Ketamine wasn't safe for Matthew Perry. Is it safe for you?
Matthew Perry’s cause of death was related to the “acute effects of ketamine,” according to an autopsy report released last December by the County of Los Angeles Medical Examiner.
"These defendants cared more about profiting off of Mr. Perry than caring for his well-being,” said United States Attorney Martin Estrada, commenting on the trial of five people believed to be involved in Perry’s fatal overdose. “Drug dealers selling dangerous substances are gambling with other people’s lives over greed. This case, along with our many other prosecutions of drug-dealers who cause death, send a clear message that we will hold drug-dealers accountable for the deaths they cause.”
Lots of people are dealing in ketamine these days, and many of them are qualified medical doctors. Naturally, they deny that they are “gambling with people’s lives” and certainly, they deny that they are motivated by greed. But a typical dose of ketamine used in a clinic to “treat mental illness” costs around $1 to produce, while doctors may charge anywhere up to $1,000 per visit (for "treatment" plus recovery period).
And what about the gamble?
FDA-approved — to treat what?
Questions about ketamine often elicit the response that the drug is safe because it’s “FDA-approved.” Here, for instance, the founder of ReYou Ketamine Treatments is asked by an interviewer, “Is ketamine a legitimate medical drug?" and replies,
Absolutely. Ketamine is an FDA approved medication that is being used worldwide for the treatment of mental health conditions. The research on its efficacy is abundant and continues to grow...
It’s quite true that ketamine is “FDA-approved.” However, ketamine is approved as an anesthetic and nothing else, as the FDA itself took pains to clarify in a warning note posted on its website in 2023 titled: “FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders.”
In it, the FDA stressed that while “there is increased interest in compounded ketamine products for the treatment of psychiatric disorders ... ketamine is not FDA approved for the treatment of any psychiatric disorder..."
FDA is aware that compounded ketamine products have been marketed for a wide variety of psychiatric disorders (e.g. depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder); however, FDA has not determined that ketamine is safe and effective for such uses...
Known safety concerns associated with the use of ketamine products include abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression (slowed breathing), and lower urinary tract and bladder symptoms...
Who’s deciding the dosage?
Although it is common for drugs to be used off-label (for purposes other than those for which they were originally designed, tested, and approved), that doesn’t necessarily mean that it’s safe to take a drug originally intended to combat physical pain in the operating room and allow people to use it to combat emotional pain in some other setting that may or may not be under proper medical supervision.
Furthermore, FDA approval commonly incorporates dosing recommendations as well as necessary precautions. Neither of these will be relevant for ketamine “infusions” given that the FDA’s authorization relates to the drug when used as an anesthetic.
The same problem applies to extrapolating from the FDA’s approval of Spravato (S-ketamine, used to treat “treatment-resistant depression”) to IV-ketamine. While S-ketamine is essentially a marketing gimmick given that it is virtually indistinguishable chemically from racemic ketamine (the street drug), it is administered in an entirely different way (nasally) from either “infusions” (an IV) or orally (in the form of lozenges etc.)
While it’s possible that the FDA’s note of caution regarding ketamine is designed to boost the number of customers for Janssen’s Spravato, it’s important to note that the FDA does not dismiss the risks of using Spravato either.
The FDA notes that,
Use of compounded ketamine products without monitoring by a health care provider for sedation (sleepiness), dissociation (disconnection between a person’s thoughts, feelings, and sense of space, time, and self), and changes in vital signs (such as blood pressure and heart rate) may put patients at risk for serious adverse events.
This is why Spravato is subject to a “Risk Evaluation and Mitigation Strategy (REMS)” as an essential part of its FDA approval:
A REMS is a drug safety program that FDA can require for certain approved medications with serious safety concerns to ensure the benefits of the medication outweigh its risks. [emphasis added]
A drug that is all side-effects?
Just what are these “serious safety concerns”?
In a case report on a patient with lower urinary tract (LUT) problems, the British Medical Journal introduces ketamine (not S-ketamine) as a “complex” and “potent” drug with a number of serious associated effects:
Ketamine is a complex drug with potent anesthetic, analgesic, stimulant and psychedelic properties ... The potential paralytic effects (known as the ‘K-Hole’) give a sensation of detachment from body and surroundings with a “floating, out-of-body” experience. The effects are short-lived and tolerance to the drug quickly develops, forcing users to seek larger and more frequent doses to experience the same effects. Of extra concern, it has a tenuous reputation as a “safe” drug, with limited potential for overdose or dependence and few side effects.
What does this sound more like — a reputable treatment for depression, or a risky street drug?
Where are the long-term studies?
A superficial perusal of the medical literature surrounding ketamine gives a very positive picture of ketamine used to treat emotional disorders. However, there are no long-term studies on use of ketamine when not used as an anesthetic. Most studies follow up over just a few weeks. Most investigate only a single dose of ketamine, not repeated treatments.
A report in The Lancet from 2017 titled, “Side-effects associated with ketamine use in depression: a systematic review” notes that,
This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria.
After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depression. [emphasis added]
Furthermore, the authors of the study stressed that side-effects were most likely under-reported by ketamine users:
Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (e.g., those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.
Preventing suicide, or causing it?
Why might the side-effects of ketamine be going under-reported? There are many possible reasons, and one key reason is that people using the drug may not realize that what they are experiencing is connected to ketamine’s effects. The Lancet study found that the list of common side effects experienced was extremely long and included the following (in no particular order):
Perhaps most disturbingly, suicidal thoughts were also commonly reported side-effects, and the researchers identified at least one suicide attempt that was linked to use of ketamine. It is notable that studies of S-ketamine/Spravato also showed a clear link to suicidal thoughts and suicide.
Long-term adverse effects? Ask recreational users...
All the above are just the short-term side-effects. However, use of ketamine is also associated with serious long-term side-effects, which have been observed and documented in so-called recreational users of the drug (as noted above, there are no long-term studies of non-anesthetic ketamine in a “medical” setting).
These long-term side-effects include liver toxicity, ulcerative cystitis, neurocognitive deficits and memory problems, urinary tract problems, and dependence and addiction.
The article in The Lancet noted that,
Long-term side-effect risks or other potential side-effects, including cognition, urinary tract symptoms, or dependency risk, were rarely assessed or commented on in randomized control trials.
Urinary tract problems are well-known to recreational ketamine users. The British Medical Journal case study mentioned earlier describes the multiple associated symptoms that can result from long-term use of ketamine. It described a 30-year-old man who had been using ketamine on-and-off for five years (and had stopped 3 months prior to examination).
The clinical syndrome associated with chronic usage includes a small, very painful bladder, frequency, incontinence, hematuria [blood in the urine], upper tract obstruction and papillary necrosis.
The authors of the case study stress that those suffering from urinary tract problems, especially in the early stages, may not identify the connection until it is too late:
Infrequent users may exhibit mild, “cystitis”-type symptoms and typically do not associate these symptoms with ketamine use. Furthermore, the association of these symptoms with recreational drug use is not recognized by many healthcare professionals, and such patients have frequently been treated with numerous courses of antibiotics prior to urology referral. All the while, continued usage with larger doses of ketamine will cross a threshold with the potential for significant and irreversible damage. [emphasis added]
This was true of the man in the study, who told his GP that he had been experiencing “troublesome lower urinary tract symptoms and ... hematuria” for two years before going to see a doctor. By the time he was diagnosed, his urinary tract was ulcerated and bleeding and his bladder function was “significantly reduced.”
The authors write that stopping ketamine “often results in a degree of reversibility” but that most people are left with lasting damage for which there is no treatment, only symptom and pain control.
Many users self-medicate to relieve the symptoms of ketamine bladder; medical therapy consists largely of alternative analgesics to avoid continued ketamine use.
How often does this occur in ketamine users?
It has been estimated that over 20% of ketamine users experience urinary tract symptoms, although 13 studies from Spain and 40 studies from Hong Kong report a much higher prevalence of LUTSs (46% and 90% respectively) among users.
And what does it do to your brain?
Therapists who use ketamine to “treat” emotional distress will usually reassure patients that the amount of drug they administer will be far below the threshold for producing such severe adverse effects. If you’re the patient, ask them what the threshold amount is.
You might also like to ask them how many of the hundreds of research studies on ketamine are high-quality studies. They probably won’t know, but the answer is in The Lancet article: out of the 288 articles the researchers found examining use of ketamine, only 20 were high-quality, that is, randomized and controlled. Not only that, these 20 studies followed a combined total of just 430 people.
The study in The Lancet is not the only meta-analysis of ketamine that has been conducted. Another study, published in Pharmacotherapy, in 2022, looked at 21,298 studies related to ketamine in order to examine the drug’s neurological effects. They found that ketamine was often “neurotoxic,” especially in “developing brains” (i.e. children and adolescents):
... an expanding number of toxicology studies reached the conclusion that administration of NMDA antagonists [such as ketamine] was the most neurotoxic in developing brains where synaptogenesis and synaptic refinement occurred, eliminating unused connections.
These findings resulted in safety concerns since ketamine was already widely used as an anesthetic in children. The 2020 ketamine label contains a warning that “administration of anesthetic and sedation drugs that block NMDA receptors … increases neuronal apoptosis in the developing brain and results in long‐term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear.” [emphasis added]
The study also highlighted the potential dangers of ketamine use in adults,
at subanesthetic doses, with repeated exposure ... [causing] neuronal cell death through apoptosis in the prefrontal cortex. Another ketamine study in two species of adolescent monkeys that evaluated daily ketamine administration for 1, 3, and 6 months detected in brain section imaging hyperphosphorylated tau, a biomarker for Alzheimer's disease. These changes at 3 and 6 or more months were not seen in shorter duration exposures. A study of human chronic ketamine non‐medical users compared with controls showed reduced cortical thickness and poorer cognitive performance. [emphasis added]
When considering the approval of S-ketamine, the researchers added, “the FDA accepted three toxicology studies supposedly proving the safety of the drug, but all three involved only a single dose delivered to rats.”
If you still want to give ketamine a try, consider asking your therapist the following questions:
1. What dosage of ketamine do you administer? Based on which safety and efficacy studies?
2. What are the adverse effects of the drug in the short-term?
3. And in the long-term?
4. How long will I need to take ketamine to heal my disorder? Based on what evidence?
5. If I stop taking ketamine for whatever reason, should I expect withdrawal symptoms?
6. Given that a dose of the drug costs around $1, why does each treatment session (drug administration plus monitoring) in your clinic cost $1,000?
7. If I suffer lasting health issues due to treatment, who is liable?
8. How do you distinguish the euphoric effects of this drug from “relief from depression” or whatever other disorder you claim to treat?
9. Do you know that ketamine is a date-rape drug? Please videotape the entirety of all my sessions, including recovery period, and give me the tapes, so that even if I temporarily (or permanently) lose all memory of what occurred, I will have documentation of it.
Disclaimer: 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.
