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Ketamine: Peril and Promise

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Ketamine: Peril and Promise m a p s • v o l u m e x v i i n u m b e r 1 • s p r i n g ~ s u m m e r 2 o o 7 23 Ketamine: Peril and Promise Those following science news will have noticed some recent buzz about ketamine. What’s going on? Carlos Zarate Jr., MD, of the National Institute of Mental Health (NIMH) recently injected 18 patients who had treatment- resistant depression with ketamine and found that their depres- sion significantly improved within hours - an improvement that 1 R. Andrew Sewell, MD lasted for up to a week after a single dose. This is in striking [email protected] contrast to conventional antidepressants, which have to be taken every day and need weeks to months to have any therapeutic effect. The importance of these findings was articulated by the NIMH director, Thomas Insel, MD: “To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose.” This study corroborates earlier findings by researchers in 2000 who gave ketamine to seven depressed patients and noted a Veterans began to return remarkable and lasting remission of depression in all of them.2 to the United States By coincidence, Zarate was an attend- 1). It was invented in 1962 by the phar- with unusual stories ing physician at the medical center where macist Calvin Stevens and patented in I did my training, and I remember well 1966 by Parke-Davis for use as an anaes- about psychedelic the dismay everyone expressed when he thetic in humans and animals. It is a left for bigger challenges at NIMH, as he neurotransmitter antagonist that blocks experiences they was renowned for his excellent clinical excitatory glutamate from reaching the N- skills and teaching ability. Strangely methyl-D-aspartate (NMDA) receptor. In had experienced enough, I don’t remember his ever higher doses, it also stimulates the mu and expressing an interest in psychedelic sigma opiate receptors and increases while on the drugs! epinephrine and endorphin levels. It Given that this is a major positive affects primarily the hippocampal forma- operating table… news story related to psychedelic drugs, it tion (responsible for memory) and the is perhaps worthwhile to step back and prefrontal cortex (responsible for abstract see what work has been done with this thought), explaining its profound effects unusual psychedelic and where we might on both. see ketamine research leading. Ketamine saw initial use in army field What Is Ketamine? hospitals in Vietnam – where it was Ketamine is an arylcyclohexylamine, considered useful because it acts quickly, the same class of drugs as allows rapid recovery, and depresses dextromethorphan (DXM, “robo”) and consciousness without disrupting breath- phencyclidine (PCP, “angel dust”) (Figure ing or circulation, unlike most 24 m a p s • v o l u m e x v i i n u m b e r 1 • s p r i n g ~ s u m m e r 2 o o 7 anaesthetics. This means that monitoring Moore, who penned one of the first and support by an anaesthesiologist is not descriptions of the effects of ketamine in necessary, and a single surgeon can in her autobiography Journeys Into the theory perform an operation unaided.3 Bright World, vanished one night under Veterans began to return to the United the influence of ketamine in 1979, and States with unusual stories about psyche- her skeleton was found in a tree two years delic experiences they had experienced later.6 Ketamine slowly acquired a reputa- while on the operating table, however. tion for insidiously trapping those who Similar to LSD, ketamine induces vibrant really knew better. The psychedelic was hallucinations, but unlike LSD, ketamine added to the Drug Enforcement lasts only an hour or so and induces an Administration’s “emerging drugs” list in “out-of-body” state similar to that of a 1995, then moved to Schedule III – the near-death experience. In 1965, professor same class as buprenorphine and anabolic Unlike most Edward Domino coined the term “disso- steroids – in 1999. ciative anaesthesia” to describe ketamine’s Medical Use of Ketamine of the other trancelike effects.4 Interest in the psycho- Why, given ketamine’s evident logical effects of the new drug spread dangers, was it not put into Schedule I psychedelic drugs, rapidly. Karl Jansen, MD, PhD, who instead? Schedule I is reserved for drugs devoted his entire career to understanding with “no currently accepted medical use,” society never really lost ketamine from the receptor to the social and the medical uses for ketamine are level, came to believe that ketamine had plentiful. Aside from applications on the sight of the benefits potent healing powers (see Ketamine: battlefield and in veterinary medicine, Dreams and Realities, published by lower doses also appear to be helpful in of ketamine… MAPS). By the mid-1970s ketamine was managing chronic pain conditions. When being used in Argentina to regress clients pain fibers from an injury site activate, “back to the womb,”5 and psychotherapeu- they trigger a chain reaction that changes tic use continues to this day. This use is the structure of the pain neurons them- even reflected in popular culture. An X- selves. These changes can sometimes Files episode in 1993 (“Demons”) featured provoke the neurons to fire even more, in Agent Mulder being given ketamine by a an out-of-control feedback loop called rogue doctor in order to help him recover spinal sensitization, or the “wind-up” his lost memory. phenomenon, that creates even more pain. However, recreational use of ket- Unlike most anaesthetics, ketamine’s amine also mushroomed over the same NMDA-receptor (and thus long-term period, together with scare stories in the potentiation) blocking effects prevent this media. It was immediately dubbed a “date- sensitization. At doses of 0.1 to 0.5 mg/ rape” drug, just as MDMA and GHB had kg/h, ketamine is useful as a local anaes- been in turn, despite the fact that the drug thetic and as a treatment for chronic pain. most overwhelmingly implicated in rapes It acts synergistically with opioids to is alcohol. Alarm started to grow within further improve pain relief and is particu- the psychedelic community as well, for larly useful in treatment of pain that is different reasons. Although psychedelic caused by cancer.7 drugs are generally considered to be One form of pain resulting from nonaddictive, ketamine seemed to be the sensitization is called complex regional exception. The American researcher Dr. pain syndrome (CRPS), in which a John Lilly, well versed in other seemingly minor trauma becomes more psychedelics such as LSD, found his painful with time rather than less and is ketamine use spiralling beyond his accompanied by changes in the skin and control, and he nearly drowned once autonomic response in the affected limb. while under its influence. D.M. Turner, The pain can be severe and is often both author of The Essential Psychedelics chronic and resistant to conventional Guide and Salvinorin - the Psychedelic therapy. In 2002, a team in Germany led Essence of Salvia Divinorum, also became by Ralph-Thomas Kiefer, MD, kept six addicted and was finally found drowned patients with CRPS unconscious with a in a bathtub at the age of 34, having continuous ketamine infusion for a week succumbed during a ketamine trip. Marcia and found that four were cured and two m a p s • v o l u m e x v i i n u m b e r 1 • s p r i n g ~ s u m m e r 2 o o 7 25 were relieved of their pain for one and Psychotherapeutic Use 8 three months respectively. Mindful that a of Ketamine week of intensive monitoring in the ICU During the late 1960s, Lilly conducted is seldom a practical treatment for any- initial research with ketamine as an agent thing, G.E. Correll’s group at Penn State to induce nonordinary states of conscious- Hershey Medical Center reviewed the ness. He was the first to characterize the medical records of 33 patients given low- relationship between dosage and the dose (subhallucinogenic) ketamine for nature of the ketamine experience.15 CRPS instead and found that three- Jansen has since argued that rather than quarters had experienced complete pain using ketamine as an adjunct to psycho- relief and 31 percent were still pain-free therapy, in the way that MDMA is typi- six months later.9 This was enough to cally useful, the altered state induced by prompt a prospective trial in which 40 ketamine is in itself therapeutic. Its patients with CRPS were given resemblance to a near-death experience …ketamine subhallucinogenic doses of ketamine. can have a similar effect as an actual near- They reported significant pain relief that death experience. For example, it can might be useful lasted for weeks in most of the patients supposedly reduce anxiety about death, and caused a permanent remission in increase altruism, and make people less in the treatment three.10 concerned with material goals. There are also suggestions that In 1973, the Iranian psychiatrist E. of heroin ketamine might be useful in the treat- Khorramzadeh, MD, published the first ment of heroin withdrawal. In one recent report on the use of ketamine as an withdrawal. study, 58 opiate-dependent patients were adjunct to psychotherapy.16 His patients given “ultra-rapid detox” under general reported a number of different effects. anaesthesia with either ketamine or Many vividly recalled painful childhood placebo saline infusion.11 The ketamine events.
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