Ketamine as adjuvant treatment in eating disorders: an exploratory study of a case series and retrospective analysis

Abstract

Background

Eating disorders (EDs) significantly impair physical health and psychosocial functioning. Few effective therapeutic approaches exist for EDs, particularly in Anorexia Nervosa (AN). The use of ketamine, already characterized as a noncompetitive NMDA antagonist anesthetic in depression and suicidal ideations, could be an innovative adjuvant treatment for the AN spectrum.

Methods

We describe a case series of eight patients treated with intravenous Ketamine Adjuvant Treatment (KAT) combined with usual care. We also review the literature and discuss the theoretical mechanisms behind the influence of KAT in EDs. Our patients were all female, with a diagnosis of AN spectrum, and aged between 16 and 44. We offered KAT attempting to remodel rigid food-centered thoughts. Some sessions were guided by psychomotor or psychological support, thus working on self-image, body perceptions, self-esteem, and sensorial re-exposure to “forbidden” food.

Results

KAT significantly improved BMI, with a coefficient of 0.71 (0.23–1.20, p = 0.002), with a tendency to improve weight regain dynamics from the fourth or fifth infusion onwards. It could also reduce AN psychopathology and obsessive-compulsive-like symptoms (ruminations, cognitive rigidity, guilt), improving clinical evolution.

Conclusions

Our findings underscore the potential of KAT as a therapeutic approach for restrictive EDs as an adjuvant treatment or after failure of first-line treatments. It particularly addresses rigid thought patterns and neurocognitive biases that are notoriously difficult to target. Ketamine’s “pro-plasticity” and “pro-neurogenesis” properties may facilitate this effect. KAT represents a potential tool after failure of first-line treatments. Future research in controlled studies is imperative to corroborate its effect.

Introduction

Eating disorders (EDs) are well-known as persistent disturbances in eating behavior, resulting in altered consumption or absorption of food, which significantly impairs physical health or psychosocial functioning [1]. EDs are prevalent, with a higher prevalence in women (8.4% vs. 2.2%) [2]. Anorexia Nervosa (AN) has a lifetime prevalence of 1.4% (0.1–3.6%) for women and 0.2% (0-0.3%) for men [2], with a higher incidence in high-income countries [3]. Furthermore, EDs accounted for 318.3 (285.7–386.0) deaths in 2019, of which 268.7 deaths (242.5-326.9) were due to AN [3], with total ED years of life lost (YLL) calculated as 17,361.5 (15,518.5–21,459.8) in 2019. Of note, following the COVID-19 pandemic, existing EDs worsened [4, 5], and the incidence of EDs showed an alarming increase, doubling from January - March 2020 to November 2020 - January 2021, especially in women aged 10–19 [6].

The pharmacological and psychotherapeutic treatments currently rely on limited evidence, although efforts have been made to guide the clinical approach [7,8,9]. A recent umbrella review measuring the effects of different pharmacological treatments in EDs found no significant effect for any drug [8]. Common antidepressants (paroxetine and sertraline) improve ED symptoms and traits in some, but not all, studies analyzed [8]. Additionally, opioids, ghrelin, and oxytocin are potential molecules for treatment, but further evidence is needed [8]. Kotilahti et al., studied psychological as well as pharmacological and deep brain stimulation therapies, with inconclusive results where ketamine, olanzapine, and dronabinol were suggested as potential adjunctive therapies [9]. Other promising ED treatment options include psychedelics, which might be able to target ED symptoms like cognitive and behavioral rigidity, distorted body image (DBI), and maladaptive reward processing [10]. Psychedelics could also aid in trauma processing, potentially leading to a treatment for this disorder [10]. The ketamine effect has been studied in mice, showing that ketamine might suppress maladaptive behaviors of AN [11,12,13]. This potential effect has also been suggested in humans, in non-responding patients with severe EDs [14].

Ketamine is an anesthetic derived from phencyclidine [15]. It is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, but effects on other neurotransmitter pathways have also been identified, including opioid sigma and mu receptors, serotonin 5-HT3 receptors, muscarinic receptors, nicotinic acetylcholine receptors and catecholamine transporters [16]. Ketamine is a 1:1 racemic mixture of its enantiomers (R and S). The S enantiomer, commonly referred to as esketamine, exerts a more powerful effect of the NMDA antagonism, thus offering a greater potency [17, 18].

The clinical effects are likely related to enhanced glutamate release due to inhibition of pyramidal neurons, changes in connectivity in cortico-limbic networks, and increased connectivity in the hippocampus and prefrontal cortex [18, 19]. These could be explained by the effect on Glycogen Synthase Kinase-3 (GSK3), Brain-derived Neurotrophic Factor (BDNF) pathways, and the mTOR pathways [16, 18].

Ketamine has primarily been used in treatment-resistant depression [20, 21] and suicidal behaviors [22]. Esketamine has also shown significant, albeit modest, beneficial effects in depression, although no effect was found in suicidality [23]. In recent years, ketamine and/or esketamine use has expanded to encompass a growing number of disorders, including anxiety spectrum disorders [24], obsessive-compulsive disorder, and substance abuse disorders, yielding promising results [15, 25]. Ketamine was first used for EDs in 1998 [26], where it improved compulsion scores in 9 of the 15 patients, who consequently gained weight and resumed menses [26]. Nevertheless, evidence of ketamine treatment in EDs is limited. The few existing publications [14, 26,27,28,29,30] have used ketamine treatment in patients with EDs and concomitant depressive disorders or suicidal risk, which might act as a distractor factor due to the already known anti-depressor and anti-suicidal effect of ketamine [24]. Interestingly, a recent review suggests that ketamine might be effective as treatment in clinical non-respondent ED patients, irrespective of affective symptoms [14].

Here, we present an exploratory study of a case series treated with Ketamine Adjuvant Treatment (KAT) in patients with restrictive ED, i.e., AN spectrum disease, admitted to a full-time psychiatric inpatient unit, specializing in treating EDs, mainly in young adults.

This report presents the cases of eight patients treated with KAT, reviews the literature regarding ED treatment and discusses the alleged mechanisms of KAT effect in ED.

Methods

Study description

From June 2021 to July 2023, we offered KAT to all patients with restrictive ED admitted to our full-time psychiatric inpatient unit at the University Hospital of Nîmes. Eligible patients had previously not responded to standard treatments aimed at improving food intake and weight gain, and did not have other somatic comorbidities or affective disorder comorbidities. None of the patients who were offered KAT declined the treatment.

The usual care offered in our unit includes regular psychiatric monitoring, endocrinological and nutritional somatic monitoring, biological monitoring, and psychological and psychomotor support. Patients can also receive psychotropic drugs to treat anxiety, improve mood, or regulate emotions. Any usual somatic treatments are continued and adjusted. Patients can also receive oral nutritional supplements (ONS) or enteral nutrition (EN) via a nasogastric tube if necessary.

When proposed, patients were informed of the off-label use of ketamine and agreed to this treatment. Patients, and their parents or guardians for minors, were informed and accepted the treatment.

The study was conceived retrospectively after the treatment. The local Institutional Review Board (#23.12.05) approved access to the data.

Clinical data such as diagnosis, use of ONS or EN, weight evolution, height, body mass index (BMI), and pharmacological treatment during the clinical follow-up were extracted.

Description of intervention

KAT consisted of perfusion of ketamine over 40–50 min, once or twice a week. According to the literature, the usual dosing of ketamine was based on 0.5 mg/kg [22]. Doses were modified depending on clinical tolerance and response, with a minimum administered dose of 25 mg and a maximum of 40 mg in our sample.

A registered nurse from the unit administered KAT and monitored the patient’s clinical condition and vitals during the infusion period, followed by post-ketamine monitoring, with an average surveillance of one to two hours, depending on the patient’s clinical condition. Following the positive impact observed for the first patients treated with KAT, as perceived by the physician in charge, psychomotor or psychological guidance was added, if available, to improve results. Half of the patients benefited from this guidance, focused on body self-perception, self-esteem, and food re-exposure.

Statistical analyses

We analyzed data from the entire period of clinical follow-up (from the day of admission until the last recorded visit as an outpatient). Quantitative variables are presented as mean and quartiles, and qualitative variables as numbers and percentages. The effect of KAT on weight gain was evaluated using a mixed linear regression model explaining BMI at each session according to KAT, with a random intercept per patient. The model was adjusted on age, the occurrence or not of psychomotor or psychological guidance, concomitant treatments with potentially orexigenic, anorexigenic, or neutral effects on weight gain, and the prescription of ONS and EN. A subgroup analysis explored the association between BMI and KAT for each patient through a linear regression model. Statistical analyses were performed at the conventional two-tailed α level of 0.05, using R software version 4.1 (R Core Team (2021), Vienna, Austria).

Case presentations

Case 1

Patient 1 was a 16-year-old female. Around one year before admission, she started wearing a therapeutic corset for scoliosis, with little improvement. This triggered progressive weight loss as a compensatory control method (“I control my weight since I cannot control my scoliosis”) by increasing physical activity and food restriction. She started psychological follow-up but continued to lose weight down to 37.1 kg (BMI 13.63 kg/m²), presenting with bradycardia, and was thus admitted to the hospital. After initial somatic stabilization, she was transferred to our unit and a first episode of restrictive anorexia was diagnosed.

On admission, she showed high cognitive rigidity and an overthinking tendency. She presented a DBI and high resistance to weight gain with associated anxiety symptoms, which partially improved with anxiolytic treatment. Mood was preserved and there were no suicidal thoughts. After one month of hospitalization, despite the implementation of well-managed dietary hygiene rules, ONS (188 Kcal) and EN (600 Kcal), weight gain was not significant. KAT was initiated for 11 sessions. She showed progressive improvement, with more flexibility and tolerability to food intake. The caloric intake provided by supplements and EN was therefore reduced, while continuing the ketamine sessions. After gaining more than 10 kg (weight 48.5 kg, BMI 17.81 kg/m²), she was discharged and continued with outpatient follow-up.

Two months later she had a major dental intervention with reduced food intake and loss of 3 kg. She described the return of restrictive thoughts and voluntarily requested hospital admission to improve symptoms. She received two more sessions of KAT with fast improvement, and was released home five days later.

Over the following eight months, she showed a positive evolution, regularly attending follow-up appointments. She showed overall weight stabilization between 46 and 47.5 kg, without rehospitalization. At 10 months of follow-up, a relapse in weight was noted, which was subsequently reversed, though the patient did not wish to be readmitted to the hospital or to resume KAT sessions and was able to improve symptoms on an outpatient basis.

Case 2

Patient 2 was a 17-year-old female patient, previously diagnosed with restrictive AN and epilepsy, treated with Lamotrigine 200 mg per day. Eating symptoms originally started with selective intake restriction and progressive weight loss (basal weight 67 kg; BMI 22.13 kg/m²). She initiated a psychiatric follow-up six months later but continued to lose weight. By month eight, after the start of symptoms, she presented minimal food intake, with severe malnutrition (weight 45.2 kg; BMI 14.9 kg/m²) and bradycardia. She was admitted for somatic stabilization for three weeks, received EN, and was then transferred to our unit.

On admission to our unit, she initially refused to eat, exerting depressive symptoms and suicidal ideation, alongside cognitive rigidity. KAT was started in month nine (weight 44.8 kg; BMI 14.8 kg/m²). She received nine sessions over one month and showed improvement in affective symptoms with cessation of suicidal ideation. She additionally improved her food intake with progressive weight elevation. After gaining 11 kg (weight 55.5 kg; BMI 18.33 kg/m²), she was sent home and continued outpatient treatment.

The evolution was favorable in the first month following the end of KAT, without restrictive relapse. Over the following eight months, she showed a transition towards a phase of bulimia (one year after the first consultation: 77 kg; BMI 25.4 kg/m²), without readmission.

Case 3

Patient 3 was a 16-year-old female with a previous diagnosis of panic attack, which was successfully treated without requiring psychiatric follow-up. Around one year before admission, she started worrying about her physical appearance because of some friends’ comments “You are fat”. She started dieting for a wedding and lost control afterward, maintaining restrictive behaviors. She lost weight (down to 38 kg, BMI 14.8 kg/m²) and needed hospitalization. During that hospitalization, she gained weight up to 41.7 kg (BMI 16.3 kg/m²) and was sent home. Nevertheless, she was unable to maintain stability at home and lost weight again, down to 38.7 kg (BMI 15.1 kg/m²), prompting admittance to our unit.

On admission, she presented a restrictive AN with cognitive rigidity and DBI, without depression or suicidal ideation. She was started on EN and experienced anguish because of high resistance to weight increase. KAT was initiated, and six sessions were received, with an impressive improvement in cognitive rigidity, ruminations, and guilt after meals. She gained weight up to 44.8 kg (BMI 17.5 kg/m²) and returned home to continue treatment on an outpatient basis.

The evolution was positive. Over the following five months, she maintained a progressive weight gain (49.8 kg, BMI 19.45 kg/m2) with clinical stabilization. She never required rehospitalization or further KAT.

Case 4

Patient 4 was a 20-year-old female. She was previously diagnosed with binge-purging AN with continually fluctuating disease evolution. Her disease history began at age 14 when she exerted purging and excessive psychical activity. At 17 years old she progressed to a more restrictive binge pattern, persisting with vomiting. At that same age, she received the diagnosis of type I diabetes and started endocrinologist follow-up and treatment. She started losing weight and was admitted to another healthcare center for eight months. After hospitalization, due to the increased frequency of binging and purging, she was hospitalized in our unit.

During admission, she presented high cognitive rigidity and DBI, without depression or suicidal ideation. She experienced loss of control while eating, feeling guilty immediately after meals, and persisted with purging. KAT was initiated, for six sessions, showing a positive evolution, with improvement in cognitive rigidity thus allowing more permeability for the psychological approach. She reduced binging and purging, gained some stability, and was discharged from the inpatient unit one month later (51.7 kg, BMI 18.32 kg/m²). However, over the following eight months, a weight relapse led to a second hospitalization (47.2 kg, BMI 16.72 kg/m²) with seven additional KAT sessions but without achieving clinical stability afterward and she continued to show clinical and weight fluctuation (with BMI oscillating from 16.3 to 18.3 kg/m²).

Case 5

Patient 5 was a 16-year-old female, who first showed restrictive AN symptoms at age 16, presenting progressive intake restriction, calorie counting, increased physical activity, and evolving DBI. She started psychological follow-up, yet continued to lose weight (11 kg in the following four months, weighing 46 kg, BMI 16.69 kg/m²), being then admitted to our unit.

On admission, she showed traits of perfectionism and cognitive rigidity. She had difficulties increasing food intake, experiencing anxiety around meals and DBI, without depression or suicidal ideation. She received five sessions of KAT, with an impressive improvement in cognitive rigidity. She gained around 5 kg (52 kg, BMI 18.87 kg/m²) and normalized intakes. She was therefore sent home and continued outpatient follow-up.

Eleven months after the end of KAT, evolution remained favorable with nutritional stabilization and a slight improvement in weight (53 kg, BMI 19.23 kg/m2).

Case 6

Patient 6 was a 44-year-old female with a previous history of obesity (maximum weight of 95 kg, BMI 35.8 kg/m²). She tried dieting and exercising for five years, initially without the desired effect, but finally lost 30 kg in a short period, stabilizing at 62 kg (BMI 23.3 kg/m²). During the COVID-19 lockdown, because of the sudden interruption of physical activity, she started worrying about gaining weight. Therefore, she started intensive cardio workouts alongside progressive intake restriction. She lost weight down to 40.6 kg (BMI 14.91 kg/m² at admission) when she was admitted to the endocrinology unit for restrictive and purging AN, where she continued to lose weight (after one month of hospitalization: weight 39.7 kg, BMI 14.94 kg/m2). Therefore, KAT was initiated independently of thymic or suicidal symptoms. After somatic stabilization, she was transferred to our psychiatric unit to continue KAT and a specific psychiatric approach. She received 13 KAT sessions over a month and a half. The evolution was positive, with a gradual improvement in food intake and weight (48.6 kg, BMI 18.29 kg/m2) prompting return home. She initially maintained good evolution (Month 7: 59 kg, BMI 22.2 kg/m2). However, six months after the end of the KAT, a relapse was noted, with a loss of 10 kg between months 8 and 12. She, therefore, received another course of KAT with a total of six sessions, with the same beneficial effect (Month 16: 59 kg, BMI 21.67 kg/m2).

Case 7

Patient 7 was a 21-year-old female with a diagnosis of restrictive AN for five years. Her disease history started when she was 10 years old. She was on a gymnastics team, exposed to food intake limitation and weekly weight control. She practiced sports for around 30 h each week. At age 15 she left the team because of injuries, reducing sports practice to around 15–20 h/week. Over five months, she gained 10 kg and had her first menarche. The next year, she started to worry about weight and increased sports activity, stabilizing her weight at 54 kg (BMI 20.1 kg/m²). In the following years, the patient started progressive intake restriction with weight loss down to 46 kg (BMI 17.1 kg/m²), upon which she had her first contact with a nutritional center and was followed up by her general practitioner. During the COVID-19 pandemic, she increased control of her food intake and physical activity and was hospitalized for the first time in 2 months. Despite gaining weight, she experienced a relapse into food restriction and intense physical activity behaviors soon after discharge. She was referred to our center and despite multidisciplinary follow-up for some months, she continued to lose weight down to 39.8 kg (BMI 14.8 kg/m²). At that point, a physical examination revealed lanugo, edemas during the evenings, and lymphopenia, with hypoalbuminemia and altered renal shape and size, therefore, she was admitted for inpatient treatment.

On admission, mood was preserved and there were no suicidal thoughts. However, she showed high resistance to progressive normalization of food intake and weight gain. She showed little improvement with psychotherapy or anxiolytic treatment so KAT was initiated. She received 11 sessions over six weeks, showing positive results, with fast improvement in cognitive rigidity, being more permeable and flexible to psychotherapeutic approach, with consecutive weight gain. After gaining almost 5 kg (Week 6: 44.6 kg, BMI 16.58 kg/m²), she was sent home and continued outpatient treatment. She maintained stability of intake and weight (Month 16: 49.5 kg, BMI 18.4 kg/m²). Additionally, she continued her university studies and is progressively resuming a normal life. To date, she has not required rehospitalization or new KAT sessions, and the positive effects seem to continue.

Case 8

Patient 8 was a 19-year-old female, diagnosed with restrictive and purging AN. She had been admitted to our unit several times before for AN relapse and undernutrition. The minimum weight reached was 37 kg (BMI 14.68 kg/m²) and the maximum was 42 kg (BMI 16.7 kg/m²). She had a previous history of pathological bereavement and post-traumatic stress disorder secondary to the abrupt death of a parent, for which she received treatment and is currently asymptomatic. She presented renewed restrictive behaviors five years later, losing weight down to 39 kg (BMI 14.33 kg/m²), and was admitted to our unit.

Since admission, she exhibited restrictive behavior, with consecutive loss of weight of almost 1 kg during the first week of admission. The patient showed high cognitive rigidity alongside DBI, but without depression or suicidal ideation. She was started with parental nutrition, which triggered anguish. Therefore, KAT was initiated and she received 19 sessions over 11 months. She showed cognitive improvement, gaining flexibility, with consequent improved food intake and weight increase. She gained weight up to 44.3 kg (BMI 16.27 kg/m²). She was released home, continued follow-up on an outpatient basis, and restarted her studies. Five months after stopping KAT, the evolution remained very favorable with continued weight gain, which the patient linked to the perceived effectiveness of KAT (Month 18: 51 kg, BMI 18.73 kg/m²).

Results

In our sample, 100% of patients were female, 55.6% were younger than 19, 77.8% were younger than 25, and 88.9% were younger than 30, and most were diagnosed with restrictive AN. The duration of disease varied from a few months to over six years, implying different stages of the AN spectrum disease. The follow-up ranged from 7.3 to 25.7 months, with follow-up weight and BMI measured per patient between 15 and 28 times. Patients of the sample received a minimum of 5 and a maximum of 19 KAT sessions. Four patients (50%) had psychomotor or psychological guidance during KAT, of which two (25%) benefited from it at all their sessions (Table 1).

Table 1 Patients’ characteristics. BMI = Body mass index; kat = ketamine adjuvant treatment

The effect of KAT on BMI was statistically significant for six patients (75%), with a coefficient of 0.71 (0.23–1.20, p = 0.002) (Tables 2 and 3). The improvement in BMI was observed independently of mood or suicidal ideation. The change in BMI is represented over time per patient (Supplemental materials S1 and S2). Figure 1 represents all patients on the same graph with a t0 determined by the first KAT administration.

Table 2 Linear regression analysis of impact of factors on BMI. BMI = Body mass index; NG tube = nasogastric feeding tube; ons = oral nutritional supplements

Table 3 Per-patient analysis of KAT estimated effect on BMI. BMI = Body mass index; kat = ketamine adjuvant treatment

Fig. 1

Change in BMI according to KAT. KAT sessions are denoted with dots connected by continuous line. KAT sessions mediated by psychomotor or psychological guidance are indicated by crosses. Weight monitoring outside the KAT sessions is represented in dotted lines. BMI = Body Mass Index; KAT = Ketamine Adjuvant Treatment

A tendency to improved weight gain pattern was observed from the fourth or fifth KAT session onward. This was associated with consistently reported improvement in intrusive thoughts (centered on food, calories or body shape) and obsessive-compulsive-like symptoms (ruminations, cognitive rigidity, and guilt). No side effects of KAT were reported. Also, an orexigenic effect of pharmacological treatment on BMI was found, with a coefficient of 1.60 (1.04–2.17, p < 0.001).

Discussion

According to the literature, some pharmacological treatments might have a positive impact on weight gain, while others might help by acting on the psychopathology of EDs [31]. Nevertheless, the literature is inconclusive on the effect of treatments in EDs, and new therapies are being studied, with psychedelics gaining attention [32]. Our sample reflects the epidemiological demographics usually described for EDs [2], being predominantly female and young. In our case series, KAT had a net significant effect on weight gain, with consistent result in six of the eight patients suffering from restrictive EDs, supporting the application of KAT regardless of the clinical stage of the AN spectrum disease [33].

Our data contribute to support the benefit of (es)ketamine as a treatment option, although the mechanisms of impact of ketamine on the psychopathology of patients are unclear. Here, we observed a clinical improvement in the intrusive food-centered thoughts and obsessive-compulsive-like symptoms (ruminations, cognitive rigidity, and guilt), frequently observed in patients with AN, as a consequence of KAT, improving clinical evolution. Similarly, we found weight gain and improvement of BMI, with a pattern of response after four to five KAT sessions, which might reflect the underlying effects on the psychopathology of the disorder.

Historically, ketamine was initially used for its soothing attributes but has lately been used as a fast-acting antidepressant and for suicidal ideation [34, 35]. It is proposed to inhibit NMDA receptors in the GABAergic interneuron to activate glutamate release in the prefrontal cortex [36], which might play a role in improving EDs symptoms. This glutamate activation contributes to activating α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors and the mTOR signaling pathway [36]. In turn, mTOR pathway activation leads to dendrite proliferation, with a pro-plasticity effect contributing to restoring synaptic connectivity, proposed to be the basis of neuroplasticity secondary to ketamine treatment [37] permitting “readaptation” of synapses.

Additionally, ketamine has an anti-inflammatory effect [38]. This might be important since chronic malnutrition seen in AN is accompanied by inflammation [39] and potentially diminished neurogenesis. Ketamine has been shown to elevate BDNF in people abusing ketamine [40]. In some studies, increases in BDNF have been associated with the neurotrophic properties of ketamine [41]. In contrast, a recent meta-analysis showed no changes in peripheral BDNF in humans associated with the use of psychoplastogens, suggesting that signaling may not be the best marker of neuroplasticity [42]. Future research may clarify this discrepancy.

In the context of EDs, ketamine may contribute to a reduction in inflammatory cytokines and an increase in BDNF, thereby enhancing neurogenesis and neuroplasticity [37]. We hypothesize that adjuvant psychomotor or psychological guidance during and after administration might maximize its potential, harnessing the effect on neurogenesis and neuroplasticity to restructure thoughts and other psychological aspects of the disease.

Few other studies have focused on ketamine in EDs, and more evidence is needed. A pilot study tested a therapeutic ketogenic diet combined with ketamine infusions to improve AN symptoms, with positive results. The authors proposed that ketosis, by changing the source of energy, protects dopaminergic neurons from neurotoxicity which, combined with ketamine treatment, contributes to dopamine release and emotional processing. These effects together appeared to improve AN symptoms [43].

Other hypotheses support ketamine as a promising treatment in AN. Ketamine’s effect in glutamatergic synapses helps lower the neurotoxicity arising from zinc depletion secondary to chronic malnutrition seen in AN [44]. Zinc is an allosteric modulator of NMDA receptors, frequent in the limbic system. In severely malnourished patients, zinc depletion causes hyperactivation of NMDA receptors and decreased GABA activity, leading to neurotoxicity, low neuroplasticity, and neurogenesis [44]. Thus, ketamine might help restore normal glutamatergic functioning. Low-dose ketamine and adjunctive zinc treatment could be a promising therapeutic strategy in AN [45].

Furthermore, there are psychopathological and neurobiological similarities between EDs and obsessive-compulsive traits [46], such as intrusive, repetitive, ego-dystonic thoughts and consecutive compulsion. Ketamine has proven efficacy in OCD, reducing obsessions and compulsions [25], which could reflect effectiveness in common pathways with EDs where global functioning resembles that of OCD.

Finally, patients with EDs demonstrate serotoninergic hypo-functionality -presenting as obsessions and anxiety- and also impairment in the reward system [37]. All these symptoms may be perpetuated by elevated inflammation, reduced neuroplasticity, and lower cognitive flexibility, worsening symptoms. Additionally, BDNF reduction might explain other anatomical disturbances like the diminution of gray matter in the hippocampus [37]. In response to these disturbances, ketamine could improve serotoninergic synapses, and therefore the reward system function, reestablish adequate neuroplasticity and neurogenesis with consequent normalization of BDNF level, and even increase hippocampus volume.

Altogether, we hypothesized that KAT could be a promising approach in patients with EDs, mobilizing the “pro-plasticity and pro-neurogenesis” effect of ketamine, potentially improving rigid thoughts and neurocognitive biases of EDs, which is normally difficult to work in therapy. Therapy could be offered either to accompany or facilitate the psychedelic experience to remodel EDs (and especially AN) thoughts while working on self-image and body perceptions, self-esteem, and sensorial re-exposure to “forbidden” foods. All these approaches, in particular the food re-exposure, improved the initially persistent and disabling intrusive food-centered thoughts of our patients, which had arisen due to reactive anxiety, secondary to weight gain and food intake.

Another hypothesis for the effect of KAT in EDs is the dissociative effect induced by ketamine. Indeed, ketamine can induce different drug-induced dissociative states, such as ‘ideolytic effects’ (dilution of thoughts, including anxiety-provoking negative ones), ‘decorporation’ (altered perceptions of one’s body, autoscopy/out-of-body) or ‘dysmorphopsia’ (altered proprioception). Furthermore, ketamine could also reduce the accuracy of body perception predictions via interoceptive predictions [47], which is connected to one of the central characteristics of these disorders. The dissociative experience induced by ketamine could be specifically studied in EDs to better understand the changes in perceptions and representations of one’s body in time, space, proprioception and interoception. The use of KAT could then offer a pharmacological model of dissociation in EDs, and could pave the way for (es)ketamine-assisted psychotherapy in EDs.

All these theories may explain the positive effects of KAT in our sample. Given the current limitations of pharmacological interventions for EDs, the use of (es)ketamine presents a potential new therapeutic avenue worth exploring. It is important to note that this treatment does not replace the established multidisciplinary approach that is recommended for this population. However, the neurobiological effects of ketamine may facilitate changes that enable a clinical response in cases where previous interventions have proven ineffective, thereby enhancing the likelihood of a positive clinical outcome. Consequently, we advocate for considering (es)ketamine treatment in patients who have not responded to other pharmacological options, always in conjunction with a comprehensive multidisciplinary strategy.

To our knowledge, this case series is unique in studying KAT targeting nuclear symptoms of EDs, specifically AN without depression or suicidal ideations. Nevertheless, we acknowledge some limitations. Firstly, our sample size was small, with a modest number of EDs represented (restrictive AN, restrictive and purging AN, anorexia-bulimia), limiting generalizability. Secondly, this case series is based on a retrospective analysis of off-label KAT use in our service, thus, the intervention did not include a rationale of the intervention. Therefore, the therapeutic pathways were highly heterogeneous (in response to the clinical picture of each patient), with patients receiving between 5 and 19 KAT sessions, of which some patients exclusively had psychomotor or psychological guidance, while others had none. Furthermore, no standardized measurements were employed to quantify improvements. Future prospective interventional studies are now needed with adequate design and structured KAT protocols for dose, frequency and number of doses, as well as standardized methods to evaluate response, to determine the effect of KAT in EDs.

In conclusion, according to our data, we suggest that KAT might be helpful in patients with restrictive EDs (regardless of the clinical stage of the AN spectrum disease), in patients who have not responded to previous pharmacological treatments. Specifically, KAT should be an adjuvant treatment, only used in conjunction with a comprehensive multidisciplinary approach. The clinical effect seems to be due to influence in the psychopathology of EDs, but also with a direct impact on weight. These effects might be related to all or some of the known actions of (es)ketamine: the synapse level action (modifying neurotransmitter’s dynamics); induced neurogenesis and neuroplasticity; anti-inflammatory properties; and dissociative effect.

Future research is imperative to corroborate its effect and explore new therapeutic options such as KAT and zinc.