Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models
Claire J. Foldi, Paul Liknaitzky, Martin Williams, Brian J. Oldfield
Frontiers in Neuroscience, 2020 | Volume 14 | Article 43 : 1-8
doi : 10.3389/fnins.2020.00043
Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. The recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of AN that relate to serotonergic signaling and cognitive inflexibility. Clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. The first clinical trial to use psilocybin in patients with AN commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. Animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. We argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activitybased anorexia (ABA) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine.
Keywords : anorexia nervosa, psychedelic medicine, psilocybin, serotonin, 5-HT2A, animal models, activity-based anorexia, cognitive flexibility
THE RESURGENCE OF PSYCHEDELIC MEDICINE AND THERAPEUTIC POTENTIAL FOR AN
Psychedelics were first investigated as therapeutic agents for mental disorders in the 1950s (Neill, 1987) and more than 1000 clinical papers were published on classical psychedelics between 1950 and the mid-1960s (Grinspoon and Bakalar, 1981). However, political concerns over widespread non-clinical use and governmental interventions associated with an emerging counter culture led to regulatory obstacles and an abrupt end to this promising research. Recently, a resurgence of research into the clinical application of psychedelics has emerged (Strassman et al., 1994; Sessa, 2012; Nichols, 2016) and clinical trials have already highlighted psychedelic medicine as a promising alternative to conventional methods in what is being hailed as a “paradigm shift” for the treatment of psychiatric disorders, including
depression, post-traumatic stress and substance use disorders (De Gregorio et al., 2018; Schenberg, 2018). In addition, the U.S. Food and Drug Administration (FDA) have twice designated psilocybin for treatment-resistant depression as a “breakthrough therapy,” in 2018 and 2019. Combined with specialized psychotherapy, psilocybin has been shown to decrease symptoms of anxiety and depression that accompany life-threatening cancer diagnoses (Griffiths et al., 2016; Ross et al., 2016), alleviate symptoms in patients with treatment-resistant depression (Carhart-Harris et al., 2016a, 2018a) and improve adherence to abstinence regimes in nicotine-dependent smokers (Johnson et al., 2017). Moreover, patients with obsessive-compulsive disorder (OCD) have shown short-term improvements following psilocybin treatment (Moreno et al., 2006). Multiple studies investigating the safety and efficacy of psilocybin for the treatment of major depressive disorder have recently commenced across the U.S. and Europe (Clinical Trials: NCT03866174; NCT03775200; NCT03429075; NCT03715127; NCT03181529; NCT03554174; NCT03380442). Importantly, the first Phase 1 study exploring the safety and efficacy of psilocybin in patients with AN was launched in 2019 to examine a range of outcome measures including self-reported anxiety, depression and quality of life as well as changes in body mass index (BMI) and food preference (Clinical Trial: NCT04052568). The findings from this trial will indicate efficacy one way or the other; however, understanding the biological mechanisms that underpin any effects of psilocybin on AN await carefully controlled clinical and animal-based studies. It should be noted that preliminary support for the efficacy of psychedelics on eating disorder symptoms has been shown in qualitative interviews with patients following the ceremonial consumption of ayahuasca, another serotonergic psychedelic (Renelli et al., 2018).
An important consideration when interpreting the findings from clinical trials using psychedelics is the inability to circumvent certain methodological biases. Even when niacin or very low dose psychedelics are used as active placebos, most participants and therapists are quickly unblinded to the condition, potentially resulting in expectancy biases. The subjective scales used to measure the efficacy of psilocybin in some studies introduces further bias in the assessment of outcome measures (Muttoni et al., 2019). Irrespective of these limitations, the neurobiological “mechanisms” underlying the efficacy of psychedelics for treatment-resistant depression are beginning to be elucidated in very broad terms through administration of psilocybin in combination with brain imaging techniques (Carhart-Harris et al., 2012, 2017). The insights with the most experimental support include alterations in activity
and functional connectivity within the default mode network (DMN) (Carhart-Harris et al., 2012, 2013), a group of neural structures that represent resting-state cognition (Raichle et al., 2001; Greicius et al., 2003) (depicted in Figure 1). Functional connectivity between the DMN and other resting state networks
is generally shown to increase following administration of psilocybin (Roseman et al., 2014), and unusual levels of coactivation between DMN and task-positive structures has been found under psilocybin (Carhart-Harris et al., 2012, 2013) and ayahuasca (Palhano-Fontes et al., 2015). The mechanisms underlying the action of psilocybin on functional activity in resting state networks remain poorly understood, particularly the role of the serotonergic system, considering that the major midbrain nucleus in which 5-HT cell bodies lie (raphe nucleus; Figure 1) is not included in canonical resting state networks. Regardless, mechanistic models have been developed that assert the action of psychedelics as relaxing high-level prior beliefs and liberating bottom-up information flow (Carhart- Harris and Friston, 2019), and progress is being made to explain the action of psychedelics in the context of complicated
neurotransmitter pharmacology, molecular pathways, and plastic changes that contribute to the central actions of these compounds (Ly et al., 2018).
Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disorder (Harris and Barraclough, 1998) and is characterized by a relentless pursuit of weight loss despite severe emaciation. The majority of patients with AN also engage in excessive physical exercise and other compulsive locomotor strategies to avoid or counteract weight gain (Davis, 1997). A number of brain imaging studies in AN point to a combination of decreased neural activity in ventral reward regions (ventral and dorsal striatum) and increased neural activity in prefrontal control regions (orbital and dorsolateral prefrontal cortices) (Kaye et al., 2013). This imbalance may underlie the rigid adherence to punishing diet and exercise regimes by patients with AN that is characterized by both excessive behavioral control and diminished cognitive flexibility (Tchanturia et al., 2004, 2011, 2012). Despite the high mortality and the array of pharmacological and psychotherapeutic strategies that have been employed to treat AN (Davis and Attia, 2017), up to 50% of AN patients suffer with chronic, often life-long illness (Pike, 1998), indicating that therapeutic strategies remain inadequate in treating the core symptoms of the disorder.
In this respect, psychedelic medicine in combination with specialized psychotherapy represents a novel therapeutic strategy to treat disorders such as AN where treatment options have historically languished.
The purpose of this review is to highlight the potential suitability of psychedelic medicine for improving long-term treatment outcomes in AN, based on what is known about 5- HT signaling and cognitive function in patients and animal models. Although much of our argument is likely to be applicable to the therapeutic potential of other serotonergic or “classical” psychedelic compounds, including lysergic acid diethylamide (LSD) and ayahuasca, we focus here on psilocybin for three reasons: (1) the two FDA designations as a “breakthrough therapy” for treatment-resistant depression; (2) its prevailing use in numerous clinical trials for mental disorders; and therefore (3) the proximity to approval as the first widely used psychedelic in medicine and therapy. Further, we argue that fundamental research in animal models is necessary to reach a comprehensive understanding of the therapeutic effects of psychedelics in psychiatric disease. This is no different to the genesis and clinical acceptance of virtually every other pharmaceutical approach; however, in this instance the use of animal experimentation has the profound advantage of eliminating context and expectation that introduce confounds in the understanding of the neurobiological and pharmacological actions of psychedelic compounds.