Planning to use ketamine? Do magic mushrooms work better?

In our previous article on using ketamine to treat depression and other emotional problems, The Gold Report highlighted the risks associated with the drug and the lack of long-term clinical studies showing its safety.

Ketamine’s proponents, however, continue to portray the drug as both safe and effective. It is being most persuasively marketed to those who are desperate to find something that works after years or decades of disappointing and often painful experiences with psychiatric drugs. These people may be willing to accept a risk in their search for relief.

But does ketamine really work as well as is claimed?

Placebos and suicides — safe and effective?

Hundreds of research studies have been conducted on ketamine. Very few are high quality studies using a genuine control group with a placebo that goes some way toward mimicking the sensations that ketamine induces. Most studies only have a few dozen participants, or are single-patient case studies. One larger study that was billed as randomized and controlled was conducted in 2022 in France. 156 patients were enrolled and randomly assigned to receive either two ketamine infusions (IV administration) or saline.

Participants were what one might categorize as “severely mentally ill” in that most of them had attempted suicide in the past and experienced regular suicidal thoughts. Some had a diagnosis of bipolar disorder while others were depressed or had diagnoses of anxiety disorder, PTSD, or the like. Follow-up continued over 6 weeks following the infusions and focused on the occurrence of suicidal thoughts.

The bipolar group seemed to fare best — over 84 percent of those in the ketamine group had no suicidal thoughts 3 days after the infusion, in contrast to 28 percent of those in the placebo group. This was the only statistically significant finding in favor of ketamine in the study. For those suffering from depression, anxiety, PTSD, etc., ketamine provided no statistically significant benefit at 3 days following infusion. At the 6-week mark, the ketamine group was doing no better than the placebo cohort.

The authors of the study admit that, “Indeed, the rates of suicide attempts during follow-up were similar between the groups.” They also note that,

In the ketamine arm, one patient died from suicide (determined by the oversight committee to be unrelated to the intervention).

This person committed suicide within the first few days of treatment. No one in the placebo group committed suicide.

Flawed studies... and still ketamine does badly

Commenting on the study in a BMJ editorial, Riccardo DeGiorgi at the University of Oxford writes that it,

... perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine...

In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7 percent and 42.3 percent for suicidal ideation, respectively, in patients with depressive disorder.

Furthermore, the study had significant flaws. For instance, the “double-blinding” was not very blind given that a) the nurses administering the drug or the saline knew what they were giving, and b) saline does not mimic ketamine’s effects, making it likely that patients knew what they were receiving. These aspects of the trial would seem to have stacked the decks in favor of ketamine and yet the drug still did not perform well.

But when ketamine works... it works like cocaine

If you’re one of the people who have tried ketamine and found astonishing relief from depression within just hours, such results won’t necessarily deter you. Ketamine has been described in the most fabulous terms by users — the late Matthew Perry wrote that it was “like being hit in the head with a giant happy shovel.” It’s not for nothing that ketamine is a so-called recreational drug. But those using it in medical settings to treat people with official psychiatric diagnoses (mostly) vigorously deny that ketamine is nothing more than a psychedelic.

Settling this question one way or another is virtually impossible, given that each psychedelic drug works in a unique way. Those who claim that ketamine is different point to the ways in which it functions distinctly from other street drugs. Ketamine’s action on the brain is not fully understood; it acts on many brain regions and affects each person differently. But its similarities to other dangerous, addictive, euphoria-inducing drugs are nonetheless quite remarkable.

One study, for instance, describes ketamine’s apparent ability to reverse the effects of stress on dendritic spines. The study’s authors write,

These insights into ketamine’s effects on brain circuits could guide future advances in managing mood disorders ... Our results suggest that interventions aimed at enhancing synapse formation and prolonging their survival could be useful for maintaining the antidepressant effects of ketamine in the days and weeks after treatment.

However, the precise function of dendritic spines in humans is unclear. Moreover, the study also found that ketamine causes behavioral changes before any effect on dendritic spines is observed.

And, even if scientists were to prove conclusively that increasing the number of dendritic spines is the key to healing depression, what of it? Cocaine has the same effect, as this study notes:

Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain.

The government National Institutes of Health (NIH) certainly knows about this, and yet, with regard to the study on ketamine and dendritic spines, it writes that,

Researchers uncovered how the fast-acting antidepressant ketamine’s effects are sustained over time in mice.

A better understanding of ketamine’s effect on brain circuits can help guide the development of future treatments for mood disorders.

No trip, no benefit

Depending on the target audience, ketamine clinics either stress or downplay the psychedelic aspect of the drug. Some clinics deliberately omit all mention of the drug’s dissociative effects in their promotional literature as they are marketing toward people who would otherwise shy away from mind-altering drugs. Other clinics highlight ketamine treatment as “psychedelic-assisted therapy” which has become fashionable in certain circles. For instance, the Pacific Neuroscience Institute writes that,

... using a psychedelic-assisted therapy model with ketamine produces a short-lived but intense subjective experience — the mystical or peak experience — which triggers or elicits an afterglow, accompanied by a subsequent positive change in affect, insight, motivation, cognition, and behavior.

Ketamine’s effects on the brain’s NMDA receptors are actually shared with other “recreational” drugs such as phencyclidine (angel dust). In fact, the results of many studies (such as this one that appeared in the Journal of Psychopharmacology) have strongly suggested that ketamine’s effects are highly dependent on whether the patient experiences “ego-dissolution”:

A systematic review of clinical and biological factors which could predict the response to psychedelics ... found that the subjective intensity of the psychedelic experience is the main predictive factor of response across all diagnosis. Subjective experiences with mystical-like qualities or emotional breakthroughs are associated with a reduction in depressive symptoms and increase in quality of life measures, while subjective experiences lacking these components are associated with poor therapeutic outcomes.

This study provides another clue to ketamine’s efficacy — the accoutrements of the treatment. Using ketamine in a clinic is an hours-long experience, starting with intake interviews, followed by some level of preparation for the infusion, then treatment itself, and afterward monitoring for several hours. Could it be that all this attention being lavished on the patient is at least partially responsible for them feeling better at the end?

Moreover, the strength of the therapeutic relationship predicts the quality of the acute subjective psychedelic experience ... This evidence is very hard to reconcile with the neuroplastic hypothesis — as molecular and cellular-level stimulation of neuroplasticity should be dependent on dose, not therapeutic relationship...

Magic mushrooms work better?

Eleusis is a company in the business of “clinical development of psychedelic infusion therapies.” A few years ago, it acquired Kalypso, a leading provider of ketamine infusion therapies. Eleusis' CEO Shlomi Raz describes how,

Eleusis is transforming psychedelics into medicines across a broad range of unmet needs, starting with major depressive disorder where conventional psychedelic drug therapies may be undermined by problematic tolerability, reliability, accessibility and affordability.

In 2020, Eleusis partly funded a study that was published in ACS Chemical Neuroscience which concluded that while ketamine has some therapeutic benefits, other psychedelics such as LSD and magic mushrooms (psilocybin) have clearer and more long-lasting benefits.

... a single administration of psilocybin or LSD produced persistent antidepressant-like effects ... In contrast, ketamine produced only a transient antidepressant-like effect.

Several studies have shown that magic mushrooms display long-lasting effects even after a single administration:

Psilocybin, a psychedelic prodrug [an inactive substance that becomes active after administration] long excluded from biomedical research due to legal restrictions and social stigma, has been shown in multiple clinical trials to have rapid, long lasting antidepressant and anxiolytic [anti-anxiety] effects in humans after only one or two acute treatment sessions. These trials included strictly controlled and highly supervised sensory environments incorporating several psychotherapy sessions post drug administration to “integrate” the subjective experience.

But what the two drugs do have in common is the “rollercoaster” of emotions they elicit, ranging from joy and love to terror and panic:

In the psilocybin trial, most patients described that during dosing sessions, they experienced intense emotions of different affective qualities (joy, fear, terror, compassion, love and bliss) — with some patients describing the experience as an emotional rollercoaster — and that after the sessions they felt that their emotional repertoire was expanded, with long-lasting openness to emotional experiences.

In the ketamine study, an important theme was the inherent contradiction of the experience, with positive feelings of calmness, peace and relaxation and negative emotions such as fear or panic.

The ‘terrifying rollercoaster’ of ketamine

Patients are frequently not warned about the possibility of experiencing what recreational users call a “bad trip” or “falling into a K-hole.” Usually, the treatment is presented as consisting entirely of peace, love, and light, as Kelsey (not her real name) relates:

After making an appointment I met with the doctor, who explained that ketamine was safe and would reroute my brain circuits.

The doctor also had me meet with another person getting ketamine who was there in the next room. She was all enthusiastic about it and told me how ketamine took the edge off her trauma and how she felt differently after. She also told me that during her infusion she saw animals and colors and other things I don't remember now. I was really scared about “seeing things” but I was told that it wasn’t scary...

What she experienced, however, was traumatic:

I had such weird sensations, like I was falling into a deep pit and like I was in outer space floating around and spinning. That was followed by excruciating headaches and terrible nausea that lasted for hours.

Anita (not her real name) was told to expect a "nice, relaxing experience”:

They gave me instructions on what music to bring along, etc. But my first session was horrific. What I experienced was extreme dizziness, nausea, and disassociation. I once used VR [virtual reality] glasses that simulate going on a rollercoaster over steep mountains and crashing into the ground — that was basically what it felt like. I was terrified and had no way of stopping the crazy rollercoaster. I was dizzy from the lights and sounds.

From the outside, a person in a ketamine trance can appear “lost in a self-inflicted paralysis.” From the inside, it can be no less frightening:

It can be terrifying: they are temporarily unable to interact, and even move. Users feel separated from their body and reality. Time is grossly distorted: hours passing can feel like a few minutes. Anyone who works in A&E [emergency wards] will see people in K-holes regularly.

These are not "side-effects" of ketamine use or abuse — they are the very effects that “therapists” seek to induce when “curing” people of depression.

An alternative to antidepressants for life?

And what about long-term?

Ketamine is frequently touted as “one infusion and you’re good to go.” Sometimes that’s adapted to “one cycle of treatment.” Compared to life-long antidepressants with their often devastating side-effects, a drug that doesn’t need to be used in the long term sounds incredibly attractive.

But where’s the evidence that these claims are true?

Virtually every study and medical journal article agrees that ketamine’s effects don’t last long. The American Psychiatric Association, for instance, in a meta-study, describes ketamine as having,

... a rapid, yet transient, antidepressant effect.

The Chemical Neuroscience article mentioned earlier concludes that,

Unfortunately, for patients with treatment-resistant depression, ketamine is an efficacious antidepressant only for approximately half of the people infused, and the mean time to relapse of another depressive episode is only 17 days. To prolong the antidepressant effect, ketamine requires repeated clinical visits (typically 6 visits over 12 days), but symptomatic relief lasts only for about 5 weeks before another round of infusion therapy is needed.

One last thing to consider before using ketamine to relieve emotional distress is: What are you trying to achieve?

The scales doctors used to measure depression contain no hint of anything approaching happiness in the “no-depression” zones. The euphoria that can be induced by drugs such as ketamine is not identical to emergence from depression. But if euphoria is what you want, there are safer ways of inducing it than taking drugs with a very dubious safety and efficacy profile.

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In the third and final part of this series, we will examine the dangers of addiction to ketamine and the experience of withdrawal.

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The information contained in this article is for educational and information purposes only and is not intended as health, medical, financial or legal advice. Always consult a physician, lawyer or other qualified professional regarding any questions you may have about a medical condition, health objectives or legal or financial issues. If you are struggling with suicidal thoughts, you can call a qualified free mental health helpline or seek help from a qualified therapist.