Ketamine Therapy: Everything You Want to Know

Ketamine was first synthesized in 1962 by chemist Calvin Lee Stevens, who at the time had been attempting to synthesize more stable derivatives of phencyclidine (PCP). Just two years after synthesizing ketamine, the first human trials were conducted using a cohort of Jackson State Prison inmates.

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The lead investigator of these trials, a neuropsychopharmacologist named Edward Domino, had noticed that ketamine-induced anesthesia when administered in high doses. At low doses, it produced atypical psychoactive effects.

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During this time, Parke-Davis, the now subsidiary of pharma giant Pfizer (who Domino was working for at the time), was against the idea of labeling ketamine a psychedelic as they didn't want it to be associated with the counterculture movement.

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Enter Domino’s wife, Antoinette (Toni) Domino, who, in casual conversation with her husband, would unknowingly coin a class of psychoactive drugs. 

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“I talked to my wife about (ketamine’s effects) and I said ‘Honey, I’m dealing with this goofy compound, beautiful anesthetic, but it gives people a high. They’re disconnected from their environment somehow.’ Toni then said, ‘You mean there’s some kind of dissociation? Why don’t you call it a dissociative anesthetic?’”

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And the rest is history… 


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Ketamine and Dissociation

In 1970, The Food and Drug Administration (FDA) approved ketamine as an anesthetic sold under the brand name Ketalar, which was used extensively by the U.S. Army on the battlefields of the Vietnam War.

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Despite the war on drugs outlawing the use and research of classic psychedelics like psilocybin, LSD, mescaline, and DMT, ketamine remained medically legal. Medical use and research continued undeterred by the clampdown on mind-altering substances, but ketamine soon made its way into the nightlife scene as a popular club drug in the ‘90s.

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Partygoers would typically snort low doses to induce energetic highs characterized by soothing relaxation, euphoria, and vivid perceptual distortions. High doses, on the other hand, induce dissociative effects that often result in feelings of derealization and depersonalization — referred to by recreational users as “the k hole.”

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This powerful ability to separate oneself from reality is why ketamine is considered such a vital anesthetic in Western medicine — and why it has been included on The World Health Organization’s List of Essential Medicines since 1985. Today, ketamine is used in surgery rooms for the induction and maintenance of anesthesia in both animals and humans.

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Additionally, because its anesthetic effects come without the cardiovascular and respiratory depression associated with other anesthetics, all ambulances carry a supply of ketamine. In fact, ketamine is one of the safest drugs to administer in pre-hospital emergency care. 

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The FDA quickly caught wind of recreational use and wasted no time making ketamine a Schedule III substance per the Controlled Substances Act. As this was happening, however, Dr. John Krystal and his colleagues at Yale were using ketamine as a psychotomimetic (i.e., a drug that is capable of mimicking symptoms of psychosis).

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In his investigations, Krystal inadvertently noticed that ketamine had antidepressant effects. 

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Ketamine’s Antidepressant Action

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Dr. Krystal and collaborators found that ketamine produces its antidepressant effects via a mechanism altogether different from traditional antidepressants that target serotonin, norepinephrine, and dopamine systems. Rather, they established that the healing power of ketamine lies in its effects on the glutamate system.

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Specifically, ketamine initiates the secretion of the neurotransmitter glutamate, which blocks N-Methyl-D-Aspartate (NMDA) receptors in the brain, prompting the growth of new synapses between neurons. The pioneering work of these researchers led to a much-needed alternative depression medication for the 40% of patients who are unresponsive to commonly prescribed antidepressants, and the 55% who experience unpleasant side effects. 

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Since then, researchers have come to understand ketamine as quite a pharmacologically complex compound, and have proposed several additional mechanisms of action that could be responsible, at least in part, for its antidepressant properties.

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One such theory is centered on ketamine’s ability to stimulate the production and release of brain-derived neurotrophic factor (BDNF), a protein that helps to promote the growth and maintenance of new neurons — typically referred to as neuroplasticity.

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Ketamine has also been shown to stimulate mammalian target of rapamycin (mTOR), a type of enzyme responsible for regulating processes involved in neuron growth. Simultaneous stimulation of mTOR and production of BDNF has been shown to enhance neural connectivity in brain areas important for emotional regulation and repair of stress-induced neurologic damage.

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More recently, Stanford researchers have tied the antidepressant effects of ketamine to the brain’s opioid system. Their study reported a 90% reduction in depression symptoms in patients when ketamine was preceded by a placebo, versus no effect when ketamine was preceded by the opioid blocker naltrexone — Pretty convincing stuff, but further investigation is required. 

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Regardless of what mechanisms of action are at play, ketamine’s antidepressant effects kick in in a matter of mere hours for most people, unlike traditional antidepressants, which may take weeks or even months for effects to take hold.

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A Rapid Increase in Ketamine Research and Clinics 

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Since Dr. Krystal’s seminal research, interested onlookers have observed a boom in ketamine research. In 2006, The National Institute of Mental Health (NIMH) reported that a single intravenous dose of ketamine had antidepressant effects in one of what has now been hundreds of clinical trials supporting ketamine’s ability to relieve symptoms of depression.

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Ketamine therapy has clinical efficacy for a variety of health conditions, including anxiety, post-traumatic stress disorder, obsessive-compulsive disorder, and chronic pain. However, its capacity to combat major depression, a crippling disorder affecting 21 million adults in the United States, is where ketamine therapy seems to hold the most promise. 

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In 2019, impressive clinical trials prompted the FDA to approve esketamine, a ketamine derivative nasal spray, as a medication for treatment-resistant depression and suicidality in adults.

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While esketamine’s clearance by the FDA does not extend to include ketamine treatments for other mental disorders, medical professionals can still prescribe and administer the drug off-label as a rapid but short-acting antidepressant to patients who they believe may derive benefit, enabling the business of ketamine therapy to thrive — the average clinic charges approximately $300 per treatment. 

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Stand-alone ketamine clinics offering intravenous infusions or intramuscular injections are popping up at an impressively rapid rate all over the US and Canada. Sporting  noise-canceling headphones, zero-gravity chairs, weighted blankets, and mandala coloring books, ketamine clinics have increased access to a significant number of depressed patients.

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That said, the antidepressant effects of ketamine typically last just 1-2 weeks after infusion, with maximum efficacy being reached after 24 hours. This may seem rather brief, and it is, but for depressed patients stuck in the throes of despair, many of whom have tried multiple medications, 1-2 depression-free weeks are a reassuring reminder that life can improve.

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Nevertheless, medical experts have expressed concerns over the readiness of ketamine therapy for extensive, large-scale use. 

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Concerns Surrounding The Scalability of Ketamine Therapy

The FDA has yet to publish regulations regarding the control and supervision of ketamine clinics, meaning that clinics are left to their own devices to determine how treatment operates. 

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This has given rise to the creation of guiding principles and recommended safety protocols for the use of ketamine by several associations, including the American Association of Nurse Anesthetists and the American Psychiatric Association (APA).

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In their set of guidelines, the APA advises that every ketamine clinic should have a standard operating procedure based on scientifically sound evidence which should ensure:

• Clinical screening protocols
• Collaboration with mental health providers
• Treatment is conducted in the clinic of a certified mental health provider
• Health assessments pre, during, and post-treatment
• Strategy in place for addressing issues that arise during treatment
• Consistent ketamine dosages
• Monitoring of patients in the aftermath of treatment
• Continuity and follow-up check-ins

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Similarly, the ketamine research institute, Kriya, has published ethical clinician guidelines that echo the APA’s recommendations. In addition, Kriya highlights the importance of specialized psychological care delivered by a mental health professional in preparatory and integration therapy sessions. 

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If ketamine therapy clinics are not meticulous regarding the treatment of patients from intake to discharge or are seeking mere economic gains from what is a quickly expanding industry, unsuitable candidates may be exposed to ketamine treatment. 

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An Important Role For Ketamine, But Therapy Must Be The Focus 

There is no doubt that ketamine therapy can be a powerful healing modality when it is applied with sincere intentions of alleviating suffering. 

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In line with APA and Kriya guidelines, providers must be trained in addressing psychological problems that can arise as a consequence of the psychoactive effects of ketamine, including the very serious, albeit unlikely, possibility of emerging suicidality. The true potential of ketamine therapy very much relies on the therapy aspect and the controlled environment in which that should take place. 

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Important to note, too, is ketamine’s addiction potential and high tolerance profile. Heavy and repeated use of ketamine can also cause dangerous swelling of the kidneys and inflammation of the bladder. To help manage these potential issues, clinics must incorporate health assessments and emphasize the primary role of therapy, rather than suggesting that the power of ketamine treatment lies solely in the pharmacological effects of the drug. 

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Ketamine therapy has proven to drive transformative clinical outcomes among treatment-resistant patients — who are often among the most challenging to treat — but it must be complemented with supportive medical and therapeutic care delivered in a safe container before, during, and after infusion.

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The importance of employing these supportive practices cannot be understated.

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