Ketamine: Catalyst for Paradigm Change in Mental Health

Ketamine: Catalyst for Paradigm Change in Mental Health

Scott Shannon, M.D. FAACAP

We see signs of a failing mental health care system everywhere we look. Depression is now endemic in the US. Rates of suicide have risen by about 30% in the last twenty years, despite the escalating use of anti-depressants [1] Less than half of patients respond to their first prescribed anti-depressant [2] and over time, treatment-resistant major depression affects 30 to 40% of those prescribed [3]. Ac- cording to the CDC, deaths of despair�those caused by drugs, alcohol, and suicide, more than doubled from 1999 to 2017 [4]. Furthermore, it is no better for teens: 42% of high schoolers have recently reported feelings of sadness or hopelessness [5], and only half of suffering children find the care they need [6].

The COVID-19 pandemic has made things even worse. The rates of depression had already increased to over 20% prior to COVID [7], and new research from a 2021 Boston University study found that only 12 months into the pandemic, bed past 30% [8]. The pandemic accelerated a pernicious trend of overwhelm and compassion fatigue among nurses and physicians, with 40 to 60% now experiencing burnout and depression [9]. Caregivers have been particularly affected. As canaries in the coal mine for the mental health of our culture, teen visits to the emergency room for suspected suicide attempts escalated by 51% between 2019 and 2021 for girls [10]. These numbers carry jaw-dropping power.

This data points to an ineffective model of mental healthcare, and the pandemic dramatically exposed and worsened the preexisting flaws of the already broken system. Despite the labors of caring, dedicated, and intelligent providers, we are not making progress. Clearly, we need a new model of care with new treatment options to tackle this growing crisis. Luckily, there are new options for care that may help address it including ketamine. Ketamine offers both the potential to more effectively treat those suffering and a catalyst for a profound and much-needed shift in our paradigm of mental health care.

With ketamine as a tool, providers can focus on holistic patient care. The problem of the ineffective model of care does not lie with the providers but in fact, with the very foundations of the care they provide. Modern psychiatry is built upon the premise that the symptomatic brain is broken, chemically im- balanced, and the only hope for relief comes from medications to rebalance neurotransmitters. This chemical imbalance theory posits that the typical psychiatrist must deeply understand the nuances of the neurochemical environment of the human brain, the most complex system in the known universe. However, after a brief interview, the psychiatrist selects a pharmaceutical agent to improve the delicately nuanced neurotransmitter soup found within the central nervous system, thereby (or ideally) relieving suffering. Not only does a psychiatrist select this without any biological assessment of the brain or neurochemicals, but they are also making this selection without any psychiatric access to a solid understanding of how anti-depressants actually work. So, while this process is sometimes effective at muffling psychic distress and misery, more often than not, they are merely dulling the inner turmoil and simply enabling individuals to care less about it. As a result, their apathy might even extend past their suffering. Studies have found that individuals treated with anti-depressants often care less about everything else, including their spouse, other relationships, sexual passion, and more. Regardless of these

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Ketamine: Catalyst for Paradigm Change in Mental Health

challenges, the vast majority of people are not cured by these agents [11].

Perhaps, then, building the edifice of modern psychiatry on an unclear, untestable model for treating those suffering is creating the real imbalance in our field. The use of psychiatric medications came on empirically without a proper foundation in science while simultaneously serving as a boon for the pharmaceutical industry. The first antipsychotic (chlorpromazine) and first antidepressant (iproniazid) were both discovered through serendipity [12] and soon after, in 1988, Prozac was introduced. Since then, the use of anti-depressant medications has steadily risen to almost 14% of the US population [13], reaching 24% in some demographics such as women over 60 [14]. This consistent increase in use provides pharmaceutical companies with $5.6 billion in US sales alone for these medications [15]. Still, the chemical im- balance of serotonin in depression has never been proven [16], and there is now considerably more evidence disproving its connection to depression [17]. This rebalancing of neuro- transmitters stands at the very core of what modern psychiatry does, yet it is never presented as the evidenced-based foundation for how and why we practice. As the evidence for the serious limitations of the existing model grows, so too does the number of dis- satisfied psychiatrists and suffering individuals, all in search of a new path. They all share a sense of impotence with our current options and an increasing impatience for something more effective.

Nevertheless, it is not all doom and gloom. The last decade has seen exciting developments in psychedelic medicine (PM). This renewed model of care utilizes a psychedelic framework to create a therapeutic container, encouraging a patient�s inner exploration via a range of medicines that act as catalysts for altering consciousness and opening new doorways of awareness, insight, and experience. Medicines such as psilocybin or

MDMA�and, of course, ketamine�are given to augment psychotherapy delivered with preparation, integration, and focused attention to set and setting (the container). They open new experiential territory in the psyche and function as catalysts for cognitive shifts�something we have not yet seen with psychopharmacology. We now have research that documents how psilocybin can alter an individual�s metaphysical belief system and their existential world [18, 19], which has benefits like decreased fear of death [20] and durable relief of depression [21]. This spiritual belief system frees our motivation, establishes hope, and secures a sense of connection, or it can lock us into despair, isolation, and apathy. PM seems to open our spiritual perspective to inquiry and revision and it may be spiritual medicine.

The research supporting the enduring value of PM has come on forcefully in the last few years. The FDA has awarded three versions of PM Breakthrough Therapy Status [22, 23]. The published effect sizes of MDMA, for example, humble those found in the suppressive tools of conventional psychopharmacology by a factor of 2x to 3x in effect size [24]. While we wait for the definitive results from the large Phase III studies, expected in May of 2023 [25], a range of other neuroimaging and smaller clinical results support the promise found in this research. However, we cannot and should not make the same mistake we have made with medications like Prozac. Psychedelic medicine, while powerful and much needed, is not a complete mental health care system. Psychedelics are merely a tool, and their efficacy does not eliminate the need for a comprehensive system of care that educates, prevents, and offers other avenues for support.

We must acknowledge that a broad range of presenting complaints in mental health are not appropriate for PM. These include child psychiatry, adjustment issues, self-limiting concerns, family conflict, and all of the

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presentations driven by epigenetic and lifestyle issues, For example, we now appreciate that diet and nutrition play a significant role in the risk for depression, bipolar disorder and anxiety. We know that our inherited genes as expressed by single nucleotide polymorphisms (SNPs) are a factor in less than 30% of major mental illnesses. The balance of the risk is driven by environmental factors such as abuse history (adverse childhood experiences-ACEs), relational support and lifestyle choices that alter the expression of our genes by epigenetic modification. Lifestyle choices include diet, exercise and self-care. These appear to alter our genetic expression by methylation of the histones found on the genes. A focus on PM alone that misses the opportunity to address our risk factors is an incomplete system.

Quite simply, psychedelic medicine should not be mistaken for comprehensive mental health care, and any overly enthusiastic attempt to make it so will ultimately harm patients. Integrative medicine (also known as natural medicine or holistic medicine) can supply this broad foundation for psychedelic medicine, partly because it and PM share the same roots. Integrative medicine builds upon a foundation of body-mind-spirit unity, and both posit that all healing�and health it- self�is built upon the innate ability of our being to move towards wholeness when barriers, such as excessive self-referential thinking, are removed. These models are built on the concept that each person we meet has the innate capacity to self-heal. This stands in stark contrast to the chemical imbalance model of conventional psychiatry that does not embrace the concept of healing, just medication maintenance. Integrative psychiatry and psychedelic medicine can represent a complete mental health care system.

This concept of body-mind-spirit unity brings us quickly to spiritual medicine. Spiritual medicine embodies a different perspective and requires a different type of caregiver.

relationship�one that�s built more on per- sonal journeys and emotional insight rather than one centered around enduring and im- personal neurotransmitter manipulation. PM validates this new perspective of wholeness by moving the seat of power from the therapist to the person immersed in the psychedelic experience. The therapist takes on the role of sitter, container, and facilitator. At the same time, the individual immersed in the close encounter with the depths of the psyche plays the role of expert and explorer. Thus, the classic polarity of wise expert and suffering patient or client so central to the psycho- therapeutic paradigm becomes reorganized to reflect this new perspective about the primacy of the psyche and its innate spiritual wisdom.

Spiritual medicine is our most potent medicine, and is always personal: it is not scalable, cannot be commodified as a proto- col, does not embrace a postmark, and always holds irreconcilable mystery. PM and its spiritual incisiveness carry the power of a surgeon�s knife to the psyche not the blunt and often damaging instruments we have grown so frustrated with. It is no surprise that the excitement about psychedelic medicine is palpable. We see it in the professional interest in drastically oversubscribed training programs and the explosion of political action across the country. There is no mistake: our healthcare professionals, our society, and the boundless suffering populace cry out for a spiritual and grounded approach to care.

This shift from the status quo reveals that introducing a new paradigm�one that pre scribes medication to speed psychotherapy, not fuel apathy�can deepen our potential to heal and help repair the rift between therapists and prescribers. MDMA and psilocybin have been the main actors, but it is time to introduce a new character: ketamine. Keta mine offers a portal to effective mental health care that engages our spiritual self, lubricates psychotherapy, and relieves depression.

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Ketamine: Catalyst for Paradigm Change in Mental Health

Ketamine is fueling this profound shift in the paradigm of mental health care. It supports the industry in moving away from a suppressive model of care that fears the psyche to an evocative model that honors the psyche.

Ketamine plays this pivotal role in this transition from the old models of mental health (daily mediated suppression of the psyche and the therapist as an external ex- pert) to a new evocative model in a few different ways. First, ketamine typically works better for severe depression than conventional medications. Dr. C. Andrade, a well- known psychiatric researcher, described it in a 2017 review article, �the marked acute antidepressant efficacy of ketamine, even in medication-refractory patients, now seems beyond doubt� [26]. This potency has gathered the attention of modern conventional psychiatry and pharmaceutical companies, as witnessed with the release of Spravato (found as one-half of generic ketamine) by Janssen in 2019 [27]. Second, ketamine works when given in an episodic manner and does not re- quire daily doses to suppress symptoms [28]. Third, ketamine is an agent that decreases the activity of the default mode network just as classic psychedelics do [29]. So, it can trigger profound psychedelic-like insights that can alter someone's life trajectory with just a single dose. Finally, many are finding that keta- mine, like MDMA or other classic psychedelics, can enhance psychotherapy by accelerating and deepening the process.

These facets become quite apparent when you work with ketamine in a clinical setting, as they foster exploration and allow the practitioner to go beyond an infusion routine. As more and more practitioners are drawn to ketamine by one of these angles, more and more begin to embrace the paradigm of PM. It is a slippery ride on an effective slope. Many professionals were drawn to mental health by the promise of working with the human mind, and, finally, after years of ineffective medicines and faulty systems, there is a tool that

opens up this realm for exploration: keta- mine.

Ketamine can create psychedelic effects while simultaneously being an accepted part of the conventional toolbox, ultimately bridging the old and new models of care. Ketamine is a gentle, safe, and more accessible entry point for explorations of the psyche, providing flexibility and provider confidence. Whether you are a novice psychonaut (explorer of the psyche), an unseasoned practitioner, or a veteran of many decades working in the trenches, ketamine might help all practitioners understand what is available to them and become comfortable in this realm prior to full legalization of psychedelics.

To begin with, let us explore the items that reflect ketamine�s ease, comfort, and safety:

Ketamine reduces anxiety. It quiets that part of our central nervous system that worries and frets. Many classical psychedelic medicines can have a significant element of anxiety as part of the journey (found in 20% of participants in one LSD study [30]. If you are new to psychedelics, this tension can be intimidating and overwhelming. Research indicates that ketamine is euphoric and mood boosting for most people [31]. Unpleasant or frightening trips are possible but much less likely than with psilocybin or LSD as ketamine is well tolerated in a range of ages and indications [32-36]. Ketamine opens the floodgates slowly. Both ketamine and the classical psychedelics decrease the activity of the default mode network [29], which may be our closest brain equivalent to the ego [37]. The classical psychedelics can and will release a tsunami of unconscious material that can be very powerful (and overwhelming).

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when these self-created filters are decreased. Ketamine does decrease the filter of the self. However, it simultaneously decreases the power of cortical functioning [38] and thus reduces the unpredictable wave of the unconscious material brought to awareness. Traumatic experiences may be accessed, but the weight of the new in- sights is typically more limited. Ketamine can work as a gentler introduction to these inner experiences.

It is brief. The half-life of ketamine is short, about 45 minutes [39]. This means that the entire experience lasts less than one hour. Good or bad, the journey is short and manageable. The total time from check-in at the office to walking out the front door is typically about two to three hours. People clear from the effects of ketamine fully in a few hours, and the practitioner can treat multiple people in a workday.

It is safe. Over the last 50 years or so, ketamine has become a well-known and well-utilized medication in operating rooms, emergency departments, and pain centers. The track record is one of safety and predictability at the doses being employed in psychiatry (0.5 to 1.5 mg/kg) [33-36]. A few years ago, at a Kriya conference Steve Levine, then of the Ketamine Treatment Centers, noted that they had delivered over 10,000 psychiatric doses of ketamine without one serious adverse event [40]. With modest caution, keta- mine has proven to be a safe medication for psychiatric applications.

It is pharmacologically clean. Unlike MDMA and the classic psychedelics, ketamine has little in the way of

contraindications with psychiatric medications. The Phase II and Phase III protocols for MDMA, psilocybin, and LSD include a contraindication for concurrent dosing with most psychiatric medications, especially anti- depressants. This means most psychiatric patients must endure a medication taper and washout period that can take weeks to months. This is not trivial. Many patients have been on these medications for years, if not decades. After years of medication management, the body�s ability to find neuro- transmitter balance begins to weaken and fail. This is the primary unspoken liability of psychiatric prescribing, but ketamine does not challenge levels of the monoamines commonly targeted with psychiatric medications (dopamine, serotonin, and norepinephrine). As such, it does not require a taper of psychiatric medications or a washout. Plainly put: ketamine is more straightforward for the patient and the psychiatrist.

It is cheap. While it may be crass to talk about cost, it is a genuine concern. Over half of Americans limit health care simply due to the cost [41]. As deductibles and co-pays grow, so does treatment avoidance. The cost of ketamine is not a limitation. The cost of the medicine needed for a typical intramuscular injection is less than $5. The vast majority of the price for ketamine-assisted work lies in the cost of the provider�s time. Group therapy and trainee involvement offer some potential solutions to this challenge. In a very real way, ketamine frees us from the exorbitant business model of pharmaceutical companies.

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Ketamine: Catalyst for Paradigm Change in Mental Health

Ketamine can also create powerful and psychedelic-like effects, aiding the caregiver in supporting healing. Like classic psychedelics, it diminishes the effects of the default mode network. It also dramatically enhances neuroplasticity [42]. This shift may explain some of the power of ketamine to lift mood, alter insight and enhance motivation; this is a big part of the inherent attractiveness of ketamine. Overall, it possesses a number of other observable effects that make it attractive to providers working in this space:

Ketamine is powerful. Never mind that ketamine is not a true psychedelic. This experience may be one of the most profound alterations of consciousness that anyone will ever experience with any agent. As a dissociative agent, ketamine disconnects most of our cortical awareness and creates an experience that will astound patients. Patients and practitioners should not underestimate the power of this experience. This dramatic and abrupt departure from our normal state of consciousness often triggers curiosity and profound respect.

Ketamine alters our thinking. Keta- mine modifies the default mode net- work, disrupts slower thalamocortical relays, and significantly enhances neuroplasticity [29, 43, 42]. It offers a new way of thinking, particularly about one�s life and the big picture of our existence. A different vantage point offers a new perspective. People come away with a refreshed look at their life journey and options for change. After a ketamine experience, the brain is more open to change. This enhanced plasticity lasts most acutely for 24 plus hours [43], but with proper integration, the changes could last a lifetime.

Ketamine has a clear and varied dose-response curve. Individuals can dial in the intensity of experience they would like to have low dose: verbal, yet quite altered (somewhat like pe- yote); moderate dose: some verbal capacity, but without most of the personal narrative (more like psilocybin); high dose: nonverbal and disconnected from our body and earthly plane (similar to 5-MeO-DMT). This dose response curve reflects how our consciousness functions. Different doses open up unique elements of consciousness and thus unique pathways for healing awareness. We must learn this terrain well and enhance our ability to direct specific mental health and psychotherapeutic challenges in a specific direction. We have yet to map this needed but uncharted territory. Ketamine offers guidance on this needed task.

Ketamine offers therapists a pathway to process trauma and can also be applied to the therapeutic encounter in a number of other ways as well. The dissociative mechanism inherent with ketamine reduces the intensity of all emotions, including fear and anxiety, making it a valuable tool for psychotherapy. It helps to limit the excessive emotional pain linked to trauma and interpersonal conflict. Once partially dissociated, someone with a trauma history can access distressing emotions without disorganizing terror or panic. MDMA does this as well, but it maintains complete cognitive clarity. Given this difference, MDMA is a superior tool for processing trauma, but it is not yet available for therapists legally.

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Ketamine enhances immediate psychotherapy. The options for keta- mine-assisted p