The fuss about ketamine has generated interest in where it has come from. There were probably multiple beginnings.
One was with Stan Grof, who moved from Prague to Baltimore in 1967. His interest in therapy led him to a focus on early life experience. This stemmed from work with LSD and psilocybin in the 1950s and 1960s, under the influence of which many people volunteered reports of abuse in earlier life, and even previous lives.
When LSD and psilocybin fell under a cloud in the 1970s, Grof turned to holotropic breathwork. Using techniques drawn from Sufi breathing and chanting, the idea was to induce dissociative – mystical – states. And when done in groups and with appropriate music, incense and lighting, this can be very effective.
Some people however find it harder to do and for these, once Grof became aware that ketamine was like phencyclidine but legal, he turned to it to produce states with some similarities to the natural state.
There is something natural about meeting God, remembering past lives, having out of body experiences. Changing perceptions in these states, drug induced or not, can give anyone an insight on geometric or other art forms, leaving you for instance understanding the Aztecs more than you did before. It can also shrink your current problems back to size – put them in context.
One of the powerful feelings as the drug wears off is of slipping back into the dream that we call normal life – but with a feeling that the universe makes sense even if we don’t know what the sense is.
So there is a role for ketamine in what used to be called abreaction. There is another harder to define therapy role. And finally, if it helps depressive disease and not just an unhappiness that stems from earlier difficulties, there might be something biological it does.
A biological rather than a psychodynamic raionale is likely to look a safer bet for a pharma marketing department.
And so there has been a lot of talk recently about ketamine’s actions on the ultra-fashionable NMDA receptor. Do we need to learn to speak NMDA the way we all learnt to speak Serotonin?
Put that way the answer is no – if you learn to speak serotonin you get an SSRI.
Before anyone ever heard of serotonin, never mind NMDA, for centuries there were broadly-speaking two groups of nervous drugs – stimulants and sedatives. Stimulants had once been known as tonics. The johnny-come lately amphetamines a century ago brought us the word stimulant.
The sedatives over time subdivided into major and minor tranquilizers, hypnotics and later anxiolytics, with efforts to create serenics and other categories.
In the 1950s, early efforts to classify new drugs were shaped by research on the nervous system then gearing up. The first system to grab attention was the reticular activating system (RAS) – the sleep wake system. It became clear that the same outcome could in some cases be produced by stimulating or sedating the RAS.
Anaesthesia for instance is classically induced by sedatives but it could also be induced by disinhibiting or stimulating agents – which led to phencyclidine and the related ketamine. PCP rapidly gained a following – but not because it causes dependence – that led to it being banned.
This research converged on a strand of psychobiology that in the 1950s found its fullest expression in Eysenck’s Psychology of Individual Differences. Eysenck was influenced by Pavlov who, faced with dogs who had what he termed traumatic neuroses following a flooding in his laboratory in St Petersburg, found that some responded to stimulants while others, with what superficially appeared to be exactly the same condition, responded to sedatives.
Eysenck proposed that successive layers of inhibitory reflexes produce the personality dimensions of extraversion and introversion. He produced the Eysenck Personality Questionnaire, the forerunner of today’s personality questionnaires.
Early findings showed that introverts and extraverts could be distinguished on the basis of their response to sedatives. The more introverted you are the more anaesthetic needed to induce sleep for surgery. Extraverts quieten down on stimulants.
This line of thinking was eclipsed by the antidepressants and antipsychotics, which appeared more categorical than dimensional. Hypotheses like the catecholamine hypothesis of depression and dopamine hypothesis of schizophrenia made these drugs seem more like Magic Bullets than Therapeutic Principles.
Finally, the tonic group of drugs fell out of favour because of a hazard. While the stimulants didn’t cause convulsions, other tonics like strychnine and camphor were outright convulsive agents. See HERE for more.
The antidepressants and antipsychotics brought a new drive to specificity in psychiatry with even the stimulants captured and transformed into a specific Magic Bullet for Attention Deficit Hyperactivity Disorder (ADHD) rather than a Therapeutic Principle.
Anticonvulsants meanwhile, like carbamazepine and sodium valproate, were known to have beneficial behavioural effects mainly anti-impulsive. They were Therapeutic Principles not Magic Bullets.
In the early 1980s Bob Post proposed that mood disorders might resemble epileptic disorders such that one episode might kindle further episodes and if so a goal of treatment was to suppress kindling. The beneficial effects of carbamazepine and sodium valproate were reinterpreted in these terms and laid the basis for the concept of mood stabilization.
The use of the anticonvulsants is now disease specific rather than temperament based. If a patient with a bipolar disorder fails to get well, the general approach has been to add further mood stabilisers to the mix – sometimes up to 6 or 7 at the same time. This would be like Pavlov giving all his dogs sedatives and adding further sedatives if they failed to respond to the first rather than stopping the sedative and giving a stimulant instead.
A century ago, tonics had equal weight with sedatives but with the exception of stimulants for ADHD, sedatives now rule.
Among the antipsychotics, one treatment stands out – clozapine. This is generally held to have unique benefits. There have been significant efforts to replicate its benefits without its headline risk of agranulocytosis. One approach has been to produce almost identical molecules – quetiapine, olanzapine. Another has been to reproduce clozapine’s receptor profile (risperidone, iprasidone, sertindole). The consensus is that none of these reproduce clozapine’s unique benefits.
Clozapine comes with another risk – convulsions. No-one has attempted to optimise for its pro-convulsant properties. This is regarded as a side effect to be eliminated.
Among mood-stabilizers, the standout drug is lithium. There is a consensus that while many anticonvulsants can be beneficial in bipolar disorder none produce the quality of responses seen with lithium. Lithium, like clozapine, is pro-convulsant.
Finally, ECT is unique across psychiatry in producing better responses than anything else in those who are suited to it.
Ketamine is one of the few other pro-convulsant drugs.
Several years ago we treated 9 patients with 100mg I/M of ketamine.
Two were classic bipolar patients, psychotically depressed, candidates for ECT, one of whom had only ever responded to ECT before when depressed, and both of whom responded to lithium when high. This dose of ketamine given I/M lasts roughly an hour, with residual effects for a further hour.
Both showed dramatic responses to just one treatment. One has remained fully recovered for nearly a decade since. The other has had one brief wobble in the course of a decade.
The full descriptions are HERE.
The dramatic responses in the kind of condition that responds better to ECT than anything else made this look like ECT in an injection – although one of the two later described the experience on ketamine in terms of getting outside the illness and this seemed to contribute to recovery, which is not the experience anyone has on ECT.
The third was a complex case that might be described as Treatment Resistant Depression. Nothing worked, including ECT. There were lots of social issues. The response in this case was very different. There appeared to be a more abreactive working through issues. Immediately after treatment, the person appeared to have a very clear-sighted view of significant issues.
This suggested ECT was not the right option for this person. But there was no-one geared up to build on the progress produced, and there was a relapse soon after.
Three other people had PSSD. They showed no response to ketamine 100 mg I/M.
Finally, three were SSRI and medication free but had protracted withdrawal from SSRIs. In all three cases, ketamine made their problems worse.
Besides our cases that I can vouch for, I am persuaded that some people who are terminally ill with cancer or whatever and finding it difficult to reconcile themselves with their situation, who use psilocybin or ketamine in a setting with the right supports and music and incense etc can come out of the session far more settled and able to face death.
I know less about but am inclined to think that some people with alcoholism can come out of similar sessions radically changed and much less likely to drink.
Technically speaking Stravato – esketamine nasal spray – is not junk.
Is it going to be any good for anyone? It doesn’t seem likely. The case for its approval was made on the basis of responses like the ones we saw in psychotic depression. There is no reason to believe that this dose of ketamine given intra-nasally will do anything useful for severe depression. Much higher oral doses are used on cancer wards for pain relief without producing anything like the effects that are seen with 100mg I/M.
Would pharma want a response like the ones we saw. Nope. The industry has made it clear that curing patients is bad for business. A high-cost maintenance treatment is the goal.
Could Spravato make things worse? Possibly. Ketamine definitely has the potential to make SSRI withdrawal worse and on the basis of our observations seems contra-indicated in such states.
Clinically just giving Spravato for the sake of it seems desperate rather than sensible. Combining a pro-convulsant, even if only vaguely so at this dose, with anticonvulsants looks like a recipe for neutralising everything and keeping people permanently treatment resistant.
But its not likely that any doc is going to ask himself why exactly am I giving this stuff – is there something I know it does that would be useful here. And pretty unlikely anyone being offered it is likely to ask what exactly are we trying to get treatment to do – and don’t say get me better – how do you think its going to get me better?
And this in a sense goes to the nub of the issues. It sounds like and feels like people in the face of death who get the real thing are more reconciled with themselves and braver as a result.
Those giving them the treatment have of course always tried it themselves – to be able to guide their patients.
But I’ve yet to find one who is transformed into someone brave enough to speak out against current pharmaceutical industry or healthcare practices? Are somethings scarier than death?