Is ketamine the OxyContin of psychiatry?
In the first and second parts of this series, The Gold Report examined the safety and efficacy profiles of ketamine, a repurposed anesthetic drug that is proving a huge money-maker for therapists who administer this cheap substance for thousands of dollars per cycle of sessions. Despite its FDA approval as an anesthetic, ketamine is neither safe nor genuinely effective when used to “treat mental illness.” What it often is, however, is dangerous and addictive, not unlike earlier “wonder-drugs” which raised the hopes of a desperate many only to take their health and even their lives.
Medical miracle or just aping opioids?
Virtually all clinical studies of ketamine note that its effects are transient (as detailed in part two of this series). This inconvenient fact has not stopped therapists from claiming that they can provide an alternative to long-term (or life-long) antidepressant medication — that a short course of ketamine “infusions” will “reset” the brain on a permanent basis and effectively cure the patient.
Given that ketamine is a street drug, it was always highly unlikely that such claims were anything other than bogus. With regard to physiological (bodily) addiction, while ketamine appears to be less addictive than cocaine, many studies have shown it to be a “positive reinforcing agent” (having an effect that encourages users to keep using) in animals such as mice and rats which self-administer the drug given the opportunity.
Furthermore, studies have suggested that one of the multiple ways in which ketamine functions is similar to that of opioid drugs. The authors of one study, published in the American Journal of Psychiatry as a “synthesis of the current knowledge as it relates to ketamine’s pharmacology, efficacy, tolerability, and safety,” stress that,
Given the known potential for abuse of ketamine, and now the growing clinical use of esketamine and ketamine for depression, there is the potential that patients might develop physiologic dependence or outright addiction...
... there is an urgent need to refine the potential role of opioid receptors in ketamine’s antidepressant effect and safety profile.
Another study highlights a different and no less disturbing attribute of ketamine, namely that it dampens down the aversion people have to taking an action that they believe is likely to have a negative outcome. While this could potentially be advantageous to depressed patients who are too discouraged to try something new out of conviction that it won’t work, it can clearly also reduce patients’ inhibitions to doing dangerous things (including continuing to take a risky recreational drug).
An addict for every needle
Ketamine’s physical addictiveness, however, is dwarfed by the psychological dependency it can easily induce in people using it for whatever reason, as Drs. Joanna Moncrieff and David Horowitz note in their letter to the British Medical Journal (BMJ) in 2019. Moncrieff and Horowitz both stress that addiction can result not only in casual recreational users but in any type of user:
… when a drug can cause tolerance, dependence and withdrawal, it does not matter what population it is administered to – its dependence-inducing properties are characteristics of its pharmacology, and addiction will always be a risk.
Such a possibility is illustrated in a case study describing a nurse with no history of substance abuse who became addicted to ketamine to the extent that she began stealing from the hospital where she worked:
A 50-year-old anesthetic nurse, who had never been treated with antidepressants before, started with self-injecting ketamine racemate 50mg IM once a week to cope with her major depression. She continuously stole ketamine from hospital stocks.
Due to a gradually developing tolerance to ketamine’s antidepressant action, she stepwise increased dose and frequency of ketamine self-injections up to daily 2 g IM (three-fold her anesthetic dose) over six months. This was accompanied by the development of ketamine addiction, loss of consciousness, dissociative immobility, and amnesia.
A drug that works for the doctor, not the patient
Anita and Kelsey (not their real names), who were interviewed for this series of articles, were perhaps fortunate in that they were among the around 50 percent of ketamine patients for whom the drug has no positive effect. Had they found benefit from ketamine’s ability to induce euphoria or relaxation, they might have been tempted to continue using it. As it was, their therapists made multiple attempts to convince them to prolong treatment even when it was clear that they were gaining nothing (while suffering from numerous adverse effects).
Prior to trying ketamine, Anita had been taking SSRI antidepressants for over a decade in an attempt to overcome depression and was nonetheless “barely getting by.” She was desperate for something that held out the promise of improvement and hesitated to stop a treatment that seemed to be her last remaining option.
I had three sessions of IV ketamine, and I did not feel a difference at all.
After the first session, I said “never again,” but I came back with the hope it would become better.
Kelsey, like Anita, had tried several psychiatric drugs as well as therapy to treat her anxiety. The doctor she consulted at a private ketamine clinic (which targets a very insular and sheltered demographic largely unaware of the nature of psychedelic drugs) told her that ketamine would “reroute her brain circuits” and cure her entirely.
I was told that I would begin feeling better after 4 or 5 sessions, most likely, and that a typical cycle is six sessions, close together. But over the next three sessions my anxiety only got worse. When I told the doctor at the fifth time, I think he said he was going to increase my dose.
I told them that it didn't help, and complained they had said I would likely start seeing improvement, but then they said that anxiety is harder to treat than depression and I should come back for more sessions. All I remember from that time is that I felt horrible after the treatments. I didn’t go back.
'No one told me...'
Kelsey’s shaky memories from that traumatic period in her life are not unusual for people who have undergone ketamine “therapy.” The drug is known to damage certain types of memory and recall, making it ideal as a “date-rape” drug — notably, after even a single spiked drink. Claims that this can’t happen in a “short-term” treatment program are therefore baseless.
Neither Kelsey nor Anita nor many other people given ketamine by licensed therapists were warned about this side-effect; nor were they warned about any of ketamine’s other myriad adverse effects. This is clearly a breach of the principle of informed consent, but in fact it is extremely difficult to provide a patient with informed consent for psychedelic drugs, as no one can predict their effects on a specific individual.
Stop taking ketamine, start four new drugs to cope with withdrawal
When ketamine does “work,” by contrast, the results can be devastating.
An article in the American Journal of Psychiatry describes involuntary ketamine withdrawal in a 35-year-old military veteran with a history of PTSD and other emotional troubles. He had become addicted to ketamine after participating in a VA (Veterans’ Affairs) research trial for the drug, and came to the conclusion that the other drugs he had tried (both licit and illicit) failed to adequately provide relief.
However, he swiftly became tolerant to ketamine’s effect and had to increase the dosage in order to gain the same benefit. This was a strain on his finances — in fact, he could no longer afford the $600 per month that the drug was costing him. He was eventually admitted to a hospital psychiatric ward where he was put under observation and became increasingly unstable, irritable, and anxious, as well as unable to sleep. He had violent altercations with hospital staff and had to be heavily dosed with sedative drugs.
During the interview, Mr. A attributed his agitation to “ketamine withdrawal.” He stated that the cost of ketamine ($600 monthly) was becoming unaffordable, and he would sometimes go a day or two without ketamine. He reported that during these times, he experienced an intense, agitated, and dysphoric state that was only relieved by resuming ketamine. He confirmed that his current level of agitation felt the same as when he had discontinued ketamine on his own. He said that stopping cannabis did not produce similar effects.
Eventually, in order to cope with the protracted withdrawal symptoms, Mr. A had to start taking olanzapine (an antipsychotic), a high dose of lorazepam (a benzodiazepine), clonidine (another drug to calm his agitation), and valproic acid (a so-called mood stabilizer).
'It's not withdrawal — it's your disease coming back'
Many other studies document ketamine withdrawal in patients who have not been using the drug under medical supervision, describing a similar trajectory to that of Mr. A, who had made several unsuccessful attempts to stop using ketamine before he ended up in the hospital.
Research on cessation of medically supervised ketamine (or S-ketamine) is sparse, however. One of the studies presented to the FDA for its approval of S-ketamine (Spravato) did describe a small group of patients who stopped using the drug, but defined their symptoms following withdrawal from the drug as “relapse” into their previously depressed state.
As Drs. Moncrieff and Horowitz point out in their letter to the BMJ, it is very challenging to distinguish between withdrawal and relapse, given that there is so much overlap in the symptoms:
Physiological withdrawal symptoms can be mistaken for relapse, and the process of withdrawal may also precipitate or bring forward a relapse that may not otherwise have occurred. Discontinuation trials are not normally accepted as evidence of efficacy by the FDA but in this case the FDA made an exception because of the “breakthrough” nature of esketamine...
Given that the ... symptoms ‘insomnia’, ‘anxiety-nervousness’, ‘dysphoric mood-depression’, ‘difficulty concentrating, remembering’, ‘fatigue’, ‘lack of appetite’, are identical, or overlap, strongly with 70% of the items on the MADRS [depression measurement scale] one wonders how the authors distinguished relapse from withdrawal.
Indeed, ketamine withdrawal is most commonly associated with fatigue, poor appetite, drowsiness, anxiety, and dysphoria in other studies...
Psychosis and flashbacks
Many drugs, even non-psychiatric ones, have similarly challenging withdrawal effects. Ketamine, being a psychedelic drug, also has unique long-lasting effects that can persist for months or even years after cessation of use. One comprehensive study of ketamine describes how using ketamine can induce paranoid psychosis; other studies have documented ketamine making users appear “schizophrenic.” These effects can persist after withdrawal:
In addition, on stopping ketamine use, 53.5% of these abusers reported withdrawal symptoms including fatigue, excessive yawning, aggressive or hostile behavior, feeling angry, irritable, or depressed. In Singapore, two ketamine-dependent patients were observed to manifest psychotic effects that included multimodal hallucinatory experiences, a sense of slowing, paranoid ideation, and enhancement of ... sensory enjoyment.
While these alarming figures relate to ketamine “abusers,” the study stresses that even “infrequent ketamine users” and those who have given up the drug entirely can suffer from many disturbing long-term effects:
Compared to two groups of controls with no history of ketamine use (polydrug users or no drug use), however, frequent ketamine users, infrequent ketamine users, and abstinent ketamine users all had higher levels of dissociative symptoms, schizophrenia-like symptoms, or delusions ... Schizotypal symptoms and perceptual distortions may persist after cessation of ketamine use.
Even when the drug is successfully discontinued, people can still experience flashbacks and other distressing symptoms as well as memory problems months and years later. While these issues have mostly been documented in recreational users, there are no long-term studies on ketamine use in a quasi-medical setting to rule out such long-term effects following weeks- or months-long “therapy.”
As an interesting side-note, a form of therapy called “Affective Contra-Attribution” designed to combat alcoholism uses ketamine to help patients stop drinking. Ketamine here is used specifically due to the “negative hallucinatory emotional experiences induced pharmacologically by sub-anesthetic ketamine doses...” and it is reported to be very effective.
We've been down this road before and we know where it leads
In their letter to the BMJ, Drs. Moncrieff and Horowitz appeal for greater awareness of the potential dangers of ketamine usage, pointing out that previous “new and wonderful” drugs like opioids, benzodiazepines, and antidepressants were also initially billed as being non-addictive (based on short-term studies) but soon became known as extremely addictive and dangerous and also hard to stop with sometimes horrendous withdrawal effects.
It appears that history is repeating: a known drug of abuse, associated with significant harm, with scant evidence of efficacy, is being submitted for licensing, without adequate long-term safety studies. ‘Scrupulous monitoring’ has not been previously adequate in preventing the rise in prescribed drug dependence.
No one will thank the [authorities] if they introduce another drug that leads to long-term medical complications and significant problems with dependence and withdrawal, just because it has a ‘novel’ mode of action.
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.
