Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature

The obsessive–compulsive spectrum refers to disorders drawn from several diagnostic categories that share core features related to obsessive–compulsive disorder (OCD), such as obsessive thoughts, compulsive behaviors and anxiety. Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily preoccupation (i.e., eating disorders, ED) or impulse control (i.e., substance use disorders, SUD), and they exhibit intriguing similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes. The non-competitive N-methyl-D-aspartate receptor (NMDAr) antagonist ketamine has been indicated to produce remarkable results in patients with treatment-resistant depression, post-traumatic stress disorder and OCD in dozens of small studies accrued over the past decade, and it appears to be promising in the treatment of SUD and ED. However, despite many small studies, solid evidence for the benefits of its use in the treatment of OCD spectrum and addiction is still lacking. Thus, the aim of this perspective article is to examine the potential for ketamine and esketamine in treating OCD, ED and SUD, which all involve recurring and intrusive thoughts and generate associated compulsive behavior. A comprehensive and updated overview of the literature regarding the pharmacological mechanisms of action of both ketamine and esketamine, as well as their therapeutic advantages over current treatments, are provided in this paper. An electronic search was performed, including all papers published up to April 2021, using the following keywords (“ketamine” or “esketamine”) AND (“obsessive” OR “compulsive” OR “OCD” OR “SUD” OR “substance use disorder” OR “addiction” OR “craving” OR “eating” OR “anorexia”) NOT review NOT animal NOT “in vitro”, on the PubMed, Cochrane Library and Web of Science online databases. The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The use and efficacy of ketamine in SUD, ED and OCD is supported by glutamatergic neurotransmission dysregulation, which plays an important role in these conditions. Ketamine’s use is increasing, and preliminary data are optimistic. Further studies are needed in order to better clarify the many unknowns related to the use of both ketamine and esketamine in SUD, ED and OCD, and to understand their long-term effectiveness.


Introduction
Glutamatergic neurotransmission plays a critical role in modulating the activation of the cortico-striatal-thalamus circuitries that occur in OCD [1][2][3]. Several glutamate modulators, including memantine, topiramate and lamotrigine, have been evaluated, but they are still not approved for the treatment of OCD [1,[3][4][5][6]. Ketamine, an aryl cyclohexylamine derivative synthesized in 1962, was first introduced into clinical practice as an intravenous (IV) anesthetic agent in 1970 [7]. Ketamine is currently prescribed for the induction and maintenance of general anesthesia via intramuscular (IM) or IV infusion; moreover, over the past two decades, it has emerged as a promising treatment for major depressive disorder (MDD) [8,9]. In addition, increasing evidence now points to its therapeutic efficacy in treatment-resistant depression (TRD), as well as a potential agent for reducing and preventing suicide in depressed patients, as it exerts rapid antidepressant properties as early as several hours after administration. This contrasts with traditional antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]), that usually require several weeks for clinical responses [9][10][11][12][13][14][15]. An intranasal formulation of esketamine, currently branded as Spravato ® , was approved by the Food and Drug Administration (FDA) in the United States in March 2019, and by the European Commission in December 2019, for [16,17] the treatment of TRD, defined as the lack of response to two or more adequate trials of antidepressant medications in a current moderate to severe depressive episode [12,17,18]. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder [18][19][20]. The interest in the use of ketamine in OCD stems from its rapid antidepressant effect after only a single intravenous infusion [21] The rapid reduction in depressive symptom scores, even in those with refractory depression, led us to investigate its alleged use in OCD and OCD spectrum disorders.

Ketamine's Mechanisms of Action
Ketamine is a racemic mixture composed of both R and S enantiomers (50% each). Compared to R-ketamine, esketamine (the S-enantiomer of racemic ketamine) is a more potent antagonist at the phencyclidine site of the ionotropic glutamate receptor, N-methyl-D-aspartate (NMDA), and it therefore offers a stronger analgesic potency than either R-ketamine or the racemic mixture [9]. Ketamine, through its action as an NMDA receptor (NMDAr) antagonist, produces a transient increase in glutamate release, while also activating the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAr), which are both suggested to play a role in the antidepressant effects of ketamine [20,21]. It ultimately induces an array of molecular and cellular events [12,22,23] that include: (i) increases in brain-derived neurotrophic factor (BDNF) expression, synthesis and release [12,22,24]; (ii) activations of neurotrophic signaling pathways, such as extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and protein kinase B (AKT) [12,23]; (iii) inhibition of glycogen synthase kinase (GSK)-3; and (iv) activation of synaptic plasticity genes, such as those related to the activity-regulated cytoskeleton (ARC)-associated protein [20,25]. All these changes increase the levels of synaptic proteins and synaptogenesis, and eventually favor the restoration of synaptic function [9,12,23,25]; additional effects mediated by the modulation of monoaminergic neurotransmission cannot be excluded [12,22,23]. In this respect, one noteworthy observation is that acute and prolonged increases in dopamine levels in the prefrontal cortex, striatum and nucleus accumbens occur immediately after administering sub-anesthetic doses of esketamine [14]. Other possible cellular targets of ketamine include opioid (mu, delta and kappa) receptors, and ketamine binding to these receptors has been proposed to contribute to its anti-suicidal and antidepressant effects [16]. A better understanding of the impact of ketamine binding on serotonin, opioid, dopamine and cholinergic receptors [22,26] is needed for a full assessment of the therapeutic potentials of ketamine, especially with regard to mental health disorders. Of note, different preclinical models reported that it is unlikely that NMDA inhibition alone could play a major role in the antidepressant effects of (R,S)-ketamine, opening the door for future studies and major developments [27].

The Role of the Glutamatergic System in Mental Diseases and OCD
The excitatory neurotransmitter glutamate is prevalent throughout the central nervous system (CNS), and it has been found to play important physiological roles in neurodevelopment, cognition, learning and memory formation, as well as in the modulation of brain plasticity [28]. Glutamatergic neurons constitute approximately 80% of the synapses in the neocortex [29]. Glutamate activates various downstream pathways of nuclear genes by binding to a variety of membrane-bound receptors present on the postsynaptic membrane, which regulate secondary messenger systems. Excessive glutamate release can be toxic to the brain and has been linked to many neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. A growing body of evidence also indicates that abnormalities in glutamatergic neurotransmission play an important role in the development of many major psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and OCD. Glutamatergic neurotransmission plays a critical role in modulating the activation of the cortico-striatal-thalamus circuitries that occur in OCD [1][2][3]. Several glutamate modulators, including memantine, topiramate and lamotrigine, have been evaluated, but they are still not approved for the treatment of OCD [1,[3][4][5][6]. Recent preclinical, imaging and genetic studies support a specific role for glutamatergic transmission in OCD, also opening possible perspectives in the obsessivecompulsive spectrum [6]. The obsessive-compulsive spectrum refers to several mental health disorders encompassing several diagnostic categories that share core obsessivecompulsive features, such as anxiety, obsessive thoughts and compulsive behaviors [1]. Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily preoccupation (i.e., eating disorders [ED] and body dysmorphic disorder) or impulse control (i.e., substance use disorder [SUD], gambling disorders, trichotillomania and other behavioral addictions). Although distinct from one another, these disorders share similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes. They can also be viewed as part of a continuum that spans from compulsivity to impulsivity, and they are characterized by harm avoidance as far as compulsion or risk-seeking for impulsivity. They also share a common neurobiological background, including the presence of abnormalities in the glutamatergic neurotransmission, that can be the target of common therapeutic interventions [30][31][32][33][34][35][36][37][38]. In this respect, Ketamine, which is able to produce a transient increase in glutamate release, could represent a valuable therapeutic option.
Aim of the study: To the authors' knowledge, no review has synthesized the published data on the therapeutic potentials of ketamine and esketamine in the OCD spectrum by focusing on OCD, SUDs and EDs. In this perspective article, we have analyzed and reviewed current evidence on the drug efficacy of ketamine and esketamine in these mental disorders, and we have evaluated their advantages compared with currently available therapeutic tools. We have also outlined potential therapeutic opportunities for further investigation.

Data Extraction
The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [39]. A literature search was performed using PubMed, Medline and Web-of-Science databases in April 2021, without any time restrictions. We used the following search terms: "ketamine" or "esketamine") AND ("obsessive" OR "compulsive" OR "OCD" OR "SUD" OR "substance use disorder" OR "addiction" OR "craving" OR "eating" OR "anorexia") NOT review NOT animal NOT "in vitro". In addition, we performed further secondary searches by using the reference listing of all eligible papers.

Data Synthesis Strategy
The search of results was carried out individually by five investigators (A.M. (Alessio Mosca), A.M. (Andrea Miuli), F.D.C., G.D., R.C., I.D.M.) and supervised by S.C. and M.P.; doubtful cases were discussed by G.M., M.D.G. and SS. The selection and eligibility phases of the articles were carried out independently by the five selected members and, afterwards, the papers were subjected to a final cross-check. Any questions not solved by the team related to understanding the topic covered in the articles were requested directly from authors, if they were contactable. The data were collected in a Word table containing first names and year of publication of the study, the design, demographic variables (gender, age, psychiatric history), details of the NPS taken (dosage, route of administration) and any other substances in combination, as well as the drugs' effects on suicidal behaviors, suicidal ideation or abuse. Data synthesis was carried out by three independent members of the team (A.M. (Alessio Mosca), F.D.C. and G.D.) and compared at the end of the extraction process. All titles/abstracts were examined, and full texts of potentially relevant papers were obtained. Relevant works were selected in order to obtain a full representation of the available literature data on the selected topic. Experimental and observational studies, post-marketing surveillance reports, case reports, case series and fatality reports were included. The exclusion criteria included non-original research (e.g., reviews, commentaries, editorials, book chapters and letters to the editor), non-full-text articles (e.g., meeting abstracts), works in a language other than English and studies involving animal/in vitro experiments. Although letters to the editor, conference proceedings and book chapters were excluded from the literature review, they were still considered in the retrieval of further secondary searches. contributed to the analysis of the results and discussed possible issues and disagreements during the revision of the paper. From an initial list of 1125 studies, duplicates (n = 257) were eliminated, as were papers unrelated to the topic (n = 631) and those that did not meet the inclusion criteria (e.g., reviews, letters to the editor, commentary, book chapter n = 75; non-English papers n = 50). A total of n = 113 full-text articles were assessed for eligibility. From them, a number of 83 full-text articles were excluded, as they were considered irrelevant to the subject when reading their titles and abstracts (animal/in vitro studies, not dealing with ketamine or esketamine, not dealing with the treatment of OCD, addiction, SUD or ED). Finally, 30 studies were included in the qualitative synthesis ( Figure 1).

OCD
According to the literature [3,40,55], ketamine via IV infusion significantly improves obsessive-compulsive symptomatology, with effects that are rapid (occurring in hours to minutes) but short-lasting (days to weeks) [13,40,45,47,55,56,[60][61][62][63]. Interestingly, CBT prolongs ketamine effects [30,40,43,56,69]. Recently, a maintenance treatment with oral Sketamine combined with experimental deep-brain stimulation showed long-term (18 months) beneficial effects in a patient with severe TRD and comorbid psychotic and obsessivecompulsive symptoms [13]. Two other studies showed that ketamine infusions were effective in patients diagnosed with treatment-resistant OCD, and that the ketamine effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated [60,61]. A further proof-of-concept study that examined the time course of neurochemical effects of a single IV infusion of ketamine in OCD subjects confirmed that ketamine significantly increased gamma-aminobutyric acid (GABA) levels-but not glutamate levels-over time in the medial prefrontal cortex (MPFC). This increase was positively correlated with changes in OCD symptoms and was consistent with other recent studies suggesting that ketamine concurrently activates a subpopulation of GABAergic interneurons and projection neurons in the cortex [63].

SUD
A single-case trial with repeated ketamine IV infusions (0.5 mg/kg) over the course of 6 weeks produced positive results in a TRD patient with a co-occurring SUD (alcohol and benzodiazepine dependence) [65]. KPT was shown to reduce relapses in recently detoxified inpatients suffering from alcohol use disorder (AUD) [58,68,70]. Similarly, Dakwar et al. [50] evaluated the use of ketamine and motivational enhancement therapy in alcohol-addicted subjects and found positive effects in initiating and sustaining abstinence after 12 weeks of treatment. When combined with motivational enhancement therapy, the psychoactive/mystical effects of ketamine on alcohol-prone behavior were critical for producing a significant reduction in alcohol consumption [54]. Ketamine was also useful as adjunctive medication for managing severe alcohol withdrawal syndrome and reducing benzodiazepine requirements [71]. Interestingly, drinkers who are at risk of abuse benefited from ketamine infusions, in conjunction with a behavioral procedure called retrieval/destabilization focused on maladaptive alcohol reward memories; they showed reductions in the reinforcing behavior driven by drinking and decreased alcohol consumption when evaluated at the 9-month follow-up [53]. Currently, a phase II, multisite, randomized, double-blind, placebo-controlled, parallel-group clinical trial is ongoing to investigate the effectiveness of IV ketamine in reducing relapse rates in recently detoxified alcohol-dependent individuals with depressive symptoms at the 6-month mark [72]. However, a recent study produced conflicting results on the combined use of naltrexone and ketamine for the treatment of patients with AUD and comorbid depression [63].
In Cocaine Use Disorder (CUD), a comparison with lorazepam infusion revealed that IV ketamine effectively enhanced the motivation to quit and reduced cocaine cravings. Remarkably, these results were obtained after the first ketamine infusion [66]. A comparison with the active control midazolam also showed significantly greater reductions in cocaine use, relapse rate and cravings with infusions of ketamine [50,52].
An evaluation of ketamine treatment in a 2-year follow-up study, including 70 heroindependent patients with Opioid Use Disorder (OUD) and randomized to a single low dose IM ketamine (0.2 mg/kg) injection or a high dose one (2 mg/kg), showed that KPT was effective at maintaining abstinence and reducing cravings within the first two years of follow-up. A greater and longer-lasting reduction in cravings was obtained with high doses rather than low doses of ketamine, indicating a dose dependence of the effects [58]. Moreover, multiple sessions of KPT resulted in significantly higher rates of 1-year abstinence and lower cravings [58,68]. A combination of ketamine, repetitive transcranial magnetic stimulation (rTMS) and mindfulness therapy appeared effective for maintenance of abstinence in OUD, particularly in terms of reducing cravings [56]. Ketamine was also found to be useful in suppressing the physiological symptoms of opioid withdrawal (e.g., increases in heart rate, cortisol levels and arterial pressure) [57,70].

ED
The first attempt to treat non-responder AN subjects with ketamine infusions was made in the late 1990s by Mills et al., who reported prolonged symptom remissions in 15 patients with a chronic, complex history of AN (i.e., comorbid compulsive eating [n = 4] and/or bulimia [n = 5]; 30% of the patients were a restrictive subtype of AN) after treatment with 2-9 ketamine infusions at intervals of 5-21 days [42]. IM ketamine was administered with repeat dosing at 4-6 week intervals in four patients chronically ill with an ED for more than 7 years, and current criteria for TRD show clinically meaningful changes in depression, and to a lesser degree anxiety, and ED symptoms [46]. An interesting recent case report of a 29-year-old woman with a long history of severe AN and intermittent alcohol dependence, and diagnosed with major depressive disorder, indicated complete recovery after a ketogenic diet associated with ketamine infusions [48].

Discussion
To the very best of our understanding, current data represent the first literature review focusing on the use of ketamine and esketamine as a treatment for OCD, SUDs and EDs. Overall, studies have been recorded in the past ten years, a signal that increased interest in the use of ketamine for the treatment of depression, as well as psychiatric disorders, has developed among researchers. Regarding current findings on ketamine as a therapeutic tool in OCD, SUD and ED, some considerations are needed.

Ketamine in OCD
The anti-obsessional effects of ketamine and NMDA receptor antagonists do show therapeutic potential. However, studies appear to be heterogeneous, and comparative studies with conventional therapeutic strategies were not reported in the current literature. The current evidence is still not strong enough to recommend ketamine for clinical practice at this time. The acute benefit of ketamine on OCD symptoms needs to be confirmed in controlled trials and cannot be divorced from the psychomimetic and dissociative effects of ketamine. Additionally, we cannot eliminate the possibility that other environmental effects caused acute changes in OCD symptoms. Current speculations are that the clinical effects may relate to the ketamine-induced mystical experiences rather than to a direct effect on NMDA receptors causing a transient increase in glutamate release [48,66]. A separate ques-tion is whether abnormalities in the glutamate system could be considered a fundamental cause of OCD, or whether they are a downstream consequence of other processes that are more primary to the pathophysiology. It is widely accepted that OCD is characterized by neuronal hyperactivity in definite key brain areas-mainly the orbitofrontal cortex, the caudate nucleus and the anterior cingulate cortex [73,74]. It is possible that the observed abnormalities in glutamate in patients with OCD are simply a consequence of this hyperactivity. In light of this, the role of ketamine/esketamine should be reconsidered. Future research is warranted to establish the parameters of ketamine's efficacy. With larger clinical RCTs, a stronger argument can be made for future modifications of guidelines regarding patient care in this population.

Ketamine in SUD
Chronic use of addictive drugs produces enduring neuroadaptations in the corticostriatal glutamatergic brain circuitry. Increased susceptibility to relapse in drug-experienced individuals, even after long periods of withdrawal, might be associated with drug-related long-term morphological and electrophysiological changes in the glutamatergic synapses in the nucleus accumbens which, together with drug-induced transient morphological and electrophysiological changes, might both impair normal information processing and contribute to the uncontrollable motivation to relapse [75]. In the area of SUD, the use of ketamine appears to be promising, with most evidence in alcohol use disorder. This specific affect can be justified by the strongest role of glutamatergic neurotransmission in alcohol use disorders. The use and efficacy of ketamine in SUD are supported by the glutamatergic dysregulation and altered functioning of the prefrontal cortex and mesolimbic regions that occur in this condition [68,[76][77][78]. Meye et al. [76] found that, in mouse lateral habenula (LHb) neurons targeting the rostromedial tegmental nucleus, cocaine enhanced glutamatergic transmission, increased excitability, influenced drug-driven aversive behaviors and shaped negative symptoms after drug taking. While a direct effect of ketamine on the reward system cannot be ruled out, a modulation of the reward pathway has been hypothesized [79,80]. In this regard, Williams at al. [81] reported that a single 50 mg dose of naltrexone dramatically blocked the rapid antidepressant and anti-suicidal effects of IV ketamine, while also reducing the rate of clinical response to ketamine from 71% to 0%. These findings suggest that opioid receptor activation plays a significant role in ketamine's efficacy [81]. At odds with these findings, Yoon et al. [65] indicated that naltrexone pre-treatment did not interfere with the antidepressant effects of ketamine and that it enhanced the treatment of current major depressive disorder and comorbid AUD. In light of this, the promising results of ketamine should be interpreted with caution. If, on the one hand, ketamine's efficacy could be mediated by the pro-glutamatergic effect, then, on the other hand, it may directly influence the opioid system and the reward chain. In this respect, ketamine may simply act as a modulator of the reward system.

Ketamine in ED
The number and quality of studies regarding ketamine and ED is still in its infancy, although glutamatergic neurotransmission plays an important role in ED, particularly in Anorexia Nervosa (AN) [82,83]. After encouraging results with some NMDA modulators, such as the partial agonist D-cycloserine [84,85] and the NMDA-r antagonist amantadine [86], ketamine has been tested in ED, with the rationale of normalizing glutamatergic transmission. At present, the data regarding the use of ketamine and esketamine in subjects diagnosed with an ED are preliminary, limited and related to AN only. Moreover, despite positive results in animal models of AN [87][88][89] in terms of food intake, weight gain and reduced hyperactivity, evidence is lacking regarding the effects of ketamine in AN patients. Nevertheless, more compelling and substantial evidence is needed from large cohort studies.

Possible Advantages of Ketamine and Esketamine Compared with Current Treatments
Treatment strategies for OCD, ED and SUD are complex and difficult, and they often involve pharmacological and psychological interventions. To date, several drugs have been approved for the treatment of patients affected by symptoms belonging to the OCD spectrum, ED and SUD [30][31][32][33][34][35][36][37]90,91]. However, in severe cases, in cases with dual diagnoses or in other vulnerable categories of patients, these therapies have often failed. In some cases, off-label use of serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants have produced beneficial effects in patients with OCD [30]. Off-label use of olanzapine also has shown promising results in ED [90][91][92], while the anticonvulsants gabapentin and pregabalin [93], and the antipsychotic aripiprazole [94], have shown some efficacy in increasing abstinence rates and managing alcohol withdrawal. However, rates of treatment resistance are high and innovative treatment options are warranted. In this respect, the use of new therapeutic pharmacological approaches, including psychedelic substances such as ketamine, to treat mental disorders is increasing [95], starting from the first assumptions made in the 1970s [96]. Preclinical studies have provided a significant scientific rationale for the potential of glutamate modulators in the management of anxiety disorders [1,60]. Indeed, using animal stress models, glutaminergic dysfunction in the prefrontal cortex and other limbic regions has been detected in both acute (shown to increase glutaminergic transmission) and chronic stress (associated with a decrease in glutamate receptors, resulting in lower glutamate transmission). These models have been used to assess the anxiolytic activity of drugs acting on NMDA, AMPA, kainite and mGLuR receptors [97]. Despite the fact that results are still preliminary, and mechanisms are incompletely understood, OCD-like behavior appeared to be sensitive to low doses of ketamine [98]. In this context, ketamine and esketamine are innovative treatments that generate a variety of largely unexplored and novel neuromodulatory activities. The preliminary evidence for the benefits of ketamine and esketamine use in these mental disorders is summarized in Table 2.
As mentioned before [26], the improved prefrontal cortex glutamate homeostasis, increased synaptic functioning and enhanced BDNF signaling indicate that esketamine has the potential to be repurposed or further investigated as a treatment for OCD, SUD, PSTD and ED-disorders which have been recorded by some authors to meet the so-called definition of "internalising disorders". These are conditions characterized by internal distress that include the DSM-5 [99] diagnoses of generalized anxiety disorder, social anxiety disorder, MDD, panic disorder and OCD, which are all thought to share the common trait of neuroticism. Neuroticism is defined as a genetically inherited trait that reflects individual differences in response to subjective distress and negative affectivity, but it is not itself considered to be a form of psychiatric disorder [100]. Nevertheless, all "internalizing disorders" involve dysfunctions in different neural systems and are differentially impacted by traumatic or chronically stressful events [101]. Interestingly, generalized anxiety disorder, social anxiety disorder, MDD, panic disorder and OCD are commonly treated with SSRIs, tricyclic antidepressants and different classes of drugs that target serotoninergic neurotransmission, thereby indicating a common neurobiological background.
To summarize, the advantages of using ketamine or esketamine can be recapitulated as the following: (i) no requirement for daily administration, as the molecules are administered for limited periods, thereby increasing a patient's compliance and reducing the stigma of prolonged and daily intake of medications; (ii) the availability of nasal spray formulations that, in the case of esketamine, provide better handling and fewer safety profile issues and side effects; and (iii) in the case of concomitant medications, the possibility to reduce doses, thereby again improving safety profiles and reducing side effects [11,101]. Table 2. Use ok ketamine and esketamine as a treatment for the obsessive-compulsive disorder (OCD), substance use disorders (SUD) and eating disorders (ED).

Risk of Bias
Considering the heterogeneity of the articles selected, the risk of bias was computed using RoB v.2.0 ( Figure 2). Parameters "Mising outcome data" and "Selection of the reported results" were found to have a low risk or some concerns while, for selected parameters (e.g., "Randomization process" and "Deviation from intended process"), the assessment of risk of bias was not applicable.

Study Limitations
Despite the important data, the present review represents only a first assessment of data on the use of ketamine and esketamine and its effectiveness on OCD, ED and SUD. The first limitation of the present review was the predominance of heterogeneous studies, small samples and crossover designs. Comparative studies with conventional therapeutic strategies were not reported in the current literature. A second limitation was related to the use of a saline placebo and not of a real control for ketamine's psychotomimetic effects. Moreover, studies had limited duration of follow-up; therefore, it was not possible to estimate the long-term benefit and potential long-term consequences of ketamine use. This point will require additional attention from researchers. Lastly, this review only included studies published in English.

Conclusions and Future Directions
For several reasons, it is not an easy task to establish a clear relation between glutamatergic dysfunction and OCD spectrum, or to understand this relationship's exact functional meaning. Firstly, glutamatergic neurons are present in almost all brain circuitries and are therefore difficult to specifically localize a glutamatergic dysfunction in a specific brain area [5]. Secondly, while most studies converged on a hyper-glutamatergic state in OCD patients, it is noted that pro-glutamatergic agents also show some positive effects for OCD symptoms [69].
Many interesting new angles are offered by the implementation of ketamine and esketamine or, in general, psychedelic drugs for the treatment of many psychiatric and neurological conditions. These methods could be useful in those situations of non-response/ resistance to standard pharmacological and psychological therapies that are currently observed in everyday clinical practice. Research efforts are needed to clarify the many unknowns related to the effects of these substances. These uncharted waters include short-and long-lasting neurobiological changes, impacts on the modulation of network activity and the functional connectivity of the brain, as well as the effects of drug-driven structural and functional modulations on mind function. However, a safe assumption is that joint efforts employing psychedelic-assisted psychotherapy can provide much-needed therapeutic options for OCD, MDD, SUD, ED and more. This is a brave new world that we need to explore.