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DoubleBlind: Hand holding bag of ketamine
DoubleBlind: hand holding bag of ketamine
Photo by Georgia Love

There are 3 Types of Ketamine—Which One Works Best?

Janssen Pharmaceuticals has patented a filtered version of ketamine called Spravato. But is their drug any better than the generic ketamine that’s been around since the Sixties?

Dr. Erica Zelfand // May 18, 2020

The use of generic ketamine in the treatment of depression and suicidal ideation is not FDA approved, but that hasn’t stopped the new industry based upon off-label uses of the drug from blossoming, seemingly overnight.

When news broke that the world’s most popular anesthesia drug held promise as a treatment for depression, an explosion of interest in ketamine ensued. Several clinical trials were published exploring the drug’s efficacy in treating major depressive disorder (MDD), treatment-resistant depression (TRD), and suicidality, and numerous clinicians began providing off-label ketamine therapy to their depressed patients. 

Until recently, Big Pharma was left out of the party, on account of two main roadblocks: One issue was that ketamine is a generic drug, meaning it cannot be patented, branded, or profitized. The other hurdle was FDA approval.

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Does Spravato actually work any better than generic ketamine? 

If the ketamine molecule could somehow be tweaked chemically, however, a pharmaceutical company could patent it as a new drug, dress it up with a catchy brand name, and charge top dollar for it. That’s exactly what Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, has done with Spravato, their S-ketamine (esketamine) nasal spray. After spending millions of dollars on studies and clinical trials demonstrating the efficacy of their new formulation, Janssen was able to secure FDA approval for the drug on March 5, 2019. This came on the heels of the FDA already having granted Fast Track and Breakthrough Therapy Designation to Janssen for S-ketamine as a remedy for treatment resistant depression (TRD) in patients concurrently taking oral antidepressant medication.

But does Spravato actually work any better than the cheap, widely available generic ketamine that has been around since the 1960’s? The jury is out.

In the meantime, many ketamine providers have been slow to welcome the “new K on the block,” choosing instead to stick with the affordable, generic ketamine they already know and use in a variety of dosages, forms, routes of administration, and contexts—not just as an off-label treatment for TRD, but also for other mood, pain, and personality disorders.

Understanding chirality, or “handedness”

To better understand the potential significance—or insignificance—of how Spravato differs chemically from other ketamine preparations, a quick explanation of the chemical concept of chirality is warranted.

Like many molecules, ketamine is made up of a 50:50 mixture of two differently oriented versions of the same molecule, known as enantiomers (or optical isomers). To understand the difference between enantiomers, consider for a moment your own hands. Though they are mirror images of one another, your two hands are not identical. If you placed your left hand on top of the right, you would find your thumbs pointing in two opposite directions. In other words, your hands are non-superimposable.

In chemistry, a molecule is said to be chiral if, like your hands, it exists in different forms that are non-superimposable mirror images of one another. These different orientations of a molecule (enantiomers) can exert subtly different pharmacological effects in the body.

Although Spravato (S-ketamine) is the only ketamine formulation currently approved by the FDA for the treatment of treatment-resistant depression, the medical community has been slow to welcome the “new K on the block.”

The two enantiomers of ketamine are known as S-ketamine (esketamine)—the left-handed orientation of the molecule—and R-ketamine (arketamine)—the right-handed version. A bottle of generic ketamine is a “mixed handed” (or racemic) solution, containing a mixture of both S- and R-ketamine, and it is this preparation that is found in hospitals and ketamine clinics across the globe.

Janssen, however, has found a way to isolate just S-ketamine by filtering the racemic molecule and discarding the R- enantiomer. And this left-handed solution (S-ketamine) is the only ketamine formulation currently approved by the FDA for the treatment of treatment-resistant depression.

The oldest trick in the book

Regarding Janssen’s development of Spravato, Dr. Wesley Ryan, Los Angeles-based ketamine provider board-certified in both general psychiatry and addiction psychiatry, says: “This is one of the oldest tricks in the book. We see this all the time with pharmaceutical companies patenting isomers of generic drugs.” 

Examples of Big Pharma’s penchant for tweaking and rebranding molecules include the antidepressant escitalopram (from citalopram), the antibiotic levofloxacin (from ofloxacin), the reflux medication esomeprazole (from omeprazole), and the ADHD drug dexmethylphenidate (from methylphenidate).

Read: Ketamine: The Psychedelic Painkiller that Could Halt the Opioid Crisis?

Spravato comes in metered, single-use dose units of 56 mg and 84mg, which cost a patient or their insurance provider $590 and $885 USD, respectively. The first month of the recommended bi-weekly treatments therefore runs from $4,720 to $6,785 USD—and that’s before fees for the provider’s time and other administrative expenses. Racemic ketamine, however, costs under $4 USD for a 100mL bottle, an amount that can treat several patients. “You can’t ignore that it takes a lot of money to do the whole FDA approval process and conduct phase 2 and phase 3 clinical trials,” says Ryan. “But still, it’s an egregious price difference.”

The discrepancy in price between S- and generic ketamine, along with the cumbersome administration model mandated by the FDA (which includes longer office visits and requires a patient be concurrently taking oral antidepressant medication), has Ryan questioning if the expensive, Big-Pharma-backed “left handed” ketamine actually works any better than the cheap, widely available “mixed handed” racemate.

In other words: does left- or right-handedness matter?

Rat studies

According to studies done in rats, left- or right-handedness (chirality) does indeed matter, and “right handed” R-ketamine is the better of the two enantiomers in treating depression (in rodents, anyway).

The superiority of R-ketamine over S- in mitigating depression-related behavior in rodents has been confirmed in several studies, with R-ketamine yielding longer-lasting improvements. For example, in studies by Fukumoto et al., both S- and R-ketamine were eliminated from the rats’ blood at 48 hours post treatment, yet the rats treated with R- still had anti-depressive benefits after the ketamine had left their systems, whereas those that received S- returned to their baseline symptoms of depression. 

R-ketamine has also been observed to induce synaptogenesis—the formation of new connections between brain cells—more robustly than S-ketamine. Considering that depression may be caused by the disruption of neural circuits in the brain, strategies that increase synaptic connectivity may be of great value in restoring mental health.

S-ketamine in humans

Pharmacologist Jason Wallach, PhD, at University of the Sciences in Philadelphia, however, warns against extrapolating rat studies onto humans. He tells me that the methods used to assess depression in rats “have very poor predictive validity” in people. 

Clarity on the question of ketamine racemates can realistically come only from clinical trials performed on human participants.

While studies have demonstrated the efficacy of both S-ketamine and racemic ketamine in the treatment of humans with depression, no direct comparison between S- and R-ketamine in human subjects has been conducted as of yet. Nor are there comparisons of either enantiomer to the racemic mixture of both, although a protocol for a head-to-head study of S-ketamine and racemic ketamine in humans has been proposed.

Read: Why You Need to be Careful About the Ketamine Clinic You Choose

Nevertheless, “there are a good number of randomized, controlled trials with both individually,” Wallach says in an email. “Overall the results with esketamine suggest it is comparable with racemic ketamine in all the classic endpoints and clinical profile.” The way he sees it, both S-ketamine and generic ketamine have merit in the treatment of depression. 

A spokesperson for the Janssen Pharmaceutical Companies of Johnson & Johnson explains in an e-mail that “SPRAVATO® was studied in 28 clinical trials over eight years… with documented long-term safety and efficacy.” 

But Erick Turner, MD, a psychiatrist with Oregon Health and Science University, disagrees: “When you look at the data [on S-ketamine], it’s actually quite anemic.” In his 2019 article in The Lancet, Turner points out flaws in the S-ketamine clinical trials, cautioning: “Clinicians and patients might wish to temper their expectations.” 

Turner isn’t alone: A systematic review of S-ketamine reveals that phase 3 trials on the molecule have yielded mixed outcomes in patients, suggesting that S-ketamine might not be all it’s cracked up to be.

Why S- over R-?

Most of what we know about how ketamine works comes from the 50-something years of the drug’s use in the context of anesthesia. The drug blocks a channel in the brain known as the N-methyl D-aspartate receptor (NMDAR) and thus alters brain levels of glutamate, a neurotransmitter that stimulates nerve cells and thus allows for more effective communication between them. But the jury is still out as to whether or not NMDAR blockade explains ketamine’s effects as an antidepressant.

Because most of the currently approved antidepressant drugs affect the monoamine neurotransmitters—molecules like serotonin, dopamine, and norepinephrine—ketamine’s effects at NMDARs makes it a truly unique addition to psychiatry. This unique mechanism of action may, in fact, be what caught the FDA’s attention. When I called Janssen’s hotline for medical providers to ask why they chose S-ketamine for their new drug, a member of the company’s medical information group explained to me: “The higher NMDA receptor activity of S-ketamine allows a lower volume of solution to be administered via the intrasanal route compared to ketamine or R-ketamine.” In other words, S-ketamine has more NMDAR-blocking bang per spray than R- or racemic ketamine, thus allowing for lower dosage. But does that really matter in the context of depression? 

Some folks think not, and in fact suspect the FDA may have gotten too excited about the novelty of the drug. “I think there was excitement about the novel mechanism,” says Turner, who previously worked as an FDA reviewer. “If this had been any other antidepressant like an SSRI or an SNRI, I don’t see the FDA being convinced enough to approve it.”

A review of ketamine enantiomers in Therapeutic Advances in Psychopharmacology identifies some perks of S-ketamine over R-, namely that it causes less drowsiness, lethargy, agitation, and memory problems.

But at least three other papers argue the opposite case, stating that R-ketamine causes fewer side effects than S-, namely dizziness, dissociation, and sensory deficits. R-ketamine’s weaker activity at NMDARs also likely explains its lower potential for abuse in rats. Again, we can’t superimpose rat data onto humans, but the suggestion of this study is that R-ketamine may be more addictive than S-.

“Misty,” a woman in her 30’s who uses street ketamine to manage her generalized anxiety disorder (GAD), premenstrual syndrome (PMS), and chronic headaches, reports that she gets the best results from a 50:50 blend of S- and R-ketamine. Unable to afford above-board, prescribed treatments supervised by a physician, Misty has been self-treating with insufflated (read: snorted) ketamine every 4-6 weeks for about two years now. While there is no guarantee that the powders she buys are pure, she has played around with various ratios of the enantiomers and cannot say which one stabilizes her mood and headaches better in the weeks that follow. She does report, however, that R-ketamine alone causes more vivid mystical visualizations, but the “come down feels choppy and edgy.” She describes S-ketamine as “smoother” and more of a “body experience” and floating sensation, “almost like an opioid.” Misty finds that the lack of visualizations that come with an S-ketamine session, however, limits how deep she is able to go in her healing, explaining that “the visuals help me illustrate the feelings.” Combining R- and S-ketamine allows Misty to have a smooth yet mystical experience that affords her weeks of mood-stabilizing benefits at a time.

The matter of insurance coverage

FDA approval of S-ketamine has paved the way for insurance coverage of ketamine therapy, but anesthesiologist Shawn DeRemer, MD and nurse anesthetist Gregg White, CRNA, two of the owners of Evolve Health in Portland, Oregon, report that insurance reimbursement has been an uphill battle. White explains: “Insurance companies typically don’t want to want to spend $2,000 a week for an ongoing treatment,” and elaborates that insurers typically require that a patient try and fail three or more psychiatric medications from two or more drug classes before they’ll cover the cost of Spravato therapy.

In fact, the cost of Spravato therapy is so high that England’s National Institute for Health and Care and Excellence (NICE), which serves the National Health Service (NHS) of England and Wales, does not recommend the drug.

A spokesperson for the Janssen Pharmaceutical Companies of Johnson & Johnson, however, tells me in an e-mail: “The average total annual cost of SPRAVATO® is generally comparable with other innovative, specialty mental health drugs, like the long-acting injectables for treatment of schizophrenia, and is not reflective of discounts and rebates that may be provided to Medicare and commercial insurers or through Janssen support programs.”

Jill Carter, DNP, another owner of Evolve Health, shares the story of a patient who was doing well on Spravato, but whose insurance authorization expired at the year’s end. After switching to racemic nasal spray, the patient’s depression returned, and Carter appealed to their insurance to allow the patient to resume treatment with Spravato.

So which enantiomer works better?

Researchers, providers, and patients alike want to know what form of ketamine is best, delivered through which route of administration. The opinions on the matter are seemingly as varied as the many protocols for administering the drug.

Carter explains that the best treatment choice is unique to each patient. In her experience, however, acutely suicidal patients are typically best served by intravenous (IV) infusions of the racemate. 

DeRemer is more decisive: “I think Spravato works better than intranasal or IV racemate.” 

White also thinks that patients achieve longer-lasting antidepressant benefits from Spravato than from racemic ketamine, but admits, “each patient responds differently to the modality and the mixture.”

Nonetheless, racemic ketamine has some considerable benefits over S-, with price being just one. Whereas S-ketamine is available only as Spravato nasal spray, racemic ketamine can be administered in a variety of dosing protocols and routes of administration, including oral, sublingual, nasal, rectal, intravenous, and subcutaneous and intramuscular injections.

The FDA-mandated risk evaluation and mitigation strategy (REMS) program requires that Spravato be administered only under medical supervision at approved treatment facilities. While generic ketamine is usually administered in the office as well, some lower-dose racemic preparations, like nasal sprays and lozenges prepared by a compounding pharmacy, can be prescribed for at-home use.

REMS also requires that patients be monitored for two hours after receiving Spravato, only allows for intranasal delivery of the drug, and further limits the dosage that patients can receive to 56 or 84 mg.

“The mystical-type experiences that can happen at higher doses are correlated with greater improvements and greater change. I don’t know if people get that on Spravato.”

Ryan finds that results are dose dependent, however, and is thus concerned that REMS’s dosage restrictions may limit patients’ responses to Spravato. He also nods to the emerging field of psychedelic medicine, adding, “The mystical-type experiences that can happen at higher doses are correlated with greater improvements and greater change. I don’t know if people get that on Spravato.”

Spravato is approved for use only in patients with a primary diagnosis of treatment resistant depression (TRD) who are concurrently taking oral antidepressant medication. Generic ketamine, however, is currently being used off label not only for TRD but also for bipolar depression, anxiety, obsessive-compulsive disorder (OCD), addiction, alcohol withdrawal, post-traumatic stress disorder (PTSD), complex regional pain syndrome (CRPS), and other forms of chronic pain, borderline personality disorder (BPD), refractory headaches, and a variety of other ailments.

Ketamine is clearly a unique addition to the psychiatric formulary. As for exactly how well it works, the mechanism(s) by which it does so, and which form of the molecule is best: time will tell. In the meantime, the majority of ketamine providers will likely stick to the adage, “If it ain’t broke, don’t fix it” and continue using affordable, generic, racemic ketamine as an off-label treatment for mood disorders.

Erica Zelfand, ND, is an integrative family physician, medical writer/editor, and public speaker. She is deeply committed to a patient-centered, root-cause-oriented, nature-honoring approach to healing. To learn more and connect, follow her on Facebook, join her mailing list, and visit her website.

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