This review (2021) appraises psilocybin as a novel pharmacotherapy for treatment-resistant anorexia nervosa (AN). It observes that classic psychedelics like LSD, 5-MeO-DMT, DMT, and psilocybin show a significant decrease in anxiety and depression-like symptoms, and lasting improvement in mental health. The review suggests that classic psychedelics, psilocybin in particular, show promise in normalizing dysfunctional neurobiological systems in AN and point towards a novel treatment intervention for treatment-resistant patients.
Abstract
“Anorexia Nervosa (AN) is a major health problem with one of the highest mortalities and treatment costs of any psychiatric condition. Cognitive behavioural therapy (CBT) is currently the most widely used treatment for AN in adults but provides remission rates ≤ 50%. Treatment drop-out is exceedingly high and those that persevere with treatment often relapse, causing increased risk of morbidity and mortality. There is an urgent need to find new interventions, especially as there are no approved pharmacological treatments for AN. Ideally, new treatments would target treatment-resistance and to decrease the chronicity associated with the disorder. Over the past two decades, emerging research into classic psychedelic substances (lysergic diethylamide acid (LSD), 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT), N,N-Dimethyltryptamine (DMT) and psilocybin), indicates that marked reductions in anxiety and depression-like symptoms, and lasting improvement in mental health, can follow from one or two exposures to these psychedelic substances. Anxiety and depression are the most prevalent co-morbid psychiatric symptoms in AN. Here we suggest that classic psychedelics, particularly psilocybin, have the potential to normalise dysfunctional neurobiological systems in AN and provide a novel treatment intervention that is worthy of consideration, particularly for treatment-resistant patients.“
Authors: Sarah-Catherine Rodan, Phillip Aouad, Iain S. McGregor & Sarah Maguire
Notes
Eating disorders (EDs), of which anorexia nervosa is one, affect more than 8% of women during their lifetime and 2.2% of women each year. The number is lower for men, but still there more than 2% will be affected by an eating disorder during their lifetime. Those with EDs have severe pathological fear and anxiety around food, food, intake, and body weight. It’s common for those with EDs to also have symptoms of depression and anxiety disorders. Most worrying is that EDs are the category of mental health disorders with the highest mortality of any psychiatric illness.
It’s also so that many will live with an eating disorder for a long period of time. Of those suffering from an ED, 30% will live with it for more than 15 years. This is partly so because the current treatments don’t work. One way current treatments often break down is at the moment of success. If there is (much needed) weight gain, it’s in direct opposition to the deeply held belief or fear of those with EDs. The current paper discusses how psychedelic-assisted therapy, specifically with psilocybin, may help this patient population.
Three take-home messages
- Psilocybin has been shown to be safe when used in a carefully controlled clinical setting
- And it has been used successfully, in combination with talk therapy, in other refractory (treatment-resistant) mental health disorders such as PTSD and depression (TRD)
- The unique long-term effects could indicate that it can help long-term and also reduce the burden on the healthcare system
At this time there are three research groups investigating psilocybin for EDs in phase I clinical trials. The studies will answer if, for this population, psychedelics can be a tool for improving mental health. The studies will also need to answer if they can assist in restoring weight to ‘normal’ levels and so also improving physical health.
The paper misquotes the number, or uses the prevalence number out of context, when saying that EDs affect 9% of the population. The closest number is 8.4% and that is lifetime prevalence for women.
Summary
Researchers at the University of Sydney, Australia, have found that cannabinoids may help treat eating disorders.
Abstract
Anorexia Nervosa (AN) is a major health problem with high mortality and treatment costs. Research indicates that classic psychedelic substances, particularly psilocybin, have the potential to normalise dysfunctional neurobiological systems in AN and provide a novel treatment intervention.
- The History and Resurgence of Classic Psychedelics in Medicine
Classic psychedelics are hallucinogenic drugs that have historically been used to induce altered states of consciousness. They include the tryptamine derivatives LSD, DMT, 5-MeO-DMT and psilocybin, and the phenethylamine derivative mescaline.
2010-Present: Efficacy of classic psychedelics has been demonstrated in small studies of depression, anxiety disorders and substance misuse.
Recent clinical trials have focused on psilocybin due to its shorter duration of action and lower potency than LSD. LSD has an unfortunate reputation for causing prolonged psychosis in recreational users.
Psilocybin is considered the classic psychedelic with the least risk of adverse events and no risk of prolonged psychosis. It has recently gained FDA designation as a “breakthrough therapy” for both treatment-resistant depression (TRD) and major depressive disorder (MDD).
- The Effects of Psilocybin
Psilocybin is a psychoactive alkaloid present in more than 100 mushroom species worldwide. It was first isolated from Mexican mushrooms in 1959 by Albert Hofmann.
Psilocybin is metabolised in vivo to psilocin, which has significant affinity for the serotonin receptors 5-HT2A, 5-HT2C and 5-HT1A. Psilocin has an overall duration of 4 – 6 hours.
There have been numerous laboratory studies involving the controlled administration of psilocybin to human volunteers. The doses used ranged from 2 mg to 28 mg.
Psilocybin increases spirituality, emotional empathy, creative thinking, optimism, happiness, mindfulness, motivation, memory recovery, acceptance of others, and emotional breakthrough experiences.
Psilocybin can increase open-mindedness, psychological/cognitive flexibility, readiness to try new activities, and ability to dismantle rigid habitual mental templates. This can result in long-term salutary effects on mental health.
”A bad trip” is an overwhelming and often terrifying experience that can sometimes occur on classic psychedelics, including LSD and psilocybin. Psilocybin can be safe to use in individuals with severe and refractory psychiatric conditions when under careful medical supervision.
- Anorexia Nervosa
Eating disorders such as anorexia nervosa, bulimia nervosa and binge eating disorder affect over 9% of the population worldwide, predominantly women.
AN has the highest treatment costs and mortality of any psychiatric illness, and has a standardised mortality ratio of 5.86. Approximately 2-4% of individuals with AN do not recover and experience life-long persistence of the illness.
- Treatment Approaches for AN
There have been few recent advances in the effective treatment of eating disorders. Individuals with eating disorders often lack motivation to change and are often in denial about their illness.
4.1 Cognitive Behavioural Therapies
Adults with eating disorders are most commonly treated with cognitive behavioural therapy (CBT). However, remission rates are often low and drop-out rates high, making it urgent to improve upon currently available therapies.
4.2 Pharmacological Interventions
There are no currently available pharmacological treatment options for remitting AN, and existing treatments are generally inadequate and associated with significant safety concerns. Novel approaches include the use of the neuropeptide oxytocin, which may reduce food consumption, social cognition, and anxiety.
The psychoactive constituent of cannabis, 9-tetrahydrocannabinol (THC), has well-documented appetite stimulatory effects and a range of potential medical applications. Psychedelic-assisted psychotherapy is of significant interest as a novel intervention for eating disordered patients, although evidence is highly preliminary at present.
Three universities have received approval to conduct phase 1 open-label clinical trials for psilocybin treatment of anxiety disorders.
- Psilocybin Effects in Psychiatric Conditions Co-Morbid with AN
AN frequently appears alongside psychiatric conditions such as anxiety and depressive disorders, substance use disorder, post-traumatic stress disorder, and autism spectrum disorder. Psilocybin therapy has potential for treating AN.
5.1 Anxiety Disorders
Anxiety contributes significantly to the psychopathology of AN, and is a major barrier to weight gain. Childhood anxiety predicts increased caloric restriction, greater ED psychopathology and a lower BMI during acute phases of the illness.
Psilocybin reduced obsessive-compulsive symptoms in 9 patients with refractory OCD, and two small-scale double-blind, placebo-controlled clinical trials are now ongoing.
Psilocybin has been demonstrated to have anxiolytic effects in individuals with a life-threatening cancer diagnosis. At 6-month follow up, 83% of participants maintained clinically significant anxiolytic responses and 57% were in remission.
5.2 Fear, Trauma and PTSD
Intense fear is a key component of PTSD, and is present in individuals with AN towards food and body weight gain. Trauma is a risk factor in the development of eating-related psychopathology.
Psilocybin reduces neuronal activity in the amygdala and hippocampus, regions that process fear and threat-related stimuli, and facilitates the extinction of classically conditioned fear responses in preclinical models.
5-MeO-DMT significantly reduced PTSD symptoms in U.S. Special Operations Forces Veterans, and an increase in psychological flexibility measured by The Acceptance and Action Questionnaire II was strongly associated with reductions of PTSD symptoms.
Major depressive disorder (MDD) is often co-morbid with anxiety disorders and contributes to high rates of relapse during treatment.
Psilocybin produces rapid and sustained antidepressant effects in both MDD and TRD. Six months follow-up found that 42% of patients were still in remission and 67% experienced continued significant improvements.
In a study of 57 patients with MDD, 2 doses of psilocybin were just as effective as a 6-week course of escitalopram, and remission occurred in 57% and 28%, participants respectively.
Psilocybin has been found to improve mood and reduce suicidality in several studies, including patients with life-threatening terminal disease diagnosis, trauma-related psychological and cognitive impairment, and individuals with mild to very severe depression.
Six clinical trials involving psilocybin treatment in depressive disorders are currently ongoing in the United States, United Kingdom and Europe. The results indicate promising efficacy.
5.4 Addiction and Substance Use Disorders
AN is a form of compulsive self-starvation that persists despite obvious self-harm, and is reminiscent of addictions and substance use disorders. It is often preceded by a SUD, with functional use of a drug that reduces appetite in order to enhance weight loss.
Psilocybin is of increasing interest in the treatment of SUDs, with clinical trials currently ongoing for treatment of cocaine use disorder and opioid use disorder.
Psilocybin may reduce repetitive, compulsive, inflexible and obsessional elements present in AN, and may also reduce harmful substance abuse habits.
5.5 Autism Spectrum Disorder
A recent preclinical study reported that psilocybin improves sociability deficits in a mouse model of autism spectrum disorders, and 91 autistic schizophrenic children were given low to moderate doses of LSD over extended periods of time and showed improved speech behaviour, increased emotional responsiveness to their peers, and decreased compulsive ritualistic behaviour.
5.6 Limitations and Significance of Outlined Studies
Studies with psilocybin in mental health and addiction medicine are mostly case reports, open-label feasibility and crossover trials, with very few high quality randomised double-blind controlled trials. However, there is sufficient evidence to propose that psilocybin therapy might well provide an alternative treatment modality for many intractable mental health conditions.
- Psilocybin and the Neurobiology of AN
Although the neural mechanisms underlying the lasting therapeutic efficacy of classic psychedelics in mental health conditions are still uncertain, the acute pharmacological actions of psychedelics on brain serotonergic systems are increasingly well understood.
6.1 Serotonin
Serotonin (5-HT), an indoleamine neurotransmitter, is synthesized from the dietary amino acid tryptophan. 5-HT receptors are distributed throughout the brain and body and are implicated in appetite, mood, pain, emotion, motor function, sleep, cognition, and autonomic and neuroendocrine function.
Many prescription drugs target aspects of the 5-HT receptor, including antidepressants, anxiolytics, antipsychotics, analgesics, anti-emetics, anticonvulsant, appetite suppressant and anti-migraine drugs.
The 5-HT2A receptor is the primary target of all classic psychedelic hallucinogens, but closely related 5-HT2A receptor agonists such as the ergot derivatives, lisuride and ergotamine, are not necessarily hallucinogenic in humans.
Pseudo-hallucinations are sensory alterations caused by the modulation of the corticostriato-thalamo-cortical (CSTC) feedback loop by 5-HT2A agonists and antagonists. Pseudo-hallucinations compromise vivid imagery, illusions, visual-auditory synesthesia as well as distortions in olfactory, gustatory and tactile senses.
Psychiatric disorders such as OCD, MDD and AN display specific abnormalities in 5-HT signalling, and may be associated with polymorphisms of the 5-HT2A promoter (-1438G/A). Additionally, dysregulation of serotonin pathways in limbic structures may contribute to anxiety, behavioural inhibition, body image distortions, mood and impulse control in AN.
6.2 Brain Imaging Studies and Cognitive Flexibility
Psychedelic states induce mystical-type experiences, emotional breakthroughs, openness, ego dissolution, feelings of unity and transcendence of time and space. Increased brain connectivity, associated with increased cognitive flexibility, is hypothesised to ‘reset’ and normalise the brain.
Cognitive rigidity is a key phenotype in AN and contributes to severe anxiety, obsessiveness, impulsive and compulsive behaviours to control weight and food consumption, social introversion, body image disturbances, and obsessions related to perfectionism, symmetry, exactness, and order.
The insula is a brain region that plays an important role in switching between the salience network, executive control network and default mode network.
Psilocybin increases connectivity across brain networks, allowing for increasingly fluid modes of cognition, which may be a major psychological mechanism causing psilocybin’s therapeutic effects. This increased flexibility may help individuals with AN to address and dismantle severely rigidified thought patterns that drive the illness.
6.3 Brain Plasticity and Neurotrophic Factors
Change in cognitive flexibility is one example of neuroplasticity, which underpins learning and memory, brain development, homeostasis and recovery from brain damage.
Brain derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are important for neuroplasticity, reward processing, learning and memory, and weight maintenance.
Neuroplasticity is impaired in AN, and this may correlate with cognitive inflexibility. Reduced levels of GDNF and BDNF are also found in patients with anxiety disorders, mood disorders, and SUD.
In vitro and in vivo evidence suggests that classic psychedelics increase concentrations of neurotrophic factors, which may explain the long-term antidepressant, anxiolytic and anti-addiction effects of psilocybin.
- Safety of Psilocybin
Access to psilocybin is highly restricted in most countries, but the majority of scientific and clinical evidence suggests that the drug is safe and has a very low risk of abuse.
There is no evidence of physical dependence on psilocybin and tolerance builds up rapidly. The metabolites of psilocybin/psilocin exhibit low toxicity and do not accumulate in the body.
Psilocybin and other classic psychedelics can sometimes be thought to provide a model of psychosis, but there is no well-established link between psilocybin use and the lasting induction of psychosis.
Psychedelics can cause physiological changes, including increases in heart rate and blood pressure, but these changes are not hazardous in clinical trials.
Several patients reported anxiety, fear, nausea, paranoia and post-treatment headaches following a psilocybin session. However, none of the patients rated the experience as having decreased their sense of well-being or life-satisfaction, and most reported the challenging experiences as being incredibly effective and having long term benefits.
Recent studies suggest that microdosing of psychedelics can increase creativity, optimism, cognitive functioning, emotional balance, physical stamina and decrease social anxiety and depressive symptoms. However, a fully-fledged psychedelic experience may be required for the effective treatment of refractory psychiatric conditions.
- Conclusions and Future Research
Psilocybin is a safe and effective treatment for severe refractory psychiatric illnesses, and its rapidity and long-term durability suggests that it could be a novel, rapid-acting and cost-effective enhancement to current approaches.
Imperial College, John Hopkins University and the University of California have approved phase 1 clinical trials to examine the safety and efficacy of psilocybin in anxiety disorders.
- Methodology
The literature for this paper was searched using search terms relevant to classic psychedelics and eating disorders, and included peer-reviewed papers of original research, reviews, case-reports and studies on animal models.