The Ketamine Papers: Science, Therapy & Transformation

The Ketamine Papers serves as an essential window into the rapidly accelerating application of the anesthetic cum party drug ketamine to individuals with disorders such as treatment-resistant depression and post-traumatic stress disorder (PTSD). In addition, the book’s release coincides with other psychedelics, MDMA (aka ‘Ecstasy’) and psilocybin, being cleared for late-phase clinical trials as therapeutic adjuncts for the treatment and – dare we say – cure of those and related disorders, a process that will still take some years. Given what seems to be an increasing explosion of interest in the use of psychedelics for everything from therapy to micro-dosing of LSD to fuel creativity, The Ketamine Papers offers a range of views into how the psychiatric and psychotherapeutic communities are putting to use what amounts, for now, as the only legal psychedelic drug left standing, and for a group of people who very much struggle and suffer, at a significant cost to themselves, their relationships, and society.

The recurrent leitmotif of The Ketamine Papers is that of stubbornly lingering psychological illness – with feelings and behaviors ranging from sadness and stuckness to suicidality – that doesn’t just happen. It is often the function of trauma, childhood and otherwise, and lack of attachment not offset by a resilience that some develop and many do not. Those statements won’t be surprising to anyone who has read the works of psychiatrists and psychologists who have rooted depression – by far the most common form of mental illness – in unresolved childhood conflicts.

From both a humanistic perspective and that of those concerned about practical issues such as health care spending, the need to do better with individuals who struggle with depression and related, fear-based afflictions such as post-traumatic stress disorder (PTSD) and complex psychological trauma, and the drug and alcohol abuse and chronic physiological illness that often accompany them, is urgent. Where I work in population health management for the low-income population, there is the spreading realization that trauma – again, childhood and otherwise – underlies what haunts many of the people who are homeless on our streets, populate our prisons, and who are the ‘frequent flyers’ in our emergency departments and inpatient wards, and who represent the preponderance of the 30,000 annual US suicides.

The prevalence, basis, and effects of PTSD are relatively well known. PTSD is most typically associated with having been subjected to a life-threatening event. The prevalence is higher in women than in men because of the frequency of sexual assault against women. But it can also be the result of having served in a war zone (such as an estimated half million veterans of the Iraq and Afghanistan wars), a bad car accident, or a violent episode such as a street shooting – and includes those who have witnessed such events. The effects, including flashbacks and panic attacks, can be acute, often debilitating, and destructive of relationships and lives. Treatment options include psychotherapy, antidepressants, and exposure therapies that seek to desensitize traumatic memories. As much as 8 percent of the US population suffers from PTSD, and psychiatrist and researcher Michael Mithofer estimates that 30 to 50 percent of people afflicted are ‘treatment-resistant’.

What’s less well known is the deep body of work around complex trauma based in what are also referred to as “adverse childhood experiences,” or ACEs, which is different from PTSD. In the mid-1990s, researchers at Kaiser developed a survey assessing participants across 10 domains of ACEs, such as childhood emotional, physical, and sexual abuse. They sent the instrument to about 17,000 Kaiser members who were mostly white and middle-class. The researchers were reportedly shocked by what they found. Sixty-four percent of those responding indicated they had suffered at least one ACE, and 12.5 percent had four or more. A recently released Center for Health Care Strategies fact sheet ndicates that these proportions are unsurprisingly higher in a racially mixed population of high school graduates in Philadelphia.

The original Kaiser study then drew a straight line between an individual’s ACEs and their propensity to develop mental health issues and co-occurring physiological illness based on review of survey respondents’ medical histories. Notes the study abstract: “We found a graded relationship between the number of categories of childhood exposure and each of the adult health risk behaviors and diseases that were studied (P < .001). Persons who had experienced four or more categories of childhood exposure, compared to those who had experienced none, had 4- to 12-fold increased health risks for alcoholism, drug abuse, depression, and suicide attempts; a 2- to 4-fold increase in smoking, poor self-rated health, ≥50 sexual intercourse partners, and sexually transmitted disease; and a 1.4- to 1.6-fold increase in physical inactivity and severe obesity. The number of categories of adverse childhood exposures showed a graded relationship to the presence of adult diseases including ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease. The seven categories of adverse childhood experiences were strongly interrelated and persons with multiple categories of childhood exposure were likely to have multiple health risk factors later in life.”

(If you haven’t taken the ACE questionnaire, you can do so here).

It isn’t difficult on reflection to understand the kind of effects childhood trauma can have on the psyche. People from chaotic, violent households and / or dangerous neighborhoods at a most fundamental level will struggle with issues like trust that are the glue of healthy relationships. Beyond that is the effect on the brain and physiology, in which people become stuck in a fight-or-flight response expressed as hyperarousal that can then manifest as both anxiety and depression, as well as a range of other diagnoses such as attention deficit disorder and obsessive-compulsive disorder. Recent research affirms the link between childhood trauma and depression, as well as the likelihood that someone will be ‘treatment-resistant,’ particularly with the most commonly prescribed antidepressants.

The Ketamine Papers is a compendium of 16 articles edited by Philip Wolfson, a psychiatrist who practices in Marin County, California, and Glenn Hartelius, a San Francisco-based psychologist who edits the International Journal of Transpersonal Studies. The articles chronicle the emergence of ketamine as a novel and uniquely effective approach for treating treatment-resistant depression and a variety of related disorders, and is an effort to encapsulate the discussion of the various approaches to using ketamine as a treatment, and how to best utilize its potentially psychedelic effects, which are tied to dosage and sensitivity. The Multidisciplinary Association for Psychedelic Studies, which is driving the work to gain FDA approval for MDMA-based psychotherapy, is the book’s publisher.

The book grounds its exploration in some of the history of the movement among a subculture of therapists who first incorporated psychedelic medicines into their practice prior to LSD being made effectively illegal in 1968, with MDMA following in 1985. The histories of both drugs have become colored by their diffusion into mainstream, uncontrolled use, which in turn led to what many therapists saw as a politically tinged overreaction that led to both compounds becoming unavailable for any use. This was despite mounds of research about the safety and efficacy of LSD in controlled settings, and therapists’ own experiences in using MDMA to enable patients in four- to eight-hour MDMA-based sessions to quickly get in touch with previously unreachable parts of the psyche to resolve their traumatic experiences and inner conflicts in a process that might have otherwise taken years, if it had worked at all.

This leaves ketamine as the last legal psychedelic left standing. And the debate that The Ketamine Papers’ articles entails is whether and how to best leverage its characteristics as a psychedelic therapeutic adjunct, vs. the psychiatric establishment’s using it as a more effectively and rapidly acting antidepressant and treating any psychedelic experience as an unwanted and untoward side effect.

The reason that ketamine remains legal is because of its original and current on-label use as an anesthetic. The compound was discovered in 1962, and the government approved its use in 1970. It quickly moved into mainstream use as a battlefield anesthetic in the later days of the Vietnam War.

Over the years, anecdotal evidence grew of ketamine’s potential properties as a fast-acting and uniquely effective antidepressant, at sub-anesthetic doses, for individuals with depression. As Wolfson notes in his opening chapter of The Ketamine Papers, “Antidepressant responses to ketamine’s administration for other reasons such as analgesia and anesthesia were known, if not widespread, before researchers at National Institute of Mental Health (NIMH) in the late 1990s began to assess ketamine’s potential at low dosage levels, attempting to exclude or at least limit the psychedelic effects of the drug.”

An initial study, involving a very small sample of patients, showed that ketamine administered intravenously at a low dose over a 40-minute session would enable some patients with treatment-resistant major depressive disorder (TRD) to achieve a rapid and substantial reduction in their depressive and often suicidal symptoms. TRD is defined as continued depression after treatment with two antidepressants. This contrasts with the usual two to five weeks through which individuals with depression typically must suffer before a traditional antidepressant takes hold, if it works at all (which, based on a number of studies, does not happen in 30 to 50 percent of patients). In addition, while ketamine has its own side effects if abused, used appropriately, it lacks many of the nasty potential side effects of other antidepressants, such as weight gain, insomnia, and sexual dysfunction. Moreover, as Wolfson notes, subsequent studies have shown that about 70 percent of patients with TRD respond positively, if sometimes only temporarily, to one to three ketamine administrations.

The growing body of evidence as to ketamine’s efficacy has led many in the mental health and neuroscience communities to label ketamine as a potential wonder drug for depression and related disorders. Pharma companies are now racing to develop derivatives that achieve an antidepressant response through a mechanism of action involving blocking the brain’s NMDA receptors and that do not induce a psychedelic experience. Former National Institute of Mental Health Director Dr. Thomas Insell has said that IV-delivered ketamine “… might be the most important breakthrough in antidepressant treatment in decades.”

The off-label use of ketamine has thus been accelerating, and in a way that can best be described as chaotic. Ketamine can be administered via IV, as well as by an intramuscular injection, sublingual lozenges with the drug absorbed by the mucosa, or intranasally, and at a variety of dosing levels and frequencies. Based on the methodology laid out in the initial seven-patient study, ketamine IV administration has converged on a protocol that involves usually six IV infusions, administered in an outpatient medical office setting, over a period of about two weeks. (Steven P. Levine MD, a New Jersey-based psychiatrist currently involved in seven IV ketamine clinics nationally, succinctly details this approach in his chapter in The Ketamine Papers, “Intravenous Ketamine.”)

Given that ketamine is off-patent and its use in depression treatment is off-label, there is no big pharma company pushing for research or coverage of therapy involving ketamine as an existing compound. Based on searching around the Web, the infusion-based therapy can run anywhere from $500 to $1,000 per session times six or more, or $3,000 to $6,000. Patients must typically pay this out of pocket. But given the suffering that accompanies TRD, PTSD, and the other conditions for which ketamine is being applied, the word is getting out, and the ketamine business has been growing very rapidly. Ketamine-based treatment centers have been popping up in many American cities. These centers are as often run by anesthesiologists, and sometimes psychiatrists. As Levine notes in his chapter, the IV-based approach is proving to be effective treatment for many, and, the payment issues notwithstanding, it scales. In addition, while the IV approach is not coupled with therapy in the treatment setting, it is typically advised that the drug not be treated as a standalone but that patients also receive therapy and engage in other modalities such as exercise and yoga, meditation, and other mindfulness practices. (Where I live in the Bay Area, infusion-based ketamine therapy is provided by Kaiser, and by clinics in San Francisco, Palo Alto, and Watsonville.)

Still, much of the rest of The Ketamine Papers explores what’s possible when we break through our pre-conceptions about psychedelic experiences, largely because they cause people to feel good, and explore how such experiences can even more powerfully foster healing experiences and ones of personal growth.

Much of that territory is explored in the longest chapter of The Ketamine Papers, “Ketamine Psychedelic Psychotherapy: Focus on its Pharmacology, Phenomenology, and Clinical Applications,” authored by six clinicians and researchers with a long background and history in ketamine-based therapy. The crux of the chapter lies in the kinds of ‘non-ordinary states of consciousness’ (NOSCs) that ketamine can produce at varying dosage levels, which is also tied to the route of administration and resulting bioavailability of the drug (with higher bioavailability of a similar dosage level for intravenous or intramuscular injections vs. sublingual or oral administration).

Ketamine can be used to induce “euphorogenic” states “… that can be combined with guided imagery or verbalized meditations and may sometimes be utilized to resolve long-standing intra-psychic conflicts, to treat the after effects of trauma in the victims of physical and sexual abuse or other assault, to control the symptoms of post-traumatic stress disorder (e.g. in soldiers), or to resolve interpersonal problems in family and spousal relationships,” the chapter states. Higher doses induce out-of-body experiences that can raise unconscious material in the psyche to conscious awareness. A third type of NOSC is a near-death experience that can help one review one’s life deeds and misdeeds as an adjunct to therapy, and that can accelerate psychological and spiritual growth. Most intriguing and unpredictable is the ‘ego-dissolving transcendent experience,’ which is not necessarily dose-dependent and that induce healing by allowing someone lucky enough to have what Bill Wilson, the founder of Alcoholics Anonymous, called a ‘spiritual awakening.’

(Despite AA’s aversion to psychoactive drugs, Wilson extolled the virtues of LSD experiences he had many years after getting sober from alcohol.)

The chapter relates that some of the most interesting research on ketamine psychedelic therapy was performed in Russia in the mid-1990s, before ketamine became a popular street drug there and was effectively banned. Researcher Evgeny Krupitsky conducted studies that included using ketamine psychedelic therapy to treat alcoholics. In one randomized study, about 70 percent of the alcoholics who received ketamine therapy were sober a year later, compared to 24 percent in the control group. He conducted subsequent studies showing that patients with treatment-resistant opioid dependencies were far more likely to overcome their addictions with ketamine-based psychedelic experiences compared to patients who received sub-psychedelic doses.

Wolfson himself seems to be one of the few psychiatrists offering a distinctly psychotherapeutic psychedelic ketamine protocol. His is based on a mixture of office-based sessions that use both sublingual lozenges and intramuscular injections, overseen by himself and his female practice partner (this male-female approach is intended to help ‘reparent’ patients with childhood trauma and attachment disorders (and follows the research protocols for MDMA and psilocybin). It also dilutes the transference and creates safety for patients who are in a trance state, protecting both the therapists and the patient from misunderstandings.

The sublingual method is particularly interesting as it creates the possibility for home-based treatment that can sustain the antidepressant effect and create opportunities for further trance-based explorations outside the psychiatrist’s office. It was based on the insight of the Australian psychiatrist Stephen Hyde, whose book Ketamine for Depression preceded Wolfson’s book. Some psychiatrists for years have been using the intramuscular (IM) route for delivery of ketamine in their offices. The newer sub-lingual method extends the possibility for psychotherapy as patients are more conscious and thus have easier access to past trauma. Patients are trained in the use of the lozenges and then prescribed them for at-home sessions in which the drug is to be treated as the basis for meditation, in a way that both enables a sustained antidepressant effect and further self-exploration. Later, the sub-lingual sessions may be combined with injection-based, potentially transformational experiences that last up to three hours. This contrasts with the 45 minutes to an hour of the IV sessions. Integrative psychotherapy sessions and repeat in-office ketamine sessions are the backbone of ongoing treatment. Wolfson asserts that the at-home lozenge approach is free of abuse potential as prescriptions from formulating pharmacies are limited in the number of lozenges prescribed. In his chapter, “A Potential Model for Informed Consent,” Wolfson asserts he believes this approach will result in response and remission rates that exceed those of other ketamine-based approaches.

The Ketamine Papers is clearly aimed toward an audience of practitioners in the realm of psychiatry and psychology to deepen their understanding of a compound with a growing body of demonstrated success and enormous potential. But the book is also a good read for a broader audience of health care professionals and prospective patients who are interested in approaches that have the potential of addressing the root causes of some disorders and the illness burden of the populations practitioners serve. From a population health management perspective, as we come to understand that root causes such as childhood trauma and traumatic events such as sexual assault are behind a lot of the psychological and physical illnesses with which people present in physician, psychiatrist, and psychotherapy offices and hosptials, one of the biggest challenges we face is a distinct shortage of available and empathic behavioral health practitioners, coupled with an overreliance on a pharmacopeia that can at best palliate as opposed to cure, again, if it works at all. We need to focus on approaches that can leverage those scarce resources and empower them with the tools that can, yes, effectively cure those people so they can move on to the next group. And, of course, it would be even better if we could address public health crises like childhood trauma at their source.

Where The Ketamine Papers is most powerful is in the case studies and anecdotes of people who have been suffering and have successfully used ketamine to find sustained relief – whether they have a transcendent experience or not. It is also powerful in its calls to action for individuals in behavioral health and health care more broadly to stop viewing people as a set of mechanically treated symptoms and diagnoses and as living, breathing people with challenging life histories and relationships. The picture that emerges is of people who, as a function of traumatic life experiences, have become cut off from themselves and other people. The intriguing potential of ketamine and its sister psychedelics, albeit administered in controlled settings by trained, empathic individuals, lies in reconnecting people with shattered psyches to themselves, other people, and a genuine sense of feeling and meaning.

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6 replies »

  1. Nice review and hopeful. I hate to see us fall in love with molecules. As with THC. If you see some of the proteomic maps published in Science or Nature you begin to feel that sticking a small molecule into this Bizantine complexity is akin to pushing a pin through the workings of a fine watch and expecting to fix it.

    But we desperately need to make progress in treating depression. I wish they would re-try the breathing of 20% partial pressure CO2 for few minutes for depression. This was hot sometime in the ’60’s and was loved by patients. I think it was U. of Chicago research.

    Some of the same gene clusters we find in schizophrenia are also seen in depression and in autism. We need a few more decades to know what the heck we are really dealing with here. Medicine is chemistry.

  2. Don’t disagree. The risks need to be acknowledged. And the point about The use of ketamine and other psychedelics is that they need to be used only in an office setting (MDMA) or under a physician’s supervision for people with a mental health diagnosis. But feels like the people most like to abuse are people who are medicating one of those diagnosable conditions. So it becomes a bit circular. To the degree other treatments haven’t worked to alleviate the suffering those people are medicating, psychedelics seem pretty promising. Specifically bears looking at the trials of psilocybin for addictions.

  3. OK, just consulted Google Med School, answered my own question. The palliation efficacy literature is mixed.

  4. Interesting indeed. Hospice / end-of-life “palliative” potential?

  5. I get the potential here and it’s very interesting

    BUT I feel this review would have been more effective if the author had acknowledged the reasonable criticism of Ketamine and other similar therapies (microdosing LSD) that is circling around out there

    The problem here has to do with how information travels and what people do with it once it is out in the world and flying around on the Internet and Twitter

    There will be many people who misinterpret this research as an alternative fact (psychedelics are good for you ) and experiment on their own … We’ve seen this happen already with medical marijuana, which is becoming a very serious public health problem at precisely the same time that it is doing a lot of good for a lot of people .

    The truth is more complex