As the name would imply, the treatment of TRD is complex and challenging. Few specific treatments have direct evidence in unipolar TRD and only a handful have received specific regulatory approvals for this condition (defined in somewhat heterogenous ways): transcranial magnetic stimulation including the Stanford Accelerated Intelligent Neuromodulation Therapy, olanzapine/fluoxetine, and intranasal esketamine (14, 15). Many additional pharmacological agents for TRD are utilized in clinical practice and studied as off-label monotherapies and/or adjuncts, ranging from second-generation antipsychotics to lithium to thyroid hormones (16, 17).

The majority of real-world TRD patients end up receiving multiple psychotropic drugs (18, 19), often for years and with limited success. For instance, a recent 12-month cohort study of 411 TRD patients across multiple European countries reported high rates of polypharmacy and low rates of clinical response—only about 30% after 6–12 months of continual treatment (19). This study also found significant evidence of what might be called inertia or therapeutic nihilism: despite the cohort’s poor clinical outcomes, 60% of patients had no treatment changes after 12 months.

Apart from mainstay pharmacological therapies, electroconvulsive therapy (ECT) is arguably the most evidence-based treatment option for TRD (17). Though highly effective, ECT is associated with stigma, inconsistent availability, and significant side effects (largely due to treatments requiring general anesthesia) like amnesia (17, 20). These side-effects can interfere with concomitant psychotherapy, an adjunctive treatment with some evidence in TRD. A 2018 Cochrane review of psychotherapy for TRD, including six trials of 698 participants, found high rates of acceptability though only modest improvements with various approaches including Cognitive Behavioral Therapy (CBT) (21).

In this landscape, the rapid and potent antidepressant effects of subanesthetic IV racemic ketamine, a unique N-methyl-D-aspartate (NMDA) antagonist, have understandably generated significant excitement (22). On meta-analysis, approximately half of TRD patients will respond (>50% improvement in symptoms of depressions) within hours or days of a single 40-min IV ketamine infusion (23, 24). These results have prompted experts to describe subanesthetic ketamine as one of the psychiatry’s biggest pharmacological breakthroughs in decades (22).

While impressive, ketamine’s benefits typically fade within days or weeks (25). An extensive search for effective strategies to augment and/or maintain response has largely yielded disappointing results for a diverse variety of drugs, such as clonidine, D-cycloserine, lamotrigine, lithium, rapamycin, and riluzole (26). As a consequence, the most common strategy for prolonging ketamine’s benefits is simply to readminister ketamine (27, 28), despite a relative dearth of evidence for this practice’s long-term safety, efficacy, and feasibility (29).

The efficacy of ketamine must also be balanced against important safety considerations, including stimulatory hemodynamic effects (30), abuse potential (31) and long-term risks (at least in recreational ketamine users) like cognitive and bladder harms (32, 33). Indeed, ketamine abuse has resulted in serious urinary track complications and long-lasting adverse impacts on the nervous system and cognitive functioning, including loss of gray matter volume. These harms may only manifest with large quantities (up to 100 times greater than those used in clinical contexts) and neither ketamine or esketamine have been associated with iatrogenic dependence, cognitive decline (beyond transient memory disruption) or toxic bladder effects.

Outside of potential chronic adverse effect, ketamine can engender potentially distressing psychoactive effects in both recreational and medical contexts. These ketamine-induced altered states of consciousness have proven to be highly contentious, and have generated active debate regarding their therapeutic importance (25). Reflecting this debate, two relatively isolated bodies of research on ketamine in psychiatry have emerged, which we refer to as “biomedical” and “psychedelic.”

In the dominant biomedical view, ketamine’s dose-related psychoactive effects are generally considered to be important for tolerability but are unrelated to efficacy (22, 25, 34, 35). This perspective instead emphasizes ketamine’s pharmacological and neural effects as the main mechanisms of therapeutic action (36). Given the perception that they are adverse events, ketamine’s psychoactive effects are typically mitigated and minimized using strategies like dose-minimization, reassurance/distraction, and potentially the administration of sedatives (34).

The origins of the biomedical approach to ketamine can be traced to a ground-breaking RCT, published in the year 2000, in which seven depressed patients received an intravenous dose of 0.5 mg per kg of bodyweight, infused over 40 min (37). This study marked a major turning point in the use of ketamine in psychiatry, building upon decades of clinical research of NMDA antagonists as experimental (psychotomimetic) models of schizophrenia and fundamental studies suggesting potential antidepressant effects (38). To this day, its dosing protocol remains the most commonly used around the world [though modifications have been found to be beneficial for particular patient populations (39) or to mitigate ketamine’s side effects (40)].

In the decades since, multiple clinical trials and larger observational studies have confirmed rapid antidepressant effects of intravenous ketamine in unipolar depression and, albeit with less evidence, bipolar depression (25, 41). A notable strength of this literature is the frequent inclusion of real-world TRD patients who rarely meet eligibility criteria for clinical trials due to their severity and comorbidity (42). Another uncommon strength of ketamine clinical trials is the frequent employment of active comparators like midazolam to reduce placebo effects and unblinding arising from psychoactive effects (43)—a rigorous methodological approach that may be broadly underutilized in depression research (44). In addition to strong evidence for antidepressant effects in complex real-world patients, ketamine can also produce benefits against suicidality (45, 46) and the cognitive symptoms of depression (47, 48), which are at least partially independent of core mood improvements (49).

As with other psychiatric treatments, the exact biological mechanisms underlying ketamine’s psychiatric benefits are subject to ongoing research and debate [as described in multiple recent reviews (50–52)], including the role of NMDA receptors in its antidepressive effects (53). Amongst many identified potential mechanisms, cellular and animal studies have demonstrated that ketamine can promote neuroplasticity (e.g., dendritic spinogenesis) and thereby reduce or reverse stress-related changes (54, 55), reduce inflammation (56), and dramatically alter neural dynamics (57, 58). Studies in humans have also found ketamine to transiently alter cerebral GABA and glutamate concentrations (59, 60), increase neural activity in areas associated with reward processing (61), and potentially normalize default mode network connectivity abnormalities of depression (62).

The promising clinical and preclinical ketamine research has also fueled a search for NMDA modulators that may convey ketamine-like antidepressant effects without its psychoactive effects. These efforts, however, have largely resulted in disappointment—existing drugs such as memantine have not proven to be effective and many drug candidates have been abandoned due to poor results of costly phase 1–3 clinical trials (63, 64). The only partial exception to this trend is intranasal esketamine, the s-enantiomer of ketamine, dosed such that its psychoactive effects are relatively minor (65). As mentioned above, esketamine has recently received regulatory approval in multiple countries for unipolar TRD in combination with conventional oral antidepressants (14).

Despite these approvals, the real-world uptake of intranasal esketamine has been limited. For instance, the Canadian Agency for Drugs and Technologies in Health and the United Kingdom’s National Institute for Health and Care Excellence (NICE) both recommended against public-payer esketamine adoption (66, 67). In their report, the NICE committee cited a lack of evidence for esketamine’s efficacy beyond standard biological or psychological therapies, uncertainty regarding the duration and sustainability of its benefits, and its relatively high costs.

These same limitations also apply to some extent to the current evidence-base for racemic ketamine, with the notable difference that its drug costs are significantly lower—an advantage that is somewhat offset by the greater costs associated with IV administration (68). Nevertheless, the tremendous need for novel treatments of TRD in conjunction with meta-analytic evidence of antidepressant effects for both IV racemic ketamine and intranasal esketamine have resulted in both finding active use in a variety of models of care (25, 69).

Typical biomedical models of care for parenteral ketamine most closely resemble ECT (17); i.e., ketamine treatments are administered twice or thrice weekly for several weeks (typically alongside oral medications) to induce remission, followed by further treatments at a decreasing frequency to maintain response (29, 65). The similarity between IV ketamine and ECT protocols is evidenced by at least two large, multicenter, head-to-head RCTs directly comparing them for TRD (70, 71). For instance, the Canadian biomarker integration network in depression (CAN-BIND) study protocol describes an ECT-like approach to IV ketamine involving acute treatment periods of thrice-weekly doses followed by maintenance doses decreasing in frequency across 6 months, to weekly and then to monthly (71). Esketamine is also utilized in a similar protocols featuring gradually less-frequent doses (65).

In addition to these ECT-like care models, there is also increasing interest in utilizing ketamine in ways more resemblant of oral antidepressants. For example, studies have evaluated at-home sublingual or oral ketamine doses prescribed up to three times per day (72, 73). Such approaches are significantly less studied than parenteral ketamine or intranasal esketamine (which also requires in-person administration due to the US Risk Evaluation and Mitigation Strategy) (74). However, and in spite of their increased potential for iatrogenic abuse, their significant feasibility advantages have resulted in substantial clinical growth— partially accelerated by relaxed telehealth prescribing rules in the US during the COVID-19 pandemic (74). Of note, some of the at-home ketamine care models might also be described as partially “psychedelic” given how they frame ketamine’s effects and incorporate, for example, telehealth psychological support (75).

All of these diverse approaches to ketamine, like the conventional treatments they resemble, have been associated with both significant benefits and drawbacks. Since antidepressant response is primarily achieved and maintained by repeated dosing—possibly on an indefinite basis—there is significant potential for long-term expense, inconvenience, imperfect adherence, and adverse side-effects (76, 77). Further, as experts have recently commented (78), biological models for TRD that do not explicitly address sociopsychological factors can paradoxically reinforce symptoms of depression like demoralization, passivity, and guilt. Lastly, ketamine’s acute psychoactive effects may cause distress—ranging from mild discomfort to acute panic attacks leading to premature treatment termination (79).

The important limitations to biomedical models of ketamine have contributed to rapidly rising interest in “psychedelic” approaches, which frame ketamine’s psychoactive effects in an extremely different light. Namely, drug experiences are not seen as treatment side-effects, but rather as essential drivers of potential benefits (80). While some experts reserve the psychedelic label specifically for agonists of serotonin 2A receptors like psilocybin (81), psychedelic treatment models have been utilized with diverse psychoactive drugs including MDMA (82), ibogaine (83), and cannabis (84), in addition to ketamine.

Psychedelic ketamine models have rarely been studied in modern clinical trials or implemented in real-world psychiatric services (85, 86). Nonetheless, they are far from new—scientific publications describing ketamine’s employment in psychedelic-like models appeared within a decade of its 1962 discovery (87). Their origins can be traced even further back, to traditional uses of psychedelic mushrooms and plants over many centuries (88), as well as to psychedelic-assisted psychotherapies that were first formalized in the 1950s (89).

There are many ways by which psychedelic and biomedical approaches differ. The connotations of the word psychedelic itself—“mind manifesting”—differ greatly from those of the pathological labels dissociative and psychotomimetic. Psychedelic approaches also utilize different dosing regimens, typically administering fewer treatments at higher doses with the explicit aim of engendering powerful alterations of consciousness (87), which are then shaped with treatment adjuncts like music and psychological support (90–93). In contrast to this strong emphasis on treatment contexts in psychedelic studies, most biomedical ketamine studies neither standardize nor even report non-pharmacological factors like the presence or absence of music during treatment sessions (94).

Unlike psilocybin, the vast majority of psychiatric ketamine studies fall into the biomedical rather than the psychedelic camp—a surprising divergence when one considers these drugs’ many similarities. Ketamine and psilocybin can both produce rapid improvements in psychiatric conditions like depression that persist for days or weeks beyond the excretion of the drugs and their metabolites (25, 91). Both ketamine and psilocybin appear to act as “psychoplastogens”: agents that rapidly boost neuroplasticity (95, 96). Moreover, recent neuroimaging research has revealed shared neural features of their effects despite pharmacological differences, including heighted neural signal diversity (97), as well as reduced within-network connectivity and enhanced between-network connectivity (98).

Perhaps most importantly, serotonergic psychedelic and ketamine experiences have significant phenomenological overlap. The altered states of consciousness induced by ketamine and psilocybin have both been long employed as experimental models of psychosis (87, 99, 100). When compared on psychometrically-valid scales administered in controlled experiments, like the Altered States of Consciousness Rating Scale (101), ketamine and psilocybin produce remarkably similar results, including significant elevations on subscales reflecting key hallmarks of psychedelic experiences like “insightfulness,” “audio-visual synesthesia,” and “changed meaning of precepts” (102). In fact, ketamine’s subjective effects are mostly distinguished from psilocybin by elevated scores on the “disembodiment” subscale (potentially reflecting its “dissociative” label).

The discrepancies between the dominant models of care for psilocybin and ketamine may thus owe more to their sociohistorical differences—including ketamine’s widespread use in medicine as a dissociative anesthetic versus psilocybin’s disappearance and recent re-emergence (103)—than to their pharmacological, neural, or phenomenological differences. Nevertheless, in depression, only psilocybin currently has strong evidence supporting the central tenet of psychedelics: that certain drug experiences like “emotional breakthroughs” and mystical experiences can be therapeutic (104, 105). While even those claims have been challenged by methodological criticisms and emerging data (106, 107), psychedelic-assisted psychotherapy models for psilocybin are undeniably more formalized and better supported by clinical research than equivalent models for ketamine.

According to a recent review, five small trials have studied ketamine-psychotherapy combinations, none of which could be described as psychedelic in their therapeutic approach and only one of which was in TRD (85). That trial evaluated whether CBT could prolong the benefits of ketamine in patients who responded to a course of six infusions over 3 weeks (108), yielding mixed results. Given that participants of this trial began CBT only after completing their series of ketamine infusions, it appears that no published trial has explored ketamine with concomitant psychotherapy to treat depression. Further, the only two other recent ketamine-psychotherapy trials both administered ketamine disjointly with (mindfulness-based) psychotherapy—that is, patients received ketamine during a course of psychotherapy but did not necessarily receive psychological support or psychedelic-like contexts during their ketamine infusions (109, 110).

Given the lack of clinical trials employing psychedelic models for ketamine [despite encouraging retrospective reports (111–113)], we provide a concise review of the prevailing psilocybin-assisted psychotherapy (PAP) protocols which serve as the basis for most contemporary psychedelic ketamine models (112). We focus on the most common and distinctive approach involving one or two high doses of psilocybin, rather than the less common “psycholytic” approach—smaller doses used in conjunction with relatively frequent psychotherapy sessions (114)—or microdosing, the regular use of subperceptual doses of psychedelics without psychotherapy in a manner resemblant of oral antidepressants (115).

PAP protocols broadly aim to produce therapeutic psilocybin experiences in three distinct phases: preparation, treatment, and integration (90). The preparation phase of PAP entails patients and clinicians meeting for several hours in order to, for instance, exchange information, establish rapport, and set therapeutic intentions for the drug experiences (116). In some cases, this may entail defined preparatory practices such as mindfulness exercises (117), but most psychedelic studies do not detail specific activities.

During the second phase, referred to as treatment or dosing, patients undergo approximately 6-h psilocybin experiences, once or twice (91, 92), while receiving psychological support from their clinicians in comfortable and de-medicalized environments. The clinicians are often [but not always (118)] described as guides or “sitters” as opposed to therapists, partly to emphasize their non-directive therapeutic stance (90). Psychedelic experiences and associated insights are typically understood to arise spontaneously from patients’ minds rather than resulting from specific psychotherapeutic interventions (80), though nonpharmacological adjuncts like music are understood to be critical influences (94). Accordingly, one of the guiding precepts of this phase is “set and setting”; i.e., that psychedelic experiences are largely dictated by a patient’s mindset and the treatment setting (119), the influences of which are amplified by the drug’s effects (120). Set and setting are thus optimized in the aims of engendering certain types of putatively therapeutic experiences like mystical or “peak” experiences (121).

The third phase of PAP is referred to as integration, a phase that entails patients and therapists meeting after the dosing session (s) to revisit their experiences. The overarching aims of this phase are to process the treatment experiences by, for example, working through distressing content and consolidating insights (90, 116). Much like the preparation phase, actual integration practices are diverse—a recent review identified 10 distinct models of integration which differed in their relative emphasis on mind, body, spirit, lifestyle, relationships, and the natural world (122). The typical duration of this phase is several hours over one to three sessions (90), though PAP practices outside of clinical trials may vary significantly.

In sum, PAP can generally be understood as synergistic mind–body interventions typically conducted in three phases: preparatory sessions, one to two doses of psilocybin administered with careful attention to set and setting, non-directive psychological support, and post-experience integration (80). Actual practices vary significantly, and this is particularly true for psychedelic approaches to ketamine, where the numbers of treatment sessions range from one to dozens (112), dosages range from 0.1 mg up to and beyond 4 mg/kg parenterally (123), and routes of administration include intravenous, sublingual, intramuscular, and oral (112).

While PAP has demonstrated significant benefits in MDD and TRD (92, 124, 125), there are major knowledge gaps and obstacles to overcome before real-world implementation, which is anticipated to occur within the next several years. For instance, the current psychotherapeutic practices of PAP are heterogenous and relatively ill-defined though there are ongoing efforts to shift to evidence-based approaches like Acceptance and Commitment Therapy (ACT) (118, 126). The external validity of existing PAP trials is also limited by their populations often being highly selected, e.g., by enrolling only the 3–6% of screened patients who are relatively free of suicidality and comorbidity (91, 125). Further, treatment sessions requiring the continual presence of two trained clinicians for upwards of six consecutive hours will inevitably be associated with costs in the range of tens of thousands of dollars per treatment course and other implementation challenges, such as shortages of skilled personnel and infrastructure.

As discussed earlier, ketamine has proven to be somewhat of a chameleon in terms of its utilization in the treatment of depression, with diverse approaches variously resembling ECT, conventional antidepressants, and/or serotonergic psychedelics. In the case of the latter, ketamine has numerous advantages as a putative psychedelic: a long track-record in medicine, excellent evidence as a treatment of severe TRD and suicidality (25, 46), treatment session durations that are approximately 75% shorter (87), minimal drug–drug interactions with a wide variety of medications (psychiatric and otherwise) (127), and safety/efficacy in bipolar affective disorder 1 and potentially depression with psychotic features (41, 128). Psychedelic-like models of care for ketamine thus warrant consideration and study.

In developing the Montreal model, we aimed to create a relatively structured approach to ketamine that capitalizes on its unique strengths, is applicable to complex real-world TRD patients, and is feasible to implement in resource-limited public healthcare systems.

At the clinic’s outset, we proposed trials of three ketamine infusions to appropriate patients with subsequent treatments to be mutually decided upon based on clinical response—much as is done with ECT (20). Unlike our experiences with ECT, however, we found that this lack of a clear therapeutic frame generated numerous issues including anxieties and perverse incentives regarding future treatments. For example, a positive clinical response might be perceived to result in fewer possibilities for treatments and contact with the team, which nearly all patients felt were beneficial. Many early patients thus experienced reemergent symptoms near the end of the treatment course—in other words, “termination reactions,” which serve to illustrate how ketamine differs from psychiatric interventions like ECT.

Termination is generally a subject of some interest in psychiatry but is a critical consideration in psychotherapy (129). For instance, discussing termination is one of the two main activities in the time-limited psychodynamic therapy of James Mann (130), who highlights the importance of exploring the inevitable end of treatment throughout the entire process. This exploration aims to cultivate insight and avoid negative outcomes like regression, ambivalence, and worsening depression, which may be common and significant. The importance of termination and other psychological dynamics in psychedelic therapies are increasingly being recognized (131), mirroring our own experiences that a brief course of ketamine evokes psychological dynamics that more resemble an accelerated short-term psychotherapy than a course of ECT (80).

An essential ingredient for any kind of psychotherapy is establishing a clear and consistent therapeutic frame. This includes: a shared understanding for the treatment activities, the schedule of sessions, and clear parameters for communication and follow-up care (132). This structure is not just necessary for psychotherapeutic activities, it is also understood to be therapeutic in its own right (130, 132).

While most clinical research entails a solid therapeutic frame by virtue of the research protocol, explicit efforts are required in clinical settings. Our experiences suggest that establishing a “psychotherapy-grade” therapeutic frame is vital for safety and efficacy with ketamine, particularly given the complexity and comorbidity of TRD with conditions like personality disorders (4). Not only can such a frame reduce uncertainty and mitigate termination reactions, it provides the structure needed for psychological exploration.

Patients referred to our service often (and increasingly) arrive with unrealistically high expectations for ketamine, anticipating powerful or even miraculous benefits (133). This clinical phenomenon, paralleling the broader psychedelic “hype bubble” (86), poses challenges and risks.

Many of our early patients—even those who reported significant benefits with ketamine—were disappointed with a lack of life-changing effects and/or by their transience. This disappointment can readily lead to discouragement, hopelessness, and even increased suicidality, particularly in patients who have already experienced years of past treatment failures.

To mitigate these risks, we began systematically incorporating explicit discussions about treatment expectations during all initial evaluations, aiming to foster more moderate outlooks and greater feelings of agency from the very outset. This includes, for instance, emphasizing the importance of behavioral changes (discussed below), establishing “backup plans” to be undertaken in case ketamine should prove unsuccessful, and generally shifting perceptions of ketamine from being a panacea that is passively received toward being one important component of a multifaceted and active effort toward recovery.

Such conversations can significantly mitigate eventual disappointment and hopelessness—especially when undertaken before the ketamine treatments have begun.

As we began establishing clear therapeutic frames and exploring treatment expectations on evaluation, we evolved toward explicitly presenting ketamine as follows: an intervention that can yield benefits that may well be significant, yet are likely to be transient. Given our lack of resources for maintaining benefits by frequently repeating doses, this framing naturally led to direct conversations with patients about how a resultant “window of opportunity” of symptomatic improvement [and potentially enhanced neuroplasticity (96)] might be best utilized. In other words, what activities might be undertaken during—but also before, and after—the ketamine treatments to deliver maximal long-term benefits.

Similar questions pertain to the preparation and integration phases of psychedelic therapies. However, as experts have commented, the psychedelic literature on preparation and integration can be relatively vague and inconsistent regarding what these practices should entail (122, 126). We thus instead drew from wider bodies of knowledge about the relationship between behaviors and psychological wellbeing, as well as the well-established practices of goal setting in conventional psychotherapies like CBT and ACT.

CBT, the psychotherapy with the greatest evidence-base in depression (17), has been proposed by experts as the most obvious “default” approach for psychedelic therapies (134). One of CBT’s essential components is the collaborative development of personalized (and often behavioral) goals (135). The therapeutic value of such behavioral goals is further supported by evidence for Behavioral Activation Therapy (BAT) (136). BAT is a relatively simple, short-term therapy that partially overlaps with CBT but focuses almost entirely on pursuing adaptive behavioral changes. According to a 2020 Cochrane review of 53 studies with 5,495 participants (136), BAT is at least as effective in depression as CBT or any other approach that it has been compared to.

Based on these therapies and their extensive evidence, our model incorporates behavioral goal-setting into evaluation and preparation using the common “Specific Measurable Achievable Relevant Timely” (SMART) framework (135). Patients and our clinicians establish at least three mutually acceptable SMART goals to be initiated before beginning ketamine treatments and worked on throughout. These generally focus on evidence-based lifestyle changes, such as: improving sleep hygiene (137), improving diet (138), establishing consistent routines (139), engaging in meaningful social activities (140), and/or increasing levels of physical activity (141). Common goals include engaging in 20 min of daily walking and establishing fixed sleeping hours, which are modest yet highly relevant to our populations of patients with TRD who frequently report highly irregular routines and extreme behavioral deactivation.

For patients with healthier lifestyles and habits, either on evaluation or as the treatment progresses, our goal-setting process evolves to more resemble the “committed action” component of ACT. I.e., treatment goals become less about engaging in evidence-based lifestyle changes, and more about pursuing meaningful actions that align with an individual’s unique values (126). These ACT-style goals are often more abstract than improving sleep hygiene or engaging in exercise, for instance, yet generally remain well-suited to the specificity and clarity that the SMART framework provides.

Our experiences suggest that the ketamine “treatment situation” is an ideal opportunity for such behavioral modifications. Patients’ high expectations for ketamine and desires to optimize their chances for response can translate into high levels of engagement in pursuing changes—which is also best initiated early in the ketamine treatment process. In turn, this collaborative goal-setting process can help patients cultivate a healthier locus of control, as well as insight into the psychological obstacles that contribute to their struggles.

Extending our observations that most patients readily engaged with difficult but potentially beneficial behavioral goals, we hypothesized that the ketamine treatment process might also be an opportunity for difficult but potentially beneficial medication changes. Of many such potential changes, our most common recommendation has been to reduce the use of benzodiazepines and related sedatives (BZDRs).

For depression, guidelines only recommend short-term benzodiazepines given evidence for tolerance (142), potential harms (143), and questionable long-term efficacy (144). Nevertheless, approximately half of the patients referred to our service actively receive long-term BZDRs—often at high doses (145). In many cases, patients report no clear indication for these treatments, nor being adequately informed about their potential harms. Given their risks and especially the emerging (if conflicting (146)) evidence that benzodiazepines may dampen or shorten the antidepressant effects of ketamine (147), we consistently propose a trial of BZDR discontinuation to all patients. This typically entails a slow taper such that final doses occur within several days of the first ketamine treatment.

As with the pursuit of lifestyle goals, patients tend to readily engage in such processes when provided with education and support. Our recent results from a cohort study of TRD patients receiving ketamine in our model found that all were willing to attempt BZDR discontinuation, almost all achieved total abstinence during treatment, and the majority remained BZDR-free after an average follow-up of 1 year (145). These results are particularly noteworthy given our population’s severity, and that only one prior study that has even attempted BZDR discontinuation in patients actively suffering from depression (148). In addition to preclinical and clinical evidence suggesting that ketamine can mitigate psychological BZDR withdrawal symptoms (149–151), we have found that the initiation of a course of ketamine is an excellent psychological opportunity to undertake rational medication changes (145).

In addition to optimizing the lifestyles and pharmacological treatment of our patients, we began routinely requiring that our patients engage in at least one-hour of weekly evidence-based psychotherapy beginning at least 2 weeks before their ketamine treatments. The impetus for this addition was multifold:

Psychedelic trials similarly incorporate therapy sessions outside of drug treatment sessions, but these are almost always conducted by the same clinicians (116). Partly due to resource constraints, we are intentionally flexible regarding these therapists, who may be external therapists from our hospitals, referring psychiatric services, or the community, or learners rotating in the service. Some such therapies are in place prior to evaluations, and others are arranged to begin alongside the ketamine process. As such, our model does not specify the exact type of therapy, but rather requires any evidence-based approach, such as CBT or ACT, that a particular patient is willing to pursue.

This use of concomitant psychotherapy occurring alongside—but somewhat independently of—ketamine treatments is atypical for psychedelic approaches but very common in existing psychiatric models of care. I.e., patients being treated by psychotherapy plus conventional medications and/or neurostimulation typically receive care from multiple clinicians, who (ideally) work in close collaboration.

The flexibility afforded by this approach has obvious feasibility benefits, such as alleviating the need for all treating clinicians to be experts in both conventional psychotherapy and ketamine/psychedelic approaches. It also aligns well with extensive evidence that therapist-patient alliances are more strongly related to outcomes than are technique specifics in depression (153). In other words, one may generally expect more benefits from prioritizing concomitant psychotherapy characterized by strong therapeutic alliances than by specific techniques.

In cases where a patient’s comorbid conditions suggest that a particular technique is particularly likely to be beneficial—e.g., trauma-focused therapy for comorbid PTSD (154)—the model’s flexibility also allows for prioritizing a certain therapeutic approach. This is an important benefit given that TRD populations have high rates of diverse comorbidities (7).

In our experiences, the various benefits of implementing psychotherapy in a concomitant fashion generally outweigh the potential drawbacks, provided that ketamine clinicians and psychotherapists work in close coordination.

The aforementioned aspects of the Montreal model largely pertain to what happens outside of actual ketamine treatment sessions. They were mostly inspired by conventional psychiatric evidence and may thus hold relevance for even purely biomedical approaches to IV ketamine. In contrast, the following sections describe our approach to the actual ketamine dosing sessions, which has largely been informed by the psychedelic paradigm.

As discussed, there are conflicting biomedical and psychedelic views about the altered states of consciousness engendered by ketamine: are they inconvenient treatment side-effects, or are they essential drivers of psychological benefits? Having administered hundreds of treatments with diverse contexts and framings, our view lies between these extremes. We have come to see ketamine experiences as neither unimportant nor as essential, but rather as valuable opportunities for experiential learning when paired with appropriate settings and mindsets.