Ketamine solution poured onto glass and left to dry. Photograph Source: Coaster420 – Public Domain
Clinics offering ketamine infusions and injections for “treatment-resistant depression” are today claiming 24-48 hours remission, and ketamine is also being marketed for post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, bipolar disorder, and anxiety disorder.
“Between 500 and 750 ketamine clinics have cropped up across the United States,” NPR reported early in 2024 (“The Ketamine Economy: New Mental Health Clinics are a ‘Wild West’ with Few Rules”). This may be an underestimation, as Psychiatric News reported later in 2024, “More than 1,500 intravenous (IV) infusion clinics have proliferated nationwide.” Ketamine industry revenues of $3.1 billion were reported in 2022, and projected to be $6.9 billion by 2030.
All this has occurred despite the fact that the Food and Drug Administration has warned: “Ketamine is not FDA approved for the treatment of any psychiatric disorder.”
“Special K” is one of many slang names for ketamine, which is termed by the Drug Enforcement Administration (DEA) as a “dissociative anesthetic hallucinogen” that “distorts the perception of sight and sound and makes the user feel disconnected and not in control”—an experience that on the street is referred to as the “K-hole.”
The mainstream media reports little about ketamine’s scientific reality but a great deal about celebrity ketamine users’ testimonials and deaths. So the U.S. public has heard about Elon Musk’s praise of ketamine for his depression; and about Matthew Perry’s tragedy, which began with clinic treatment, then illegal ketamine acquisition, multiple-injections-a-day addiction, and finally death with an autopsy determining that he had died from “the acute effects of ketamine.”
All this begs some questions: (1) Why would psychiatry turn to ketamine, a “club drug” that is used by drug risk takers hoping for a euphoric out-of-body experience, used by predators to facilitate sexual assault, and is not approved by the FDA for any psychiatric disorder? (2) What do scientific studies—not enthusiasts’ anecdotal reports—actually tell us about ketamine as a psychiatric treatment? (3) What is a sane approach to so-called “treatment-resistant depression”?
Why Psychiatry is Turning to Ketamine: A History of Failed Chemical Treatments
“In my last severe depression, I took coca again and a small dose lifted me to the heights in wonderful fashion. I am just now busy collecting the literature for a song of praise to this magical substance.”
— Sigmund Freud, 1884
Before Big Pharma greed began fueling magic-bullet treatments for depression, it was ego that fueled Sigmund Freud, who at age 28 was desperately searching for a way to gain prominence (see the Cocaine Papers). To Freud’s credit, he ultimately acknowledged the correctness of fellow physician Adolf Albrecht Erlenmeyer’s warning that cocaine was dangerously addictive, the “third scourge of mankind” (along with morphine and alcohol); and Freud would abandon his interest in cocaine in favor of the psychological theories which would gain him the fame he so desired.
Freud’s cocaine fiasco is just one of many chemical failures by psychiatry that ultimately resulted in more long-term suffering for patients, followed by psychiatry’s repeated returns to the hunt for another chemical magic bullet.
An early Big Pharma magic-bullet chemical cure for depression was the amphetamine Benzedrine, first marketed in the 1930s by the drug company Smith, Kline, and French; followed by other amphetamines—commonly called “speed”—all of which have been found to be highly addictive. Then there have been the various so-called “antidepressants,” beginning with the tricyclic antidepressants (TCAs) such as Tofranil and Elavil that psychiatry began using in the 1950s. Later, the selective serotonin reuptake inhibitors (SSRIs) such as Prozac which hit the market in the late 1980s, then Zoloft, Paxil, Celexa, Lexapro, and other multi-billion dollar grossing SSRIs. Next have been the serotonin and norepinephrine reuptake inhibitors (SNRIs) such Effexor, Cymbalta, and Pristiq. And now, it is ketamine.
The major reason why psychiatry returned to the hunt for a magic-bullet for depression is their commonly used antidepressants have had such lousy depression outcomes that some psychiatrists are now saying these drugs should never have even been called “antidepressants.”
One of those psychiatrists is ketamine enthusiast Craig Heacock, who concludes: “The meds that we call antidepressants, SSRIs, mostly don’t work for depression . . . . I’m still shocked and crushed at how many physicians think that SSRIs are antidepressants” (2023 interview with psychologist and podcaster Roger McFillin).
In “Relabeling the Medications We Call Antidepressants” (Scientifica, 2012), psychologist David Antonuccio and psychiatrist David Healy cite multiple study references to support the following conclusions about so-called antidepressants:
“. . . a true antidepressant should be clearly superior to placebo, should offer a risk/benefit balance that exceeds that of alternative treatments, should not increase suicidality, should not increase anxiety and agitation, should not interfere with sexual functioning, and should not increase depression chronicity. Unfortunately, these medications appear to fall short on all of these dimensions. Many of the ‘side effects’ of these medications have larger effect sizes than the antidepressant effect size. . . . In other words, it may make just as much sense to call these medications antiaphrodisiacs as antidepressants because the negative effects on libido and sexual functioning are so common.”
Determining the scientific effectiveness of a treatment means conducting randomized controlled trials (RCTs) to discover whether the treatment is more effective than a placebo, as well as examining whether, in the long term, it is more effective than no treatment at all. A sane approach also means discovering whether drug benefits exceed drug adverse effects. Unfortunately, psychiatry has a history of eschewing sanity when it comes to its new magic-bullet treatments.
We have known for over twenty years just how scientifically ineffective so-called “antidepressants” are. A 2002 studycomparing depression remission outcomes of a placebo to the herb St. John’s wort and to the SSRI Zoloft reported that the placebo worked best; a positive “full response” occurred in 32% of the placebo-treated patients, 25% of the Zoloft-treated patients, and 24% of the St. John’s wort-treated patients. Also in 2002, a leading researcher of the placebo effect, Irving Kirsch, who had gained access to published and unpublished drug company trials on various antidepressants, reported that “all antidepressants, including the well-known SSRIs . . . had no clinically significant benefit over a placebo,” describing antidepressants as “clinically negligible” with respect to depression remission.
The psychiatry establishment actually acknowledges that the majority of depressed patients do not remit with a single antidepressant, but it has insisted that if patients are treated with enough different antidepressants, the majority will achieve remission. They justify this with the 2006 reported results of the “Sequenced Treatment Alternatives to Relieve Depression (STAR*D), a year-long study consisting of four three-month stages; in each stage, patients who did not remit with one antidepressant were prescribed a different one or augmented with another drug. STAR*D investigators claimed a 67% cumulative remission rate.
However, in 2023, psychologist Ed Pigott and his co-researchers conducted a reanalysis of STAR*D, and concludedthat if STAR*D investigators (who had financial ties to drug companies manufacturing the antidepressants used in the study) had adhered to their original protocol, “In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35%.” Furthermore, Pigott and his co-researchers had previously shown in 2010, that of the 4041 patients who entered the STAR*D study, only 108 remitted, stayed well, and remained in the study to its one-year end; and so STAR*D could only document a get-well/stay-well rate at the end of a year of only 3%.
Even if one accepts STAR*D researchers’ highly inflated results, the STAR*D outcome is still inferior to the natural course of depression without any medication. Published in 2006 was the National Institute of Mental Health (NIMH) study, “The Naturalistic Course of Major Depression in the Absence of Somatic Therapy,” which examined depressed patients who had recovered from an initial episode of depression, then relapsed but did not take any medication following their relapse. One year later, the recovery rate of these non-medicated depressed patients was 85%.
There is another major reason why so-called anti-depressants are falling out of favor for many patients and even some psychiatrists: increasing recognition of just how widespread and serious are the long-term adverse effects.
Two of the most crippling long-term adverse effects are sexual dysfunction and withdrawal difficulties that include serious physical and emotional suffering. The percentage of sexual dysfunction for SSRI antidepressants runs from 25%–73%, according to a 2010 examination of several studies; and post-SSRI sexual dysfunction (PSSD), in which sexual dysfunction exists even after discontinuation of the SSRI, is widespread enough for PSSD online support groupsto have emerged. With respect to withdrawal adverse effects when trying to reduce or come off of antidepressants, 56% of individuals experience adverse effects, and approximately 25% of individuals experience severe adverse effects.
In 2020, the CDC reported, “During 2015–2018, 13.2% of adults aged 18 and over used antidepressant medications,” and the CDC had previously reported, “More than 60% of Americans taking antidepressant medication have taken it for 2 years or longer.” Thus, if one takes into account antidepressant market size, their scientific ineffectiveness, and their troubling adverse effects for so many people, especially with long-term use, it is no wonder why many psychiatrists are turning elsewhere.
Scientific Research on Ketamine Psychiatric Treatment
While it is easy to see why psychiatry would be on the hunt for another treatment, how can psychiatrists use ketamine on depression when the FDA made clear in 2023 that ketamine is not an FDA approved treatment for any psychiatric disorder, and repeated in 2024 that ketamine is FDA approved for general anesthesia but not for any psychiatric disorder?
The answer to this question is that doctors are allowed to prescribe a drug “off-label” for a condition that the FDA has not approved if the FDA has approved it for another condition. So ketamine intravenous (IV) infusions and intramuscular (IV) injections for depression are not illegal despite not being FDA approved for that use. Unlike ketamine, psychedelic drugs such as LSD, mescaline, ayahuasca, and psilocybin are DEA classified as Schedule 1 drugs, meaning no acceptable medical use and a high potential for abuse, so these psychedelics cannot be legally prescribed off-label. Thus, a major reason for the ketamine industry’s growth is its “off-label loophole.”
Ketamine enthusiast psychiatrist Craig Heacock’s web site claims: “Ketamine is perhaps the most hopeful new psychiatric treatment to appear in the last decade, often bringing people out of severe depression or suicidality within 24-48 hours.” Quite a magic bullet.
In the short-term, dramatically destabilizing treatments for depression will often result in some positive anecdotal reports. This is true for ketamine, as it was true for Freud and cocaine. It was also true for bloodletting, which is why bloodletting continued to be used by physicians for over 3,000 years, until scientific analysis was applied to it
No doubt Heacock and other ketamine enthusiasts have seen these dramatic outcomes, but their observations are not scientific evidence of effectiveness. Scientific studies, in contrast, tell us a more sobering story about ketamine for depression and other psychiatric conditions. While the mainstream media is not covering the scientific research on ketamine, Peter Simons, managing editor of the webzine Mad in America, has been reporting on the important studies.
In 2023, Simons published “Ketamine Fails to Beat Active Placebo for Depression,” reporting on a Stanford University study, lead-authored by anesthesiologist Theresa Lii (published in the journal Nature Mental Health in October 2023). This study, in contrast to previous ketamine depression studies, was designed to create a true control. In virtually all previous trials on ketamine for depression, controls were ineffective because subjects could easily guess whether they had received a saline solution or the ketamine because ketamine has such strong side effects. Lii and her co-researchers created a true randomized controlled trial (RCT) by using a subject pool of patients diagnosed with major depressive disorder (MDD) with moderate to severe levels of treatment resistance, all of whom were scheduled to undergo surgery; this allowed researchers to give all participants standard surgical anesthetic with half randomly assigned to receive ketamine, and this created the type of blinding or masking necessary for a true RCT.
The results of the Stanford study? Both the placebo group and ketamine group showed large improvement post-infusion at one, two, and three days; the likely explanation, according to the researchers, was that heightened expectations created this improvement, as such expectations can be created by the belief that one is taking a powerful antidote. However, in comparing the effectiveness between the placebo group and the ketamine group, the researchers concluded: “A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder . . . . Our results suggest that ketamine may actually be ineffective for the short-term treatment of MDD.” The patients were followed for two weeks and assessed at 7 days and 14 days, and the placebo group actually did better than the ketamine group, especially at the beginning of this time period.
In sharp contrast to the many online ketamine anecdotal enthusiasts, to get a sense of what a bona fide research scientist—with no financial conflicts of interest—sounds like, I suggest listening to Theresa Lii’s talk about her study “Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients.”
Ketamine is similarly ineffective compared to a placebo when used to treat post-traumatic stress disorder (PTSD). In 2024, Simons reported “Ketamine Fails to Beat Placebo for PTSD in New Analysis” about an analysis of six existing trials of ketamine treatment for PTSD lead authored by psychologist Nicholas C. Borgogna (published in the European Journal of Psychotraumatology). As with depression, both the ketamine and the placebo groups improved rapidly, however, the researchers concluded: “While ketamine was associated with a reduction in symptoms, the effect was generally not stronger than control conditions . . . . Placebo is the likely mechanism behind reported therapeutic effects.”
In three of the six studies analyzed by Borgogna and his co-researchers, the placebo used was an active placebo (or active control), designed to mimic some of the side effects of ketamine. In the other three studies, the placebo was a saline infusion, which routinely has no side effects, thus making it easy for subjects to guess that they are receiving a placebo (and so they are not truly blinded). The results? At 24 hours, the ketamine group did slightly better than the group receiving the saline placebo, but the ketamine failed to beat an active placebo that mimicked ketamine’s side effects. Moreover, at one and two weeks post-infusion, ketamine failed to beat either the saline or the active placebos.
While ketamine infusions and injections are not FDA approved for any psychiatric condition, in a highly controversial process in 2019, reported by Kaiser Health News (“FDA Overlooked Red Flags in Drugmaker’s Testing of New Depression Medicine”), the FDA did approve esketamine for treatment-resistant depression. Esketamine (or s-ketamine) is an enantiomer of ketamine (with similar molecular structure), and the journal Medicine reports esketamine is approximately twice as potent as ketamine. The brand name for esketamine is Spravato, taken as a nasal spray and sold by Janssen (part of Johnson and Johnson).
Why was the FDA approval of esketamine so controversial among many researchers? Researchers Mark Horowitz and Joanna Moncrieff, both psychiatrists, noted (in the British Journal of Psychiatry in 2021) that among the six published studies (which were 4-week trials), five of the six studies did not report a statistically significant difference between a placebo and esketamine, and in the single study in which the esketatmine did slightly outperform the placebo, the difference was smaller than the threshold that even Janssen researchers had established to be clinically significant.
Previous to the FDA’s controversial approval of esketamine, many scientists had criticized the FDA’s standard requirement of needing only two short-term statistically significant trials for antidepressant drug approval. One criticism is that the short length of trials does not accurately reflect the longer periods antidepressants have been used in practice (recall the CDC has reported, “More than 60% of Americans taking antidepressant medication have taken it for 2 years or longer”)—and the 4-week esketamine trials were even shorter than the 6–8 week trials the FDA routinely requires. A second criticism is about the two positive studies requirement that allows drug companies to discount negative trials and conduct as many studies as necessary to get those two positive studies—and in the esketamine approval process, “even that low bar was dropped,” Horowitz and Moncrieff point out, as only one of the short-term trials conducted by Janssen showed a statistically significant difference between esketamine and placebo.
As noted, a sane approach to medications means discovering whether a drug is more effective than a placebo, and independent researchers argue that ketamine and esketamine fall short of this standard when compared to true controls in which the placebo group is truly blinded. Moreover, a sane approach also includes assessing whether or not drug benefits exceed drug adverse effects, and in the case of ketamine and esketamine, the adverse effects are significant.
In 2021 in the British Journal of Psychiatry, Horowitz and Moncrieff, reviewed some of the troubling adverse effects of ketamine recreational use:
“Deaths from ketamine include accidental poisonings, drownings, traffic accidents and suicide. As a dissociative anaesthetic, ketamine can reduce awareness of the environment, increasing risk of accidental harm. . . . putting people at increased risk of driving accidents. In Hong Kong, where it achieved particular popularity, ketamine had been used by 9% of individuals involved in fatal traffic accidents between 1996 and 2000. Ketamine also induces ulcerative cystitis, found in 30% of regular UK ketamine users and known as ‘ketamine bladder’. The condition can lead to difficulty passing urine, hydronephrosis and kidney failure. . . . Ketamine is also addictive. It quickly induces tolerance and stopping regular use causes a withdrawal syndrome characterised by anxiety, dysphoria and depression, shaking, sweating and palpitations, and craving the drug.”
With respect to esketamine, Horowitz and Moncrieff reported: “A large range of other side-effects occurred: half of participants experienced dissociation and one-third dizziness; increased blood pressure, vertigo, hypoaesthesia, nausea and sedation were each present in between 10 and 30% of participants.” They also reported that even with only weekly or fortnightly esketamine dosing that “17% of patients (136/802) in the long-term safety study demonstrated symptoms reminiscent of ‘ketamine bladder’, a known and potentially serious complication of ketamine use.” Kaiser Health Newsreported that in the esketamine/Spravato trials used for its approval that “three patients who received the drug died by suicide during clinical trials, compared with none in the control group, raising red flags Janssen and the FDA dismissed.”
A Sane Approach to So-Called “Treatment-Resistant Depression”
“Treatment-resistant depression,” according to establishment psychiatry, “happens when at least two different antidepressants don’t improve your symptoms.” However, if research has shown SSRIs and other antidepressants to have “no clinically significant benefit over a placebo,” to be “clinically negligible” with respect to depression remission, and less effective in a year’s time than no treatment at all, does it makes sense to diagnose patients with “treatment-resistant depression” because they did not improve after two antidepressants?
The reality is that some patients ultimately labeled as “treatment resistant,” earlier on, could have been helped by a highly-skilled psychotherapist. Such a therapist not only helps patients understand why they are depressed, but also has the talent for energizing patients to take constructive actions that include: extricating from toxic relationships; healing from traumatic wounds; incorporating regular physical exercise; finding meaning and purpose; and acquiring confidence to connect with others and the skills to maintain healthy relationships.
However, it is true that some patients become so immobilized and demoralized—sometimes because of repeated lousy treatments that consist of uninspiring talk therapy and/or numbing drugs—that they lose hope and feel they need some kind of altered state to get them out of their deep rut. For them, a chemical agent that can dramatically alters one’s consciousness is going to be attractive. This is true for ketamine, for LSD and other Schedule 1 psychedelics, and for cocaine as Freud discovered.
However, chemical agents are not the only way to achieve dramatic alterations in consciousness. Such states have been achieved without drugs—through fasting, a week alone in the wilderness, an authentic sweat lodge ceremony, and various other extraordinary experiences outside of one’s comfort zone.
In all of such experiences of dramatic alteration in consciousness, drug-induced or otherwise, some people report breakthrough benefits. Sometimes these benefits occur because of the phenomenon referred to as a “noetic experience” in which the dramatic alteration of consciousness allows for thoughts not previously taken seriously to now “feel more real than reality”—and to become powerful and liberating (for example, taking seriously previously discarded insights about the distinction between self-acceptance and self-absorption). However, unless this experience results in constructive actions that become habits, depression will return.
So, what do ketamine enthusiasts say upon hearing that well-controlled research shows ketamine works no better than a placebo, and that patient expectations rather than the ketamine is what produces improvements which are often short-lived? Some will say, “It makes no difference whether it was the ketamine or a placebo effect if the patient showed such immediate improvement.” There are problems with this way of thinking.
First, among the experiences that result in altered states, ketamine is one of the most physically dangerous. This relative unsafety is certainly true compared to non-chemical experiences that produce altered states. It is even true compared to psychedelic drugs such as LSD, mescaline, ayahuasca, and psilocybin, which may sometimes result in psychological problems such as a “bad trip” but, unlike ketamine, are not addictive nor shown to cause organ damage.
Second, to legitimize the ketamine treatment, enthusiasts talk about ketamine “triggering the brain to create healthy circuits” and “helping the brain regrow synapses.” However, in 2024, internist and epidemiologist G. Caleb Alexander, co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins, told Psychiatric News, “There’s lots of evidence that ketamine is toxic to neurons”; and Dutch researcher reported (Frontiers in Neuroanatomy, 2022), “Long-term recreational ketamine use was associated with lower gray matter volume and less white matter integrity, lower functional thalamocortical and corticocortical connectivity,” adding that this may explain some of ketamine’s long-term adverse effects such as memory impairment.
Ketamine “brain-benefit” theories obviously benefit the ketamine industry. Moreover, like the now discarded serotonin-imbalance theory of depression, such biological theories divert people from the depressing nature of their society and culture, depoliticize them and subvert change to the status quo—and thus are welcomed by the ruling class.
While it is possible that some individuals may take ketamine and use its consciousness-altering experience as a springboard to make beneficial life changes, many others, seeking a repeat pleasurable ketamine state, will simply become regular clinic customers. Most of them will not, as was the case with Matthew Perry, proceed from legal clinics to purchasing ketamine illegally and die from it. However, if they believe that ketamine can “create healthy circuits” and “regrow synapses,” they may see their relapses as indicating a need for more ketamine, rather than recognizing that a long-term antidote to depression requires difficult life changes.
Alexander also told Psychiatric News in 2024 that much of the research on ketamine is plagued by nontrivial limitations, including studies that were too short, had too few participants, were conducted by researchers with conflicts of interest, had no active comparator, had researcher and participant bias due to lack of blinding, and he concluded, “What’s not unclear, what’s not ambiguous [about ketamine], are the potential risks.”
If that’s not concerning enough, Psychiatric News also reported in 2024 that “nearly half (47%) of individuals who are receiving ketamine therapy [are] doing so outside of a clinical setting and in their own homes, ingesting a compounded formulation such as a lozenge or lollipop after being prescribed the medication via a virtual clinic.” And if that’s not troubling enough, ketamine is now being promoted by some clinics as a “treatment option” for children and teensdiagnosed with psychiatric disorders.
“Are we repeating mistakes of the past?” is the rhetorical question posed by Mark Horowitz and Joanna Moncrieff, psychiatrists concerned about their profession. If, as the saying goes, “The definition of insanity is doing the same thing over and over again and expecting different results,” then much of psychiatry is insane.
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