Ketamine therapy is a fast-acting alternative to psychiatry’s long-trusted tools. Easing symptoms in as little as one hour in some cases, Ketamine acts much faster than antidepressants, which can take as long as four weeks to make a difference. Although useful for many, talk therapy requires a time and financial commitment that often makes it inadequate for people in acute states of distress.

At sub-anesthetic doses, Ketamine promotes synaptogenesis, leading to an effective rewiring of the brain. These changes allow a person to view themselves and their past traumas from a new, more flexible perspective. Especially when combined with psychotherapy, Ketamine can bring relief without a daily prescription.  

Along with other psychedelic-assisted approaches, Ketamine therapy can transform the psychiatric paradigm. Yet many questions linger as it gains traction. Differing opinions about the role of integration, how Ketamine’s pharmacological profile should inform the psychotherapeutic models applied to it, and whether Ketamine infusions are a viable long-term option are among the many questions that remain unanswered.

Please also see our Blog, “Ketamine for anxiety” in A Comprehensive Guide to Ketamine Therapy

A Medical and Psychiatric History of Ketamine

Ketamine evolved to replace phencyclidine (PCP), the leading choice for easing pain during surgeries. Ketamine is an analog to PCP, a powerful analgesic known for its prolonged side effects like psychosis, delusions, and delirium. These effects encouraged researchers to pursue an analog with similar anesthetic uses but fewer psychomimetic properties. A researcher at Parke-Davis Company, Calvin Stevens, synthesized Ketamine in 1962. As it entered human trials in 1964, investigators noted that its hallucinogenic effects were minor and shorter-acting compared to PCP. Still, they labeled Ketamine’s potent sensory and perceptual distortions as “emergence phenomena,” classifying it as a dissociative anesthetic. 

Ketamine’s high safety profile cemented its use within human and veterinary medicine. It also could induce anesthesia without depressing breathing or circulation, qualities that were important for anesthetic purposes. It received FDA approval in 1970 as the prescription drug Ketalar.

As Ketamine became a staple in medicine, it caught the attention of various researchers interested in its psychiatric uses. In 1973, investigators in Iran administered Ketamine to 100 subjects with mental health and psychosomatic complaints as diverse as anxiety, phobias, obsessive compulsive disorder, tension headaches, ulcerative colitis, among others. After six months, 91 of those participants reported relief from their symptoms; after one year, 88 remained well. At the time, the researchers attributed the study’s success to Ketamine’s mind-expanding qualities. Around the same time, psychiatrist Dr. Salvador Roquet used Ketamine in an experimental approach to psychedelic psychotherapy he called psychosynthesis. 

Using photos from participants’ early lives, intermittent flashing lights, and disturbing sound effects, Roquet’s protocol centered on creating an experience of sensory overload. Its purpose was to jolt individuals out of their ordinary mindsets and personality patterns. After this over-stimulation, he administered various psychedelic substances such as Peyote, Psilocybin mushrooms, Morning Glory seeds, and Datura ceratocaula, an anticholinergic deliriant. The administration of these substances, along with the sensory chaos, broke down participants’ psychological defenses. Such a breakdown brought forth awareness of early traumas and relief from fixed ways of being. These abrupt changes strengthened the bond between therapist and participant and dramatically increased the speed and effectiveness of his therapeutic approach. 

Roquet aimed to simulate a psycho-spiritual rebirth. The process began with intense pain but functioned to initiate people into more expansive states of consciousness. Nevertheless, participants often had lingering anxiety and inner conflict in the later stages of the experience. To lessen these effects, he worked with an anesthesiologist to administer sub-anesthetic doses of Ketamine, which became the final part of the dosing sequence that characterized his protocol. Through his innovative, 10 to 20-session approach, Roquet recorded success treating individuals with neurosis, antisocial personality disorders, and Schizophrenia. 
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Although Ketamine always remained medically legal, “War on Drugs” hysteria led to a pause in much of the mainstream inquiry into its psychiatric uses. During this time, books like The Scientist by John C. Lilly and Journeys into the Bright World by Marcia Moore and Howard Alltounian led to the growing public interest in its potent effects and its subsequent entry into club and rave settings. It returned to mainstream psychiatry in the 1990s when the discovery of Ketamine’s effects on the NMDA receptor led to a new body of research into the mechanisms behind depression. Berman et al. (2000) conducted the first placebo-controlled, double-blind clinical trial to assess the antidepressant potential of a single dose of intravenous (IV) Ketamine. Researchers found that Ketamine provided significant relief from depressive symptoms in just 72 hours. Since this discovery, hundreds of clinical trials have lent support for Ketamine’s psychiatric uses. 

By 2010, dozens of Ketamine infusion clinics appeared throughout the U.S. Although the Drug Enforcement Administration categorized Ketamine as a Schedule III Controlled Substance in 1999, clinicians enlisted Ketamine as an off-label treatment for depression and suicidality since it earned FDA approval in the 70s. 

A Molecule with Many Hands

Chemically, Ketamine contains two mirror-image isomers, which are molecules with identically bonded atoms yet different spatial arrangements known as enantiomers. The differences between these enantiomers are usually explained in terms of the right and left hands. Hands are mirror images, but when placed on top of one another, they reveal themselves to be non-identical. Because these enantiomers have different structural orientations, they bind within the brain and body in distinct ways. As a result, chemists isolate them for distinct physiological effects. 

There are three forms of Ketamine:

R, S Ketamine: The generic or racemic form of Ketamine is a 50:50 synthesis of arketamine and esketamine. Racemic Ketamine has the longest history within medical research, and it’s the variety given in clinical settings. 

S Ketamine (esketamine): Since racemic Ketamine is generic, it couldn’t be branded or patented. Janssen Pharmaceuticals isolated the R-enantiomer from the S-enantiomer to create a unique formulation. Esketamine is available as Spravato, a nasal spray approved for use for individuals with “Treatment-Resistant Depression,” defined as depression unresponsive to at least two different oral antidepressants. In March 2019, Spravato received FDA approval after getting Fast Track and Breakthrough Therapy designations.

R Ketamine (arketamine): This form of Ketamine is currently the subject of research into its potential for severe depression. Perception Neuroscience began studying arketamine in clinical trials in 2020. Arketamine has diminished activity at the NMDA and sigma receptors, indicating less potent hallucinogenic, dopaminergic, and dissociative effects. Research is ongoing, but arketamine may have longer-lasting antidepressant properties. 

Ketamine’s Effects

Ketamine has multiple mechanisms of action. Unlike traditional monoamine antidepressants, which operate on the serotonergic or dopaminergic systems, Ketamine stimulates the growth of synapses, the connections between neurons, via its action on the neurotransmitter glutamate. Ketamine stops signals from passing between the brain and spinal cord by preventing glutamate from being activated by the NMDA receptor, accounting for its pain-relieving properties. Researchers have taken a particular interest in Ketamine’s ability to restore regions of the brain damaged by long-term stress. When a person is chronically anxious or depressed, the brain becomes awash in cortisol and other stress hormones. Chronic stress actually reduces the brain’s plasticity. Glutamate, the most ubiquitous excitatory neurotransmitter in the brain, is central to learning and memory and even the relaying of thoughts and feelings. Since glutamate is an excitatory neurotransmitter, accelerating neuronal communication, Ketamine likely enhances neuroplasticity. Given that depression correlates with neuronal atrophy in brain regions responsible for mood and emotion, this may partially explain Ketamine’s antidepressant actions.

Ketamine’s antidepressant effects may also be related to its activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which in turn stimulate brain-derived neurotrophic factor (BDNF) production, promoting neuronal growth. BDNF additionally supports neuroplasticity by increasing the functional connectivity between different brain regions. Also, like serotonergic psychedelics, Ketamine reduces connectivity in the default mode network (DMN). The DMN is an interconnected group of regions of the brain associated with self-referential processing: self-criticism, worry about the past or future, and the like. By decreasing connectivity in the DMN, Ketamine gives a person freedom from their ordinary patterns of thought and fixation.

These pharmacological actions often feel subjectively like a resetting or a rewiring of the brain. Under Ketamine’s influence, people experience major shifts in bodily awareness and the ability to view their emotions from a distance. These changes minimize the sharp edge that ordinarily stops people from facing their trauma directly, making it especially useful within trauma-informed therapy. Ketamine can also free a person from tight ego boundaries, or their sense of being a separate self, isolated from everyone else.

As explained in Frontiers in Pharmacology, Ketamine and other psychedelic-like compounds are catalyzing significant conceptual shifts in mental healthcare. Rather than creating daily neurochemical “fixes” to brain chemistry, psychedelic therapies focus on cultivating experiences with long-term positive mental health consequences. For this reason, research often hinges on identifying the approach to Ketamine therapy that yields the most far-reaching results. Those interested can receive either Ketamine infusion therapy, a medically oriented procedure, or Ketamine-assisted psychotherapy (KAP), which pairs Ketamine with psychedelic-assisted therapy frameworks. Because of the differences in the paradigms behind them, these protocols depart from each other in significant ways.

Ketamine Infusion Therapy

Delivered by primary care practitioners, anesthesiologists, and other medically trained professionals, Ketamine infusion clinics focus on optimizing Ketamine’s biological effects. Since the early 2000s, researchers have found success using Ketamine for anxiety, depression, chronic pain, Post-Traumatic Stress Disorder (PTSD), addiction, and other conditions. 

Initially, Ketamine intrigued psychiatry because of its rapid action. When studying individual reactions to a single, low-dose Ketamine infusion, Ketamine reduced symptoms of depression within 72 hours or less. However, single infusions led to a return to baseline within only one to two weeks. Due to its short-lived success, investigators began developing multi-dose protocols. Currently, physicians usually administer Ketamine through a tapering sequence spanning over two to three weeks, starting with three dosing sessions in the first week, two in the second, and one in the third. 

The process begins with a detailed inventory of a person’s mental and physical health status. Understanding a person’s medical and psychological history helps clinicians develop personalized dosing strategies, but the typical antidepressant dose is 0.1 to 0.75 mg/kg over a 40- to 55-minute period. Compared to KAP, clinicians put a greater emphasis on the physiological, rather than the psycho-emotional, dynamics of the procedure. Throughout the infusions, individuals are connected to EKGs, blood pressure, pulse, and oxygen monitors. Many clinics offset the medicalized nature of the experience by creating a spa-like environment, providing blankets, dim lighting, and soothing playlists.

At lower doses, people feel emotionally open, grounded, and less inhibited by their everyday ego boundaries. Higher doses can generate out-of-body experiences, distortions of time and space, and ego dissolution. Although response times vary, some people notice perceptual changes as little as a few minutes into the infusion. Others may not notice effects until their third session, or even until the end of an infusion series.

Ketamine infusion specialists regard IV infusions as the gold standard route of administration because they’re 100% bioavailable. Other routes of administration, including intramuscular, oral, and subcutaneous have bioavailabilities of 93%, 16-24%, and 24-29%, respectively.  Interestingly, the focus in KAP tends to be on the emotional space between the therapist and individual, and on pairing the experience with suitable psychotherapeutic frameworks. Conversely, Ketamine infusion practitioners often prioritize the optimization of dosing and administration schedules as the central determinants of the treatment’s success. 

In some cases, these strategies have led to major breakthroughs. For example, in a discussion on The Psychedelic Therapy Podcast, Dr. Steven and Sam Mandel reported raising the baseline Ketamine infusion success rate from 70% to 83% through their methodological dosing and administration protocols. Using digital infusion pumps, they can precisely program Ketamine delivery at a fine-tuned pace. They can even take personalization a step further by creating continuity or by gradually escalating or de-escalating doses across visits, adjusting based on the unique needs and preferences of the individual under their care.

In the short term, Ketamine infusions deliver dramatic and rapid antidepressant effects. According to this review, over 60% of those who receive a single dose of IV Ketamine experience relief in four and a half hours after a single dose, with 40% of those individuals continuing to experience relief after seven days. Some studies even report relief for up to three months after a prolonged infusion series of four to 14 days. However, Ketamine infusions aren’t a quick fix for depression, and without a therapeutic integration process, long-term diet and lifestyle changes or maintenance doses, their effects can be relatively short-lived.

Nevertheless, Ketamine drives emotional openness, relaxed ego defenses, and other profound shifts. These subjective changes, along with their promotion of neuroplasticity, can be powerful facilitators of new, more adaptive ways of thinking and being. Accordingly, many believe that pairing Ketamine with psychotherapy may be key to prolonging its benefits.‍

Ketamine-Assisted Psychotherapy

Because Ketamine allows for the exploration of traumatic events normally walled off by everyday psychological defenses, it’s ripe for psychotherapeutic applications. So far, KAP practitioners have documented success treating Major Depression, Generalized Anxiety Disorder, PTSD, and alcohol and cocaine addiction.  

Ketamine entered a psychotherapeutic context after investigators gathered anecdotal reports that it rapidly improved symptoms of anxiety and depression, even when given through less invasive intramuscular and oral routes. The many non-invasive administration options not only set the groundwork for the practice of KAP itself but also made the practice compatible with different treatment environments. KAP can take place in an office setting or given as an at-home prescription under supervision.  

Practitioners can administer Ketamine intramuscularly, subcutaneously, topically, in the form of patches, or orally, as sublingual tablets, lozenges or troches, or as suppositories. Unlike Ketamine infusions, which are usually 40 to 55 minutes, KAP sessions can be as long as three hours. The longer sessions are due not only to differences in the theoretical approach but to differences in Ketamine’s metabolism across various routes of administration. Practitioners determine dosing protocols individually, first assessing a person’s sensitivity with an oral dose, which then forms the basis for future doses.

The process occurs within three distinct stages: preparation, dosing, and integration. During the preparation stage, the therapist will take a medical and psychiatric inventory and learn about a person’s history and lifestyle habits. KAP practitioners follow the Multidisciplinary Association for Psychedelic Studies (MAPS) protocols for psychedelic-assisted therapy, paying special attention to set and setting, or an individual’s immediate internal and external environment. The concept of set and setting, though important throughout the entire process, plays a particularly important role in the preparation stage. Trust between the practitioner and individual is paramount and can often be the difference between a traumatic and a healing experience. 

As noted in Expert Reviews of Clinical Pharmacology, the development of the “therapeutic myth,” or a shared understanding about the intent and rationale behind the experience, is vital. Because psychedelics amplify the contents of one’s psyche, establishing shared goals for the process increases the likelihood of success. Practitioners also aim to minimize any clinical or sterile aspects of the setting, striving to create what psychoanalyst D.W. Winnicott called a “therapeutic holding environment,” or a context safe and welcoming enough to encourage new ways of being.

As with infusions, practitioners deliver KAP in a series of sessions over two to three weeks. In the  Journal of Psychoactive Drugs, the authors describe a dosing escalation strategy that allows individuals to explore the spectrum between trance to an out-of-body experience. Other KAP practitioners note at least four distinct non-ordinary states of consciousness: empathogenic, out-of-body, near death, and ego-dissolving transcendent experiences. An empathogenic experience is a sub-psychedelic state, involving reductions in ego defenses, and a sense of understanding and compassion for themselves and others in their lives. At the highest psychedelic doses, a person feels complete dissolution from their body and unity with all people, nature, and the universe, and other profound shifts. 

These expansions in consciousness make Ketamine pair especially well with holistic approaches that engage a person from a biopsychosocial, or a whole person, perspective. In this framework, a person’s emotional, psychological, spiritual dimensions are given as much weight as the diagnostic categories described in medical or psychiatric reference texts. Psychedelic therapy protocols draw heavily from the work of Stan Grof, particularly his concept of the “inner healing intelligence.” Along with other holistically minded practitioners before him, Grof believed that interventions can only enhance, rather than replace, a healing process driven primarily by the individual. As a result, KAP practitioners avoid viewing Ketamine as a pharmaceutical that helps patients “manage their symptoms.” Ketamine instead helps to facilitate greater awareness of a person’s ability to heal themselves.
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Unlike Ketamine infusion therapy, which prioritizes optimizing the drug’s pharmacological effects, KAP practitioners focus on complementing the experience with psychotherapeutic models that help individuals understand the root cause of their emotional distress. Infusion specialists certainly aren’t oblivious to the need for long-term dietary and lifestyle optimizations, but their emphasis leans more in the direction of the physiological than in the psychodynamic. Conversely, KAP practitioners often pair Ketamine therapy with Internal Family Systems (IFS), a therapeutic model that supports periods of inner restructuring. IFS, developed by Richard Schwartz, holds that individuals consist of a multiplicity of sup-components (“parts”) with their own drives, burdens, and principles. IFS urges individuals to engage in dialogue with their frightened, anxious, or control-seeking parts, giving them a toolset to which they can return long after therapy.

Ketamine Therapy: A Tale of Two Paradigms

Despite their shared goals, Ketamine infusion and Ketamine-assisted psychotherapy have fundamental paradigmatic divides. For instance, the question of whether Ketamine is a psychedelic, and whether psychotherapeutic models normally applied to “classic” serotonergic psychedelics should be applied to Ketamine therapy, remains a source of polarization. Some Ketamine infusion clinics even warn visitors to avoid KAP practices altogether. However, while their pharmacological profiles may be different, they also profoundly resemble each other. As explained in a recent study in Frontiers in Psychiatry, both Ketamine and classic psychedelics induce neuroplasticity, and both cause network connectivity changes within the DMN, which allows for the possibility of long-term cognitive and emotional flexibility. As a result, optimally timed psychotherapy may be a crucial component to Ketamine’s best use.

There’s also disagreement about whether the induction of a psychedelic state is necessary for the success of the treatment. KAP practitioners usually see the dissociative or hallucinogenic properties as important to the success of therapy. Conversely, during Ketamine infusion, doctors regularly administer benzodiazepines for individuals who feel anxious or agitated during their experience. This speaks to the assumption that Ketamine’s antidepressant effects aren’t the product of its psychedelic dimensions. 

As many have pointed out, this assumption lurks within many pharmaceutical investigations of Ketamine. Pharmaceutical companies have on several occasions tried to develop drugs with Ketamine’s actions against depression but without its dissociative and hallucinogenic components. They haven’t yet done so successfully. In 2014, a study in the Journal of Affective Disorders found that Ketamine’s antidepressant effects were only “robust and sustained” when people disassociated during their infusions.

There are also fundamental differences in the way Ketamine infusion and KAP specialists view pain. From a biomedical perspective, pain can be easily eliminated through the right series of biochemical interventions. On the other hand, KAP practitioners often encourage a sense of openness and surrender to challenging experiences. They may even see pain as a kind of initiatory process necessary for the growth encouraged by the medicine. Arguably, the delivery of benzodiazepines could be understood as an obstacle to the full realization of Ketamine’s therapeutic potential. 

Finally, practitioners hold conflicting views on the importance of integration. It’s well known that Ketamine lays the groundwork for new adaptive neural connections. Psychotherapy can clearly enhance these changes. Even so, medically oriented practitioners sometimes view integration as more of a helpful adjunct than a fundamental part of the process. While many studies have used infusion alone to prove Ketamine’s viability against depression, the effects are short-term, and usually prolonged only with “boosters,” or maintenance sessions. Though clinical Ketamine infusions pose a very low potential for abuse, over the long term, they may lead to tolerance and other adverse health consequences. Currently, researchers are working to optimize maintenance approaches for safety and efficacy. Still, as with all substances poised to become readily available drugs, there’s a risk that people will see Ketamine as a magic bullet. 

Along with Ketamine’s neurochemical actions, it’s also crucial to acknowledge its impact on a person’s patterns of thought. Perceptual shifts require deliberate re-tuning to remain potent. Over-focus on biochemical actions separates the mind from the body, creating a distinction between neurochemistry and psychological processes. The interpretive shifts Ketamine invites engage a person emotionally, mentally, and spiritually, extending beyond the neurochemical. Without a therapeutic integration process, the insights offered by Ketamine may collapse under the pressures of an unbalanced life. 

Fundamentally, this problem lies in the divide between biomedical and holistic medicine. Conventional approaches typically correct the downstream symptoms of mental illness, holistic therapies such as KAP empower people with tools that can help them understand and reverse imbalances at their source. Fortunately, integrative approaches to Ketamine therapy are gaining increasing traction. A recent study in Frontiers in Psychiatry combined dosing protocols validated by electroencephalogram (EEG) measurements with attention to set and setting, appropriately timed psychotherapy, and other psycho-emotional coordinates. 

By bringing biomedical and holistic principles together, integrative approaches like these guard against the possibility that psychedelic medicines will be viewed as simple neurochemical quick fixes. The most far-reaching approaches position the individual as the active source of their recovery, not the passive recipient of psychiatric intervention. 

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Ketamine’s important role in relieving depression, suicidality, and other steep forms of distress is overwhelmingly clear. Yet certainty around its best use can only be found by studying its real-world impact over time. As was first expressed in the 14th century epic poem, The Divine Comedy, sometimes the only way out is through. Best practices related to maintenance protocols, the most effective modes of delivery, and how pharmaceutical and healthcare incentives will impact Ketamine therapy’s trajectory and forms of availability are questions that can only be answered through long-term, objective data collection and analysis. Although it’s essential that those who receive Ketamine therapy get the best possible care, the only way to determine how to deliver it is to proceed in spite of the many questions that remain open.