet been directly studied in humans. In a study involving diet-induced obese mice, psilocybin only had a modest effect on food intake and body weight [73]. However, since psychotherapy cannot be administered to mice to facilitate targeted behavioural changes, animal models may be limited in assessing the efficacy of PAT for obesity. Ultimately, a task-based fMRI study is required to explore how PAT could modify functional biomarkers associated with compulsive eating behaviour in patients to produce therapeutic effects in the long-term. Pre-clinical studies should also continue to refine animal models that can better simulate the psychological aspects of eating behaviours in humans, while clinical trials could explore optimal dosing, timing, and the psychotherapeutic framework necessary for PAT’s efficacy.

Abbreviations

BDNF

Brain-derived neurotrophic factor: A protein that supports neuronal growth, survival, and plasticity

CBT

Cognitive behavioural therapy: A psychological treatment targeting thought and behaviour patterns

DCM

Dynamic causal modelling: A computational method to infer directional brain connectivity

DMT

N,N-dimethyltryptamine: A potent psychedelic compound that acts on serotonin receptors

D2R

Dopamine D2 receptor: A receptor in the striatum involved in reward and motivation pathways

EDD

Energy dense diet: A diet high in calories per gram, often rich in fats and sugars

Fmri

Functional magnetic resonance imaging: A neuroimaging technique to measure brain activity via blood flow changes

GBA

Gut-brain-axis: The bidirectional communication network between the gut and the brain

LSD

Lysergic acid diethylamide: A classic psychedelic that alters perception and cognition

mPFC

Medial prefrontal cortex: A brain region involved in decision-making and emotional regulation

PAT

Psychedelics-assisted psychotherapy: Therapy combining psychedelics with psychotherapy

PCC

Posterior cingulate cortex: A brain region involved in self-referential thinking and memory

PFC

Prefrontal cortex: A brain region critical for planning, decision-making, and social behaviour

PH-RSC

Parahippocampus-retrosplenial cortex: A network linked to memory, navigation, and contextual processing

RSFC

Resting state functional connectivity: Neural activity patterns measured during rest to understand brain network communication

VS

Ventral striatum: A brain area involved in reward processing and motivation

5-HT2AR

5-Hydroxytryptamine receptor 2A: A serotonin receptor targeted by psychedelics to modulate brain activity

GLP-1

Glucagon-like peptide 1: A hormone involved in appetite regulation and glucose metabolism

Author contributions

D.A. wrote the main manuscript with supervision and guidance from co-author R.P.

Funding

N/A.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

N/A.

Consent for publication

N/A.

Competing interests

The authors declare no competing interests.