key: cord-1053479-d0wuatqe
authors: Swainson, Jennifer; Klassen, Larry J.; Brennan, Stefan; Chokka, Pratap; Katzman, Martin A.; Tanguay, Robert L.; Khullar, Atul
title: Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing
date: 2022-02-14
journal: CNS Drugs
DOI: 10.1007/s40263-022-00897-2
sha: 250eb4e2f2716fc2fa47d3258840eb8afdd5678e
doc_id: 1053479
cord_uid: d0wuatqe

Intravenous (IV) ketamine is increasingly used off-label at subanesthetic doses for its rapid antidepressant effect, and intranasal (IN) esketamine has been recently approved in several countries for treating depression. The clinical utility of these treatments is limited by a paucity of publicly funded IV ketamine and IN esketamine programs and cost barriers to private treatment programs, as well as the drug cost for IN esketamine itself, which makes generic ketamine alternatives an attractive option. Though evidence is limited, use of non-parenteral racemic ketamine formulations (oral, sublingual, and IN) may offer more realistic access in less rigidly supervised settings, both for acute and maintenance treatment in select cases. However, the psychiatric literature has repeatedly cautioned on the addictive potential of ketamine and raised caution for both less supervised and longer-term use of ketamine. To date, these concerns have not been discussed in view of available evidence, nor have they been discussed within a broader clinical context. This paper examines the available relevant literature and suggests that ketamine misuse risks appear not dissimilar to those of other well-established and commonly prescribed agents with abuse potential, such as stimulants or benzodiazepines. As such, ketamine prescribing should be considered in a similar risk/benefit context to balance patient access and need for treatment with concern for potential substance misuse. Our consortium of mood disorder specialists with significant ketamine prescribing experience considers prescribing of non-parenteral ketamine a reasonable clinical treatment option in select cases of treatment-resistant depression. This paper outlines where this may be appropriate and makes practical recommendations for clinicians in judicious prescribing of non-parenteral ketamine.

Major depressive disorder (MDD) is a prevalent and disabling illness associated with substantial personal and societal burden [1] . Traditional antidepressants and psychotherapies require several weeks to elicit a response [1, 2] , and if a patient fails to respond/remit to the first or second antidepressant tried, the likelihood of response to subsequent trials of traditional antidepressants drops to around 15% [3] . This poses a need for alternative antidepressant agents, particularly with a more rapid onset of clinical effect. The recent approval of intranasal (IN) esketamine for treatmentresistant depression (TRD) in a number of countries and the recent Canadian Network for Mood and Anxiety Disorders (CANMAT) recognition of intravenous (IV) ketamine's rapid antidepressant effects [4] bring new hope and offer promise for patients who have otherwise failed to respond to traditional treatments.

Despite the therapeutic potential, administration of IV ketamine or IN esketamine presents somewhat of a clinical conundrum. Although effective, both treatments must be delivered and supervised in a healthcare setting, placing them out of reach for most prescribers and their patients. Publicly funded IV ketamine and IN esketamine programs to support observed use are rare even in urban centers, so much of the population is unable to access these treatments. Where public programs do exist, they are limited by regulatory frameworks and resource requirements for treatment, monitoring, and development of treatment models to accommodate patient flow through programs, and concerns about longer-term safety and tolerability. While a number of private clinics (very few in Canada, where the authors clinically practice) offer these sorts of ketamine services, cost is an obstacle to many patients who could otherwise benefit. Additionally, limitations have been further accentuated by the global coronavirus disease 2019 (COVID- 19) pandemic, which has shifted a focus to virtual care to limit patient contacts with hospitals, clinics, and any healthcare setting where they could potentially be exposed to, or transmit, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This paradigm shift may have also decreased patient compliance with face-to-face appointments, as many wish the convenience of a remote appointment, and this seems likely to persist as a shift in care delivery.

Given these constraints, there is an appeal for prescribers to offer IN, oral (PO), and sublingual (SL) racemic ketamine formulations. Generic ketamine is comparatively cost-effective (5 Canadian dollars (CAD$) for a 50-mg vial) compared to IN esketamine (CAD$273 per 28 mg) (SPRAVATO) [5] , so compounding ketamine into IN, PO, and SL formulations for use breaks the treatment barrier of drug cost itself. IV ketamine must be monitored due to the IV nature of administration. IN esketamine has monitoring requirement set by regulatory bodies-and these differ globally. For example, a 2-h monitoring period is required in Canada and the USA [6] , but the European Union and several other countries do not specify a time, and the language is more loose [7] . This monitoring is due to transient hypertension and dissociative effects, but there are no data to determine whether IN, PO, and SL ketamine should carry the same requirements for supervised administration and monitoring. These requirements may, in fact, be bulky and overcautious. A recent meta-analysis demonstrated that the transient blood pressure increases of ketamine and esketamine brought blood pressures to a transient stage I hypertension level, which is not considered dangerous, and there was no difference between the two drugs [8] . It would appear that ketamine/ esketamine overall does not produce dangerous blood pressure changes when used at antidepressant doses in most patients. This study included primarily IV ketamine, and all the esketamine studies included were IN. While keeping in mind the existence of outliers and need for clinical discretion, the fact that blood pressure increases most typically led to a transient level stage I hypertension only could suggest that widespread regulatory requirement policy to monitor blood pressure for IN esketamine may be excessive, and benefits of universal monitoring to catch the rare dangerous event may not outweigh the accompanying limits in access for the greater population of otherwise healthy patients. Similarly, this suggests that route of administration may also not produce differing blood pressure effects despite differences in absorption and kinetics with varying routes. Additionally, IV and IN administration produce the most rapid onset of action, so while more data are needed regarding IN, PO, and SL ketamine, it seems unlikely that IN ketamine would be more dangerous than IN esketamine or IV ketamine, or that PO or SL ketamine would produce greater escalations in blood pressure than more rapidly acting IV or IN ketamine. It is also unclear whether dissociative effects may differ across formulations, but the experience of dissociative effects alone does not clearly preclude home use following psychoeducation for appropriate patients. More research is required regarding these two issues for definitive answers. Another clear limitation to the use SL/PO/IN ketamine is the lack of data on optimal dosing strategies across formulations.

Another major consideration for less supervised use comes from ketamine's history as an illicit drug. The addictive potential of ketamine when used as an antidepressant has been repeatedly raised and cautioned by a number of expert consensus statements worldwide [4, [9] [10] [11] . While there is due cause for attention to potential harms, these warnings appear to have been stated repeatedly in the absence of further literature to assess level of risk, and without contextual discussion to place risk of ketamine abuse in context with other potentially abusable yet necessary medications prescribed in psychiatry. The authors of this paper include psychiatrists from multiple centers in Canada with extensive combined expertise in treating resistant mood disorders with ketamine, including prescribing IN and SL formulations for home use. Our group also has specialties in attention deficit hyperactivity disorder (ADHD), addiction, pain, and sleep medicine, with extensive experience in cautious prescribing of potentially abusable therapies such as psychostimulants, benzodiazepines, and even the home use of gamma-hydroxybutyrate (GHB) for narcolepsy. This paper will discuss the relevant literature from psychiatry, anesthesia, and pain medicine surrounding the safety of ketamine use, with a focus on potential risks of misuse and abuse. This will then be placed in context to discuss specific practical clinical implications for psychiatric prescribing of non-parenteral formulations of ketamine that could ostensibly be less supervised.

Ketamine use in psychiatry remains in its infancy. Since the 2016 CANMAT depression guidelines designated it as an experimental treatment, it has rapidly matured to designation as a third-line adjunct for bipolar depression [12] and a thirdline treatment for TRD in Canada [4] . Other disorders with published data and growing evidence include obsessivecompulsive disorder, social anxiety, post-traumatic stress disorder (PTSD), substance use disorders (SUD), suicidal ideation, as well as schizophrenia [13] [14] [15] [16] [17] [18] . Ketamine has also been used as an adjunctive agent in electroconvulsive therapy (ECT) [16] .

Another growing dimension of ketamine use in psychiatry is "ketamine-assisted psychotherapy" (KAP). This is based on the premise that the dissociative effects of ketamine can be harnessed under the guidance of a psychotherapist to help a patient adopt "an openness to the expansiveness of mind with access to self in the larger sense" [19] . For KAP, SL or intramuscular (IM) ketamine is commonly used to induce a more open and vulnerable state that promotes communication with the therapist. Although of limited quality, there has been published case series data on KAP treatment of patients with depression, PTSD, ADHD, anxiety disorders, and SUDs [19] .

The usage of ketamine for depressive disorders has been extensively reviewed elsewhere [14, 15, [20] [21] [22] [23] , including its excellent safety and tolerability [24, 25] . Consensus statements from Canada, the United Kingdom (UK), and USA, as well as a recent international consensus statement, recognize and make recommendations for use of ketamine in depression, with a focus on IV ketamine as this is where most data lie [4, 9, 11] . Current recommendations suggest that ketamine should be considered as a short-term strategy in patients with TRD. Data to guide duration, interval, and frequency of maintenance treatment are sparse [4] , as are data on long-term risks, including any addictive potential when used longer term even in a controlled environment for IV administration. Despite the lack of data, it is known that patients tend to relapse within weeks [4] , and the notion of discontinuing an effective treatment, particularly for treatment-resistant patients, runs contrary to the clinical gestalt and guideline recommendations that advocate for a chronic disease management model for depression [26] . Once again, we face a ketamine conundrum: the patient has responded to a treatment that requires monitoring in a healthcare setting; how can this be delivered on an ongoing basis to maintain treatment response? The product monograph for esketamine nasal spray advises induction therapy with twice weekly treatments for 4 weeks, followed by step-down to weekly maintenance for four treatments, then to continue weekly or every other week, based on clinical response [6] . With caution, a similar model could be considered for IV ketamine, and this has been utilized by several of the authors (JS, AK, PC) for patients requiring maintenance IV ketamine treatment (Misericordia Community Hospital and Grey Nuns Community Hospital, Covenant Health, Edmonton, AB, Canada). Notably, this is similar to commonly used maintenance treatment schedules for ECT, for which there is also little data to guide frequency or duration of maintenance treatment [27] .

Repeated IV administrations, however, are often impractical for patients and are associated with high resource costs due to the staffing and monitoring required. Often, these costs are passed down to the patient in a private clinic setting. Anecdotally, in the hospital system, authors of this paper have seen publicly funded IV ketamine clinics in which they consult quickly reach capacity due to patients requiring maintenance treatments to maintain a semblance of stability. In the private system, both the initial and especially the ongoing cost for infusions is prohibitive for most patients. Additionally, specialized IV clinics (private or public) are generally not available outside major urban centers. These factors, along with the recent exponential growth of virtual care, leave IV treatments less palatable to many patients and clinicians. Similarly, each IN esketamine treatment must be delivered in a healthcare setting, with requirements to monitor patients for 2 h for each treatment. While evidence for use of SL, IN, or PO formulations of racemic ketamine that could be taken in less stringent settings are limited to small randomized controlled trials (RCTs), case series, and anecdotal reports [4] , other authors have discussed the potential utility and safety of PO ketamine [28, 29] , which could improve treatment access. These non-IV formulations could also be of particular utility as maintenance ketamine therapy in patients who have previously responded to IV or as initial treatment in patients unable to access IV treatments [30] [31] [32] . However, data to guide dose and frequency are lacking, and although previous authors have suggested that after a first observed dose, other formulations may be safely used at home [28, 29] , no consensus recommendations have been made for safe prescribing, other than deferring to tertiary centers with ketamine prescribing expertise [4] .

With it being a novel antidepressant therapy, clinicians and patients must become familiar with ketamine's safety and tolerability profile. Acute side effects of IV ketamine include sedation, dissociation, increased blood pressure, headache, and dizziness [24] . Dissociation is usually transient and does not typically require clinical intervention as long as appropriate psychoeducation is delivered to patients prior to treatment initiation [4] . Blood pressure changes with IV ketamine are typically mild, transient, and not clinically significant [25, 33] . This is not dissimilar to blood pressure changes observed with stimulants for ADHD, which are infrequently clinically important [34] . In terms of long-term effects, chronic ketamine abuse has been associated with cognitive deficits, confusion, and cystitis, but to date, this has not been problematic in the literature related to depression [35] . While data on potential long-term side effects of ketamine treatment are needed, it should also be noted that therapeutic ketamine doses are much smaller than is typically used in chronic ketamine abusers.

Given differences in kinetics, dosing, and bioavailability of PO (17%) [36] , SL (29%) [37] , and IN (50%) [38] ketamine formulations, it is unclear whether the safety and side effect profiles are entirely consistent across various formulations. A systematic review of PO and SL ketamine noted no significant side effects, and no problems with tolerance or substance misuse in any of the studies, which totaled 140 patients who received ketamine up to 3 years in duration [22] . The highest single doses reported were 300 mg PO every 3 days [39] , and 7 mg/kg twice weekly to every 2 weeks [40] . In a subsequent RCT of 22 patients, 1 mg/kg of PO ketamine administered thrice weekly demonstrated mild blood pressure elevations that did not require intervention, and overall side effects were not different from placebo [41] .

Side effects of IN ketamine have been more variable. One study found a dose of 50 mg was well tolerated [42] , while another study of a series of 100-mg doses given over a period of weeks [43] was aborted early due to intolerable side effects of sedation and lack of motor coordination. In contrast, a small case series reported good tolerability of IN ketamine up to 150 mg administered up to twice weekly [31] . IN esketamine has a better documented safety profile, with common side effects of sedation, dissociation, and blood pressure changes that are noted to be mild and transient [6] . Hence, although evidence for PO, SL, and IN ketamine remains limited, no studies have reported concerns of cardiorespiratory compromise or clinically significant elevations in blood pressure that would preclude home use. It would seem logical that if the blood pressure effects of a 100% bioavailable IV formulation are rarely clinically significant, any blood pressure elevation from a less bioavailable non-parenteral formulation may be of variable duration, but not of greater magnitude, so long as approximately equivalent doses are given. No studies addressed the level of concern that would be warranted in regard to addictive potential of these non-parenteral formulations of ketamine, or potential differences in addictive potential given differing absorption and time to onset of dissociative effects. Given the lack of evidence and theoretical concern, it would be advisable to exercise similar caution with home use of ketamine as is given to the home use of stimulants or other sedatives. Indeed, the sedative GHB, a drug with significant side effects, overdose risk, cross tolerance with alcohol, abuse potential, and diversion potential [44] , is indicated in a number of countries for narcolepsy with cataplexy and selfadministered without medical supervision at home, under a controlled delivery program [44] .

in Society: What Do We Actually Know?

At subanesthetic doses, ketamine can lead to psychoactive effects including perceptual disturbances, derealization, depersonalization, altered body perceptions, and impaired proprioception [45] . These phenomenological effects may be experienced as pleasant or desirable and have contributed to diversion of ketamine for recreational misuse since the 1970s. Notably, recreational users of ketamine have reported that the most appealing aspects of the drug include visual hallucinations and out-of-body experiences; in contrast, others have reported negative effects including memory loss, anxiety, emotional withdrawal, blunted affect, impaired verbal fluency, and physical effects such as palpitations, tachycardia, and blurred vision [45, 46] . The most commonly misused form of ketamine is powder produced by dehydrating ketamine solution, which is usually insufflated or snorted, but has also been smoked or added to beverages [45, 46] . Other misused forms of ketamine include liquid ketamine, which can be injected, added to other substances that are smoked, or consumed in beverages, and less frequently, ketamine is misused by IV or IM injection. Typical doses of ketamine used recreationally start at ~ 100 mg and can reach 500 mg and higher, often delivered multiple times in a single day given the rapid offset of effects [45, 47, 48] . This leads to a potential use of several grams daily, which is much higher than a typical dispensed prescription of ketamine for depression. The National Institute on Drug Abuse within the United States' National Institute of Health (NIH) designates that presence of any ketamine withdrawal syndrome is "unknown" [49] . However, a recent review cautions ketamine withdrawal symptoms that include craving, palpitations, tiredness, low appetite, low mood, chills, autonomic arousal, lacrimation, restlessness, paranoia, anxiety, hallucinations, and delusions beginning 24 h post-ketamine, and lasting up to 2 weeks [50] . This report, however, was based largely on one case [51] of a single patient who developed these symptoms after 2 years of using 4-7 g of ketamine daily, and two psychotic patients with ketamine dependence admitted to a psychiatric unit [52] . Although interesting neurochemically, withdrawal symptoms do not imbue addictive potential, as it is well known that traditional antidepressants have also been associated with discontinuation/withdrawal symptoms [50] . Concerns for development of psychological dependence in the absence of a physical withdrawal syndrome have also been based on case reports [53, 54] . Of note, fewer than 15 cases of human ketamine dependence have been described in the literature over the past 20 years [24] .

In a comparative ranking of 20 substances with potential for misuse based on a review of the available literature, ketamine was ranked sixth overall, aligned with benzodiazepines and amphetamines. This ranking considered factors reflecting risk of physical harm, dependence, and social harm [55] . With respect to dependence factors specifically, ketamine ranked 11th for physical dependence tied with methylphenidate, and was equal to cannabis at ninth overall for both pleasure and psychological dependence. Overall, this clearly places ketamine as mid-range in terms of theoretical dependence risk, comparable to other drugs commonly used as unsupervised PO medications in psychiatric practice.

The World Health Organization (WHO) lists ketamine as an essential medicine for anesthesia and analgesia and recognizes that there is substantial evidence supporting its clinical effectiveness in depression and other mental health disorders [56] . Despite the known use of ketamine as a drug of misuse, the WHO concluded that "There is no compelling evidence… to suggest that [illicit use of ketamine] is becoming a global trend." Indeed, the misuse of ketamine represents < 1% of international illicit drug use, and there is evidence that rates of ketamine misuse are declining globally [56] . There are strong indications that prevalence of ketamine diversion and misuse is lower than many other substances [56, 57] . Reviews have suggested that the overall prevalence of ketamine misuse in the general population ranges from 0.1% in the USA to 4% in the UK [45] . Prevalence in use among US college students decreased from 2.5% in 2002 to 1.5% in 2012, and decreased in high schoolers from 1.3 to 0.4% [57] . While the British crime surveys of the late 2000s reflected concern with escalating use of ketamine in the UK [58] , more recent data suggest the trend is toward decreased ketamine use in the UK, with reductions from 2011 to 2013 of 0.6% to 0.4% in adults and 1.8% to 0.8% in young adults, respectively [57] . However, reported incidence rates and drug seizures point towards potential increases in ketamine misuse and diversion in some Asian countries such as Indonesia, Hong Kong, and Taiwan [59] . Ketamine misuse also appears to be higher in certain populations and situational circumstances. For example, 32-43% of self-described "club drug" users reported having misused the substance [46] .

In terms of toxicity, ketamine has consistently accounted for a minority of emergency department visits due to recreational drug use in the USA, with reports ranging from 0.033% in 2005 to 0.12% in 2011 [57] . The risk of fatal intoxication with ketamine is very low, with a total of 12 deaths reported in Europe between 1987 and 2000, among which only three involved ketamine as the sole substance [56] . Interestingly, a review of the changing portrayal of ketamine by print news media in the USA corroborates a change in recent years towards a more favorable view of ketamine as a clinical therapeutic for the treatment of depression rather than as a street drug of misuse [60] .

Ketamine has an overall favorable safety profile in the analgesic setting as meta-analyses have reported no cases of dependence or addiction when IV ketamine was used in the acute or chronic management of pain [61, 62] . Recent large scale national joint guidelines from the USA state that "there is little to no evidence in the literature at this time that suggests that brief exposure to ketamine while in a hospitalized setting increases the chance of addiction to ketamine" [63] . In the setting of chronic pain, these same guidelines do flag active substance abuse as a contraindication for ketamine treatment and note ketamine's potential for addiction and diversion. Nevertheless, these guidelines also recognize PO and IN ketamine for home use as reasonable alternatives to IV ketamine infusions in the ongoing treatment of chronic pain [64] . Careful patient selection and use of opioid screening instruments to detect patients at risk of misuse are encouraged, even in the absence of validated screening instruments for ketamine. The guidelines caution on risks with driving, particularly in patients using ketamine for breakthrough pain. No further recommendations for safety and monitoring of home ketamine use are made [64] . Nonetheless, the US National Pain guideline recognizes take-home ketamine as a viable option for appropriate patients. It seems reasonable for psychiatry to consider this perspective of our colleagues in pain medicine and anesthesia, who have more seasoned experience prescribing ketamine, and follow their lead to consider take-home ketamine as an option in select cases.

While patients have reported an equal positive drug "liking" for ketamine and esketamine side effects [65] , misuse of ketamine or esketamine when prescribed for patients with depression has been rarely reported. Three published case reports describe the development of tolerance and addiction specifically in patients with depression using ketamine [66, 67] . The first was an untreated patient using ketamine to self-medicate [66] , and the second was a patient who had been treated with ketamine for depression with good effect initially [67] . The third involved a patient with depression and lack of remission with prescribed psychiatric medication [68] . In this case, she began using ketamine specifically for mood on the suggestion of an anesthetist and escalated her dose over time. Poor monitoring of ketamine prescribing and inappropriate patient selection were thought to contribute to the misuse [67] . Indeed, despite repeated warnings in the depression literature regarding addiction potential, a systematic review of ketamine side effects found that of 20 RCTs included in the study, none systematically evaluated for dependency as a side effect, and of the 60 total studies included, very few evaluated this [24] . A later systematic review of participant discharge summaries following trial completion in four placebo-controlled, cross-over, single-dose IV ketamine trials and one open-label study for treatment of TRD found no increased ketamine craving, abuse, or possible intent to misuse ketamine 3 months post-administration [69] . Another systematic review, of 13 RCTs, prospective open-label trials, retrospective chart reviews, and case reports of PO ketamine for the treatment of depression, yielded no reports of abuse or dependence, although again, the studies making up these reviews did not systematically evaluate addiction concerns [22] . Likewise, no identified reports of dependence, craving, or addiction with treatment periods up to 28 days were seen in four RCTs of IN esketamine for depression treatment [23] . Although the literature for maintenance ketamine treatment in depression is quite limited, it suggests that misuse and addiction may be rare with long-term use. A small case series of 11 depressed patients who used IV ketamine for up to 49 weeks reported a loss of antidepressant effect in four patients, but no dependence or abuse, although these effects were not systematically assessed [30] . In another subset of a case series, 14 patients were treated for up to 126 weeks with IV ketamine; one patient discontinued treatment due to an inability to abstain from cannabis, but again there were no reports of ketamine dependence or addiction [70] . Further evidence may be gleaned from a 48-week open-label extension phase III esketamine nasal spray trial, where there were no reports of drug seeking, overdose, abuse, or patient requests for dose increases beyond the maximum study dosage of 84 mg once weekly [71] . As such, the requirements for controlled distribution of IN esketamine and administration only in a healthcare setting are based only on the theoretical risk from the view of addiction/diversion potential.

Regulatory restrictions in North America [6] for this medication have been placed far above other commonly used psychiatric medications with documented greater misuse or diversion potential, making it untenable for practitioners to deliver it and patients to receive it. The relative scarcity of misuse/diversion reported with maintenance ketamine or esketamine matches the authors' own clinical experience and observations in prescribing compounded SL and IN racemic ketamine over periods up to 3 years [32] .

Although studies of low-dose ketamine in depression trials have not identified any cases of dependence, it remains a theoretical risk based on preclinical and clinical studies showing rapid development of tachyphylaxis when used at higher anesthetic doses, as well as the development of tolerance in frequent recreational users of ketamine [24] . It should be noted that recreational ketamine users self-report a high prevalence of depressive symptoms, particularly in users with higher ketamine craving scores [72] , and it has been observed that nearly one-third of ketamine abusers have a comorbid depressive disorder [73] . Epidemiologic data have noted that patients with no SUD history are more likely to develop an SUD when they have TRD, particularly for misuse of opioids and sedatives. Interestingly, patients with pre-existing SUD actually appeared to have a lower risk 1 year into treatment than in the first year-it is unclear whether this may have correlated with an improvement in symptoms [74] . While data for ketamine specifically are lacking, it is possible that a dimension of ketamine misuse could be an attempt to self-medicate among persons with depression or at risk for depression, and that screening and management of depressive disorders should be strongly considered in this population. As evidence for ketamine in depression has accumulated, both the continued stigma associated with mental health disorders and limited access to IV ketamine or IN esketamine may limit the ability for patients to seek treatment [78, 79] , potentially leading to self-medication with illicitly obtained ketamine. Under this paradigm, appropriate treatment of depression with ketamine when indicated may actually reduce misuse/abuse of substances, including ketamine used to self-medicate [80] .

Unlike conventional antidepressants that target monoaminergic systems, ketamine primarily affects the glutamate system, notably as a non-competitive blocker of the N-methyld-aspartate (NMDA) receptor, an effect that is responsible for its anesthetic actions [20] . Although ketamine's antidepressant mechanism of action is not fully understood, there has been suggestion that its antidepressant effects are contingent on opioid system activation, which could theoretically contribute to abuse potential [81] . A small study showed that pre-treatment with PO naltrexone significantly attenuated the rapid antidepressant effects of IV ketamine in 12 patients [82] , but another small study (n = 5) showed the opposite effect, where co-treatment of naltrexone and ketamine significantly reduced depressive symptoms as early as the first dose [83] . A view of its abuse potential based on opioid activity as stated elsewhere is likely overtly simplistic given that ketamine interacts with a myriad of receptor systems. This is summarized in Table 1 .

Despite the concerns for addictive potential of ketamine, there is actually preliminary support in the literature that ketamine may be an effective treatment for SUD [84] . There is emerging evidence for a role for ketamine in the management of SUD in patients with and without comorbid depression. It has demonstrated efficacy as an adjunct to naltrexone in MDD patients with alcohol use disorder [83] . There is also evidence for ketamine as either a standalone treatment [85, 86] or as an adjunct to psychological therapy [87] for cocaine use disorder, psychotherapyassisted management of heroin dependence [88, 89] , and opioid withdrawal [90] . Although these studies are limited by small sample sizes and short follow-up, they offer important reassurance to counter concerns that ketamine could induce addictive behavior with other substances when used for the management of depression. Although the mechanism(s) of efficacy in treatment of SUD also remain unclear, several possible pathways have been suggested and are summarized in Table 2 [91].

The emergence of ketamine into psychiatric practice brings clinical questions and conundrums for clinicians who want to offer this treatment to patients. While access to IV ketamine and IN esketamine programs was already limited, the recent pandemic has necessitated adaptation within medicine to find ways to deliver patient care virtually [92, 93] . Moreover, there is increased demand for rapid, effective, and accessible treatments for TRD as societies are now grappling with mental health sequelae of the pandemic. IV ketamine and IN esketamine must be provided in a supervised healthcare setting, and access will likely always be limited due to program capacity, cost (to the system or the patient), and increasing patient reluctance to regularly visit healthcare settings to receive care on the heels of the COVID-19 pandemic. Additionally, these sorts of treatments are available only in specialized centers, limiting the access of much of the population. As such, the ability to offer novel treatments such as ketamine in other formulations that may potentially be prescribed for use in less supervised or home environments in a safe fashion is even more crucial. While more data are needed to guide dosing and frequency of alternate formulations, on review of the limited existing literature, there is no clear evidence that addiction potential of ketamine is more serious than other drugs we prescribe with due caution in psychiatry such as stimulants or sedatives. Serious risk may exist in certain subpopulations, just as it does with other abusable medications, but this warrants a similar approach in cautious prescribing where appropriate, rather than preclude prescribing altogether. The authors of this paper have several years of experience in the use of PO, SL, and IN ketamine for mood disorders [11] ) Dysregulation of stress hormone pathways [78, 79] Reduction in oxytocin [78] (seen in opioid, stimulant, alcohol, cannabis, and MDMA addiction) Reduction in orexin-A [79] (linked to addiction via reward and pleasure) Increased ACTH Increased cortisol levels Limbic system activation-dopamine reward pathways [80] Cortical activation [80] [31, 32] . Patients have been highly treatment resistant, and these ketamine formulations have been well tolerated and life saving for many patients who have not responded to other treatments. Based on the authors' collective experience in prescribing non-IV formulations of ketamine, we have suggested potential patient characteristics for physicians to consider when evaluating patients for home use of ketamine (Table 3) . Of note, we would agree with previous authors [4, 94] that any ongoing/maintenance use of ketamine for depression should be reserved for patients who have exhausted other treatment options, including multiple trials of antidepressants and other more evidence-based augmentation strategies.

Though systematically obtained real-world data for addiction risk of ketamine when used as a psychiatric medication are lacking, existing knowledge appears not to preclude its use when indicated. Cautious prescribing of this agent is warranted, similar to our approach with substances of potential abuse such as benzodiazepines and stimulants. Clinicians should not be deterred from prescribing ketamine with appropriate cautions when it is reasonably indicated but should maintain an awareness that new information may arise to swing the risk-benefit pendulum, and require adjustment in clinical practice accordingly. Practical suggestions for judicious prescribing are offered in Table 4 .

Further to the above clinical recommendations, there is an urgent need for additional high-quality research with systematically collected data to better define the optimal dosing strategies for non-IV formulations of ketamine as an antidepressant, and for longer-term studies that prospectively monitor for safety, dose escalation, and the potential development of craving, misuse, and dependence. Other authors have wisely suggested the need for a registry to monitor use patterns of drugs with abuse potential like ketamine and esketamine [95] , and have suggested a ketamine side effects monitoring tool [Ketamine Side Effect Tool (KSET)], which includes measures of drug craving and misuse, but not drug liking [96] . The Food and Drug Administration (FDA) has previously acknowledged drug liking as an important factor in predicting abuse potential [97] , and it would be important to evaluate this factor in real-world ketamine or esketamine treatment. Future studies should include measures of drug liking/craving/ patterns of misuse. In the absence of any validated tool for this specific purpose, a patient-rated Drug Liking and Craving Questionnaire (DLCQ) for ketamine/esketamine has been created and is in use in several Canadian clinical studies [98] . Naturalistic studies of patients using maintenance ketamine or esketamine therapy could monitor for other red flags of substance misuse such as dose escalation, early refills, and development of other SUD. Similarly, it would be valuable to track data on drug-seeking behavior such as the frequency with which patients request ketamine treatment specifically, ask to prolong treatment for its dissociative effects, or try to convince clinicians of its utility simply to access and abuse it, rather than for its true antidepressant effects. Clinicians prescribing ketamine are advised to clearly assess antidepressant effect in individual patients for efficacy, and not to rely on patient reporting which may be misconstrued as drug liking. Ketamine prescribers are advised to stay abreast of current literature and engage in continuing medical education on this topic. Availability of data and material Not applicable.

Code availability Not applicable.

Ethics approval Not applicable.

Author contributions JS and AK conceptualized the idea for this article and contributed to the literature search and writing of the manuscript. JS, AK, LK, SB, PC, MK, and RT contributed to the outline of the paper, critical evaluation of and application of the relevant literature identified, manuscript revisions, and recommendations made for clinical practice. All authors approved the manuscript for submission and are accountable for this work. Informed consent-potential risks/benefits Use of patient contracts Prescribe in limited quantities and limited refills (i.e., 2-to 4-week supply depending on frequency of dosing) Prescriber experience with ketamine Affiliation with a more intensive ketamine program (for further assessment/referral/case discussions) Consider observing first treatments or dose changes in office to monitor blood pressure and dissociation (i.e., with CADSS) Educate patients on dissociative symptoms Advise patients not to drive until next day after use Dose at night when used at home Wait until dissociative/sedative effects of ketamine dissipate before using other potentially sedating bedtime medications Screen for bladder toxicity Check urinalysis at baseline and every 3-6 months for signs of microscopic hematuria Ask about urinary symptoms (i.e., frequency, urgency, hematuria) Monitor for drug liking/signs or symptoms of misuse (e.g., KSET) Lost prescriptions Requests for early refills Requests for dose escalation or increased frequency despite stable psychiatric status Consider that non-IV forms may require higher doses due to reduced bioavailability, and that documented bioavailability of each formulation is to be considered a rough estimate and may vary Prescribing clinicians should be informed of current literature and continue medical education on ketamine to learn and adjust prescribing practices as new data become available

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by-nc/4. 0/.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 2. Psychological treatments

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force recommendations for the use of racemic ketamine in adults with major depressive disorder

Ottawa: Canadian Agency for Drugs and Technologies in Health

Spravato (esketamine) nasal spray. Prescribing Information

Summary of Product Characteristics. Spravato 28 mg nasal spray, solution (esketamine)

Meta-analysis: Hemodynamic responses to sub-anesthetic doses of ketamine in patients with psychiatric disorders. Front Psychiatry

A consensus statement on the use of ketamine in the treatment of mood disorders

Committee on ECt and Related Treatments. Statement on ketamine to treat depression

Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

A Randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder

Repurposing potential of ketamine: opportunities and challenges

Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective

Ketamine: current applications in anesthesia, pain, and critical care

Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept

The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis

Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy

Repurposing of drugs-the ketamine story

A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes

Oral ketamine for depression: a systematic review

Adjunctive intranasal esketamine for major depressive disorder: a systematic review of randomized double-blind controlled-placebo studies

Side-effects associated with ketamine use in depression: a systematic review

Ketamine safety and tolerability in clinical trials for treatment-resistant depression

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder

Ketamine for depression, 4: in what dose, at what rate, by what route, for how long, and at what frequency?

Oral ketamine for depression, 2: practical considerations

Maintenance ketamine therapy for treatment-resistant depression

A response to: Repeated intranasal ketamine for treatment resistant depression: the way to go? Results from a pilot randomised controlled trial

Sublingual ketamine: an option for increasing accessibility of ketamine treatments for depression?

Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions

Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder

Urothelial toxicity of esketamine in the treatment of depression

Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children

Oral ketamine in treatment-resistant depression

Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study

Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study

A randomized controlled trial of intranasal ketamine in major depressive disorder

Repeated intranasal ketamine for treatment-resistant depressionthe way to go? Results from a pilot randomised controlled trial

XYREM(R) (sodium oxybate oral solution) Product Monograph

A Review of ketamine abuse and diversion

Curran HV. Journey through the K-hole: phenomenological aspects of ketamine use

Oral ketamine as a positive control in human abuse potential studies

The Science of Drug Use and Addiction: The Basics

Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications

A case of ketamine dependence with discontinuation symptoms

Ketamine associated psychedelic effects and dependence

Ketamine addiction

Ketamine dependence

Development of a rational scale to assess the harm of drugs of potential misuse

World Health Organization. Fact file on ketamine

Ketamine Toxicity. Stat-Pearls

Independent Scientific Committee on Drugs

To use or not to use: an update on licit and illicit ketamine use

Analysis of print news media framing of ketamine treatment in the United States and Canada from

A systematic review and meta-analysis of ketamine as an alternative to opioids for acute pain in the emergency department

The effects of low-dose ketamine on acute pain in an emergency setting: a systematic review and meta-analysis

Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists

Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists

Esketamine for treatment resistant depression

Long-term ketamine self-injections in major depressive disorder: focus on tolerance in ketamine's antidepressant response and the development of ketamine addiction

Potential risks of poorly monitored ketamine use in depression treatment

A case of ketamine dependence

Comprehensive assessment of side effects associated with a single dose of ketamine in treatmentresistant depression

Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital

Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2)

Association of craving and depressive symptoms in ketaminedependent patients undergoing withdrawal treatment

Ketamine users have high rates of psychosis and/or depression

Treatment-resistant depression as risk factor for substance use disorders-a nation-wide register-based cohort study

Decreased blood levels of oxytocin in ketaminedependent patients during early abstinence

Chronic ketamine abuse is associated with orexin-A reduction and ACTH elevation

Cue-induced brain activation in chronic ketamine-dependent subjects, cigarette smokers, and healthy controls: a task functional magnetic resonance imaging study

Mental health stigma: society, individuals, and the profession

Mental health stigma update: a review of consequences

Antidepressants for the treatment of people with co-occurring depression and alcohol dependence

A word to the wise about intranasal esketamine

Attenuation of antidepressant effects of ketamine by opioid receptor antagonism

Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder

Efficacy of ketamine in the treatment of substance use disorders: a systematic review

A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: results from a randomized, controlled laboratory study

The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers

A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: a randomized clinical trial

Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence

Experience of the use of ketamine to manage opioid withdrawal in an addicted woman: a case report

Ketamine for the treatment of addiction: evidence and potential mechanisms

The use of telepsychiatry during COVID-19 and beyond

Zulman DM. Virtual care expansion in the Veterans Health Administration during the COVID-19 pandemic: clinical services and patient characteristics associated with utilization

Is off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications

Esketamine and the need for a new type of registry for drugs with abuse potential

Development of the Ketamine Side Effect Tool (KSET)

Assessment of Abuse Potential of Drugs Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)

The Drug Liking and Craving Questionnaire (DLCQ) to evaluate addiction risk for ketamine and esketamine