I’ll grant that my headline is meant to be catchy and induce you to read this epistle.   Some of you will ask what is ketamine anyway, and most of you will know from the get-go that ketamine, whatever the heck it is, will turn out to be neither a menace nor a miracle, but something in between.   I make that prediction because, before I started the digging process, that’s exactly where I was.

I had heard of ketamine as one of those “party drugs” that came along after LSD and its shady relatives, and I knew vaguely that some people – including some supposedly well-credentialed health-care professionals – were touting the usefulness of ketamine in certain situations.   But then, thought I, no matter what the substance is, there will be some people who authoritatively claim that the particular substance in question will cure one or more serious health conditions, e.g., tiny doses of cyanide as a cure for cancer (remember laetrile and apricot pits?)

What prompted me to look at ketamine a bit more closely was a densely-written paper in The American Journal of Medicine entitled “Nonanaesthetic Effects of Ketamine: A Review Article,” by a group of physicians at the University of Montreal (Eldufani J. Am J Med 2018;131:1418-1424).   What first caught my attention was a box listing the highlights of the paper, which I reproduce here:

CLINICAL SIGNIFICANCE

• Ketamine has a variety of pharmacologic effects including sedation, analgesia, bronchodilation, and nervous system stimulation.
• It is used as an active adjutant that prolongs the duration of analgesic effects of painkillers in pain management.
• Ketamine is used in clinical practice to manage major resistant depression, enhance memory function in Alzheimer’s patients, and reduce brain damage after stroke.
• Ketamine is clinically used for managing cognitive dysfunction and immune system disorders.

As I looked through the review article, I was especially struck by the characteristics of this drug when used as an anaesthetic.   What most anaesthetics do along with suppressing pain responses and inducing loss of consciousness is to slow respiratory function and heartbeat.   This is true of opiates, whether taken purely for pain management or for other purposes. What kills people who overdose on opiates is, pure and simple, that they quit breathing.   And anaesthesiologists are extremely scrupulous about monitoring their patients’ breathing and heart rate. They want to make absolutely sure that their patients don’t quietly drift off into permanent oblivion.   But when ketamine is used as an anaesthetic, depressed respiratory function simply is not a problem. And, as the title of that review article implies, anaesthesia was the initial medical use of ketamine. Because it preserved respiratory function, it was used as a battle-field anaesthetic during the Vietnam War, and medics in the US military always have it at the ready.   

But before we get too far ahead of ourselves, let’s do some groundwork.

So, what is ketamine?

Ketamine is a small molecule related to phencyclidine, which was discovered in the 1950s and originally used as an anaesthetic.   However, the use of phencyclidine as an anaesthetic was discontinued fairly soon when a number of significant neurotoxic side effects emerged.   Phencyclidine was taken up as a recreational drug in part because of some of those neurotoxic side effects such as delusions and hallucinations.  It is sometimes called “angel dust” by its recreational drug fans.

Ketamine was discovered in 1962, tested in humans in 1964, and approved by the FDA in 1970, shortly after which it was widely used in the Vietnam War.   It is on the World Health Organization’s List of Essential Medicines, and is widely available in the generic form.

Ketamine rapidly passes the blood-brain barrier to produce an analgesic effect.   The principal mechanism of action of ketamine is that it is an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which is thought to be responsible for the anaesthetic effects of ketamine.   The effect of ketamine on NMDA receptors prevents sensitization in dorsal horn neurons, preventing pain transmission in the spinal cord. Ketamine also inhibits the secretion of nitric oxide synthase, which results in lowered production of nitric oxide.   Nitric oxide is a pain transmitter, so ketamine works to lower pain transmission by this means as well.

Ketamine is a dissociative anaesthetic, meaning that it can suppress pain in a patient without making the patient lose consciousness.   Given by injection, the anaesthetic effects of ketamine begin to be felt after about five minutes and last about 25 minutes after a single dose.   As noted earlier, ketamine does not affect heart rate or respiratory function. As an anaesthetic, ketamine is especially valuable in some specific types of cases and circumstances, e.g.  

• Ketamine is frequently used as the sole anaesthetic in children for minor procedures that can be completed in a relatively short time.
• In longer procedures in children, ketamine is used initially and then followed by other anaesthetics to permit intubation.
• Because it does not diminish respiratory function, ketamine is a preferred anaesthetic for patients with asthma or chronic obstructive pulmonary disease.
• In emergency departments, ketamine is given as a rapid-acting analgesic to permit some physically painful procedures.
• Ketamine is used in low doses to supplement spinal or epidural anaesthesia.
• Ketamine is the anaesthetic of choice when reliable ventilation equipment is not available.
• In patients with severe head injury or those with traumatic shock, low blood pressure presents an elevated risk.   Ketamine provides pain relief and anaesthesia without the risk of low blood pressure.
• Ketamine is also the anaesthetic of choice on the battlefield.
• For the same reason, ketamine is valuable in emergencies such as car crashes or accidents causing severe injuries.

As an anaesthetic/analgesic it has numerous practical advantages.   It does not need to be refrigerated, it is easily transportable, and it can be given by injection into the muscle, by IV, and in some cases is available in tablet form.   

But the effects of ketamine go way beyond pain control and anaesthesia.   The clearest and most direct interaction of ketamine is with the NMDA receptor, but it also has a large number of other interactions, including with opioid receptors and opioid receptor ligand.   It interacts as a stimulator and potentiator of some serotonin receptors, and inhibits the reuptake of serotonin, norepinephrine, and dopamine, thereby prolonging their activity. These interactions are not as potent as the effects of ketamine on the NMDA receptor, which is why the drug primarily acts as a blocker of the transmission of pain signals.   However, they contribute to ketamine’s overall capacity to deliver analgesic effects without depressing either cardiac or pulmonary function.

But what’s this about ketamine as a “party drug”?

Let’s be clear – Doc Gumshoe is not promoting ketamine for its psychedelic properties.   But it certainly does seem to induce hallucinations and excitation symptoms, which some folks apparently enjoy.   Physicians who employ ketamine as an anaesthetic in young children take care to prepare the children for the “trip,” by doing such things as reminding them of their most agreeable memories, so that any hallucinating they might experience under the anaesthetic is not scary and they emerge happy.

What ketamine does as a recreational drug is to give the user the sense that the surrounding environment is not real.   Sights, sounds, and other sense data, blend with hallucinations. The drug user takes in the whole experience as a kind of show, divorced from reality, and – at least, so it is said – derives a kind of euphoria from this experience.   In other words, they greatly enjoy this experience, see no harm in it, and in some cases repeat the “trip” nearly every day. Users call ketamine “Special K.”

The use of ketamine as a recreational drug is increasing in several parts of the world, especially in China, which has led the Chinese government to consider re-scheduling ketamine from a Schedule III drug, as it is in the US, to a Schedule I drug.   That would define it as a substance that has no currently accepted medical use, no accepted safety for use under medical supervision, as well as a high potential for abuse. China happens to be the world’s largest manufacturer of ketamine, and restricting it as a Schedule I drug would greatly limit its use, not only as a recreational drug, but in settings where it is now commonly used clinically, and not only in China, but in other nations around the world.

While ketamine used as an anaesthetic or analgesic is in most cases a very safe drug, repeated use by recreational users is much more hazardous.   A long-term study of ketamine users reported that those who used ketamine on average 20 days a month had experienced several negative consequences, including increased depression, and impaired verbal, short-term, and visual memory.   In contrast, users whose monthly use was much less frequent, averaging 3.25 days per month, were not found to be any different from controls in terms of memory, psychological well-being, and attention, suggesting that infrequent use of ketamine does not result in cognitive deficits.   The study also suggested that any cognitive deficits that might occur with the use of ketamine may be reversible if ketamine is discontinued.

The hallucinatory effects of ketamine are by no means the only effects of this agent besides anaesthesia/analgesia.   Ketamine, like all drugs – indeed, like almost any foreign substance that is taken into our bodies – has a range of effects, some of which are definitely adverse.   These affect some people more than others, and range from outright contraindications to mild side effects. We’ll take a look at these further down in this report, but for now let’s move on to some of these other “nonanaesthetic effects,” as promised.     

Ketamine for major depression and treatment-resistant depression

When we consider any kind of drug treatment for depression, we are (in my opinion) on wobbly ground.   The scientific literature generally tries to treat depression as an illness with physiologic causes, and it is certainly true that several neurotransmitters play a central role in the mechanism of depression.   Serotonin, for one, has a strong psychological effect, and the first drugs specifically targeting serotonin – the selective serotonin reuptake inhibitors (SSRIs) – are widely used in attempting to manage depression.   But a patient’s depression cannot be separated from the patient’s life circumstances.

A fact that has been of much concern to investigators into the effectiveness of antidepressants is the extraordinarily high placebo response in the clinical trials.   For the candidate drug to be judged as efficacious in treating depression, the results in the cohort of patients taking the active drug need to be statistically superior to the results in the placebo group.   In clinical trial after clinical trial, those results do indeed come out as positive for the active drug – the active drug did do better than placebo. But how can it be that a large fraction of the patients taking the placebo – sometimes up to a third – also do well in terms of their level of depression?   They were taking sugar pills, for Heaven’s sake! Are we to believe that their depression was relieved just because they thought they might be getting a useful drug?   

The real answer is that the cohort that is getting the active drug is not being compared with an untreated population.   Both the active treatment patients and the placebo patients are getting a certain level of treatment. They are discussing their depression with health care professionals.   They are reporting their progress, if any, and taking tests to evaluate their progress. The most frequently-used test is the Hamilton Depression Rating Scale, known familiarly as the HAM-D.   It is generally accepted that any kind of interaction with a therapist of any kind has a positive effect in relieving the sense of hopelessness that affects depressed persons. So the high level of supposedly positive responses to placebo doesn’t mean that the sugar pill is effective in dealing with depression.   It merely means that those individuals got a lift from talking with a health professional.

To reinforce that point, permit me to digress a bit.   Quite a few years ago, I was working on a film to introduce a new antidepressant in the monoamine oxidase inhibitor (MAOI) class.   Our major spokesperson was the investigative psychiatrist who had been central to the drug’s development, but to make the film interesting and to add some human interest we featured the cases of three real patients who had been treated successfully with the new MAOI.   The three patients were all highly grateful for the treatment they had received and willing to share their experiences for the benefit of other patients. But as we worked with these people and learned of their experience, it became clear to me (at least) that a major part of the benefit they had gotten from their experience came not from the drug itself, but from their interaction with the psychiatrist, who was a highly charismatic individual.

Each of these three patients had a life situation that, while far from catastrophic, could be seen as source of feelings of depression.   One was a young man who had been pressed by his father to go to law school. He hated law school, flunked out, and floated around for several months, living at home, and being constantly taunted by his parents and siblings to “make something of himself.”   He fell into a deep funk, had some problems with the law, and finally was referred to a rehab center, which eventually routed him to the psychiatrist.

Another was a woman who had gained a huge amount of weight, tried repeatedly to lose weight but always gained it back, and became convinced that it was hopeless.   She was referred to a psychiatrist by a person working in the weight-loss center.

The third person had no obvious cause to be depressed.   In that sense, he might be said to have been the ideal patient to illustrate the benefit of the drug – his depression, one might say, was an illness with a physiologic cause,  and not because of any exterior circumstance. This man was in fairly good health and did not have any pressing problems. He was unmarried, living alone, and not employed, having recently retired from a career in municipal service.   However, as time went on, he found that his inactivity was weighing on him and he became increasingly depressed. His regular physician detected that all was not well, and that’s how he came to psychiatric treatment.

In each case, as we talked with our three case studies, it became clear that each of them immensely valued their interactions with the psychiatrist.   In my mind, I wondered how much of their improvement was due to the MAOI and how much to their time with the psychiatrist?

This may relate to the reported effectiveness of ketamine in some clinical trials.      Several well-respected experts in the treatment of depression have suggested that ketamine may be useful in treatment-resistant depression, which affects perhaps 30% of all persons with depression.   In a clinical trial in which 3,671 patients defined as having major depressive disorder were treated according to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) protocol, patients who failed to attain remission were encouraged to move to the next treatment step.   There were four treatment steps in all. Of the initial cohort of 3,671 patients, 123 continued to the fourth step (Rush AJ, Am J Psychiatry 2006;163:1905-17).   This trial recommended the use of ketamine in some of these patients, in particular because its antidepressant effects are felt very rapidly, in contrast to the delayed response to the commonly available antidepressant agents, which typically take several weeks to produce an effect.

The STAR*D protocol for treating depression is an attempt to address the highly uncertain prospects that any single treatment form will be effective.   The results of that particular trial are perhaps representative of the overall picture of depression treatment. The study used the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) to evaluate a patient’s status.   The remission rates were 36.8% after the first treatment step, 30.6% after the second step, 13.7% after the third step, and 13% after the fourth step. Overall, the cumulative remission rate was 67% for the entire cohort of 3,671 patients.   That cumulative remission rate is far, far higher than the best remission rates attained for patients with a major depressive disorder with any single antidepressant agent. The contribution of ketamine to this outcome is not clear. Rather than establishing the success of one drug over another, the trial was intended to validate the concept that in treating depression, the clinician should keep trying until something works.

There is good reason supporting a clinician’s decision to resort to ketamine in patients who have not responded to one or more antidepressants.   A patient who has been taking a drug of any kind for several weeks without feeling any benefit is not likely to be compliant to yet another course of treatment that whose benefit, if any, is not likely to become apparent for another period of several weeks.   With ketamine, what the treating clinician can be fairly sure of is that the patient will feel something, whether it’s relief of the feelings of depression or just a psychedelic experience.

Currently, a good deal of research is going on to attempt to pinpoint the specific pathways and receptors that are active in individuals who receive ketamine.   Animal studies to date have shown the effect of ketamine on several kinds of neurons, including pre- and postsynaptic neurons. As noted earlier, ketamine is active with regard to several neurotransmitters, including dopamine, norepinephrine, and serotonin, all of which are involved in our emotional tone and  feelings.

One very small study (four subjects, all with treatment-resistant depression) evaluated the efficacy of four intravenous doses of ketamine, 0.1, 0.2, 0.3, and 0.4 mg/kg, given one week apart.   Three of the four responded, according to the Montgomery-Asberg Depression Rating Scale, with the greatest improvement occurring at the highest dose. However, all patients experienced return of depressive symptoms a week or so after the final ketamine treatment.  (Lai R. World J Biol Psychiatry. 2014;15:579-84).  Whether it is feasible for patients with treatment-resistant depression to receive ongoing treatment by means of weekly IV infusions of ketamine is open to question.    

The studies of ketamine in patients with depression have also found evidence suggesting that ketamine may be effective in reducing thoughts of suicide and alleviating post-traumatic stress disorder.

Potential uses for ketamine in other medical conditions: chronic pain

Pain relief has surely been one of the main objectives of the healing arts since there were any practitioners of what we now call medicine, but we poor humans by no means have it totally figured out.   That’s because pain is an intrinsically useful response – it’s a signal that something is wrong with us and we’ve got to do something about it. The problem with that signal is that even after we have received the message, the signal doesn’t let up.   It not only doesn’t let up, it frequently gets more intense. In fact, the pain signal is often more disrupting than the actual cause of the pain.

Treating infections caused by a pathogen, setting a broken bone, healing a wound, surgically removing certain diseased organs– all these are unambiguous, straightforward procedures.   Managing pain is fundamentally more complicated. The healer doesn’t want to stop all sensory perceptions or render the patient totally unconscious. Local pain can often be treated locally; e.g., a recommended treatment for an ankle sprain is an ice pack, and the pain of many bumps and bruises can be managed topically.

Not so with chronic pain such as cancer pain or the pain arising from many difficult-to-treat orthopedic conditions, such as lower back pain.   Pain is sensed and transmitted through the nociceptive system, and there is evidence that prolonged stimulation of this system leads to upregulation of those same NMDA receptors that ketamine addresses, which results in the enhancement and amplification of those pain signals to the brain.   In other words, the longer a person is experiencing chronic pain, the worse it gets.

Since ketamine is an antagonist of NMDA receptors, it can be used in the management of chronic pain without resulting in anaesthesia.   Several clinical studies have reported that employing ketamine in treating chronic cancer pain permits reducing the amount of morphine or other opiates during long-term management.   A paper in the British Journal of Clinical Pharmacology attests to the efficacy of ketamine, particularly in chronic pain that has a neuropathic component, not only through inhibition of the NMDA receptor, but through other mechanisms such as anti-inflammatory effects at central sites.   The paper cites three studies on prolonged ketamine infusions, from 4 to 14 days, which produce long-term analgesic effects for up to three months following the infusion. (Niesters M. Br J Clin Pharmacol 2014;77:357-367).

Neuropathic pain, by the way, is distinguished from nociceptive pain, which occurs when our nerves detect tissue or organ damage.   Neuropathic pain arises when the nerves themselves are damaged. That type of pain tends to last longer and be more difficult to treat.   A common example of neuropathic pain is shingles, where the persistent herpes virus specifically affects the nerves.

Does ketamine have anti-inflammatory effects?

Possibly so.   On this front there has been some research and a good deal of speculation.   The short answer is that ketamine inhibits several of the factors involved in the inflammatory process, including tumor necrosis factor α (TNFα), interleukins, and nitric oxide production.   (TNFα, by the way, is the inflammatory factor targeted by the most effective and widely-used arthritis drugs.) Ketamine has been used to reduce post-surgical inflammation, which can lead to the release of large amounts of pro-inflammatory cytokines causing severe adverse effects such as low blood pressure and organ failures.

There has been some investigation of the possible role of ketamine in preventing damaging inflammatory responses following strokes.   The protective inflammatory mechanism in the central nervous system that protects the brain from injury is often deregulated following a stroke.   This may lead to increased permeability of the blood-brain barrier and the entrance of damaging inflammatory cells into the brain. Ketamine may act as an anti-inflammatory under those conditions.

Another possible anti-inflammatory effect of ketamine is in relation to a relatively rare brain hemorrhage occurring in the space adjacent to the ear, termed a subarachnoid hemorrhage.   These events have a rapid onset, are extremely painful, and are frequently fatal. The standard treatment for subarachnoid hemorrhages is to open the skull just below the ear to relieve the pressure of the hemorrhage.   It is thought that a predictor of fatality in subarachnoid hemorrhages is the presence of a particular type of inflammatory cells, of which ketamine is a potential inhibitor. Thus, administration of ketamine to patients with subarachnoid hemorrhages may improve survival.

A subarachnoid hemorrhage, by the way, is probably what killed Grace Kelly.   She experienced a brain hemorrhage while driving her car in Monaco. The sudden extreme pain of the hemorrhage is thought to be what caused her to have the fatal accident.

Ketamine for dementia and Alzheimer’s disease

Here we’re in the realm of speculation.   A point of departure is that one of the very few drugs that have been demonstrated to slow the deterioration of memory in patients with Alzheimer’s Disease is memantine, a drug principally used in patients with Parkinson’s disease.   Memantine doesn’t do much for AD patients; the delay in memory loss is thought to be not much more than a few months or perhaps as much as a year. Memantine is a NMDA receptor antagonist, and so is ketamine, so ketamine might also be able to delay memory loss in AD patients.

Other mechanisms of ketamine that may be beneficial in treating AD and dementia in general have to do with increased liberation of acetylcholine in the hippocampus, due to ketamine’s positive effect on dopamine release, which stimulates acetylcholine release.   And yet another possible mechanism is the release of glutamate in the post-synaptic cleft, which leads to opening of ion channels. Both acetylcholine and glutamate release have been linked to positive effects on cognition.

There has been a certain amount of research in mice having to do with the effects of ketamine on memory function.   At this point, those studies do not appear to point in any clear direction. Ketamine certainly has some effects on the brain, but whether these end up being on the whole positive or on the whole negative is as yet uncertain.

Contraindications and side effects

Since ketamine increases heart rate and blood pressure, it is contraindicated in persons with conditions worsened by an increase in blood pressure, such as angina or a stroke in progress.   It is also contraindicated in persons who have sustained a penetrating eye injury. Ketamine increases intraocular pressure, so it can cause the loss of eye contents – the substance that fills the eyeball.

Most of the ketamine-related side effects are mild and related to the transient increase in blood pressure.

What conclusions, if any, can we draw?

Looking back over what we’ve learned about ketamine, it seems clear that ketamine is highly valuable as an anaesthetic, particularly because it acts rapidly and does not cause the sharp drops in blood pressure and pulmonary function.   The benefits of ketamine in treating depression are probably limited to those persons who have not responded to the usual antidepressants. However, that population is quite large; it is estimated that about one in three persons who seek treatment for depression fail to respond to treatment.   Ketamine may well be a valuable resource for those individuals.

It also seems likely that ketamine will find its place in the treatment of chronic pain.   There we run into the problem of habituation – those persons who use ketamine regularly for pain relief may well find themselves enjoying the experience of the ketamine “trip” and resorting to the drug whether or not they were experiencing pain.   This is not unlike the danger that persons who treat their chronic pain with opioids may become addicted. However, opioid overdosage can be life-threatening to a degree that ketamine overdosage does not appear to approach.

The other potential uses of ketamine – as an anti-inflammatory, as an aid to the preservation of cognition,  and as an antagonist to cerebral hemorrhages – are areas as yet insufficiently supported by research.

To sum up, Doc Gumshoe gives ketamine an unqualified “yes” as an anaesthetic, and a “probably yes” as treatments for chronic pain and (in some individuals at least) depression.   The other potential uses are as of now no more than trial balloons.

But why do we not know more about ketamine?

Ketamine was not discovered, developed, and brought to market by a major pharmaceutical company; therefore no entity with deep pockets has ever had a financial interest in marketing this drug.   It is sold under the name Ketalar, among others, but also primarily under the generic name, and it is far from expensive. It is extremely unlikely that the clinical trials needed to demonstrate the efficacy of ketamine in those other areas will ever be mounted.   These trials would cost many, many millions, and at present no potential sponsor of such trials stands to benefit.

It is certainly possible that a tiny tweak in the structure of ketamine might result in a new molecule, different enough to be patentable, but yet preserving the characteristics of the parent drug, such that a pharmaceutical outfit might risk a billion bucks or so to conduct the necessary trials and bring it to market.   Possible, but highly unlikely – why would anyone prescribe the tweaked version when the original continues to be available at a low price?

My prediction is that interested scientists will continue to look into the effects of ketamine in a number of areas, and the information about their research will continue to trickle out.   Doc Gumshoe will watch for it, and let you know if anything of interest turns up.

* * * * * * *

In my next offering, I’m going to try to review what happened on the broader pharmaceutical front and in health-care in general during the year 2018.   Quick take: quite a lot! And, as always, many thanks for the comments – keep them coming! Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who we like to call ”Doc Gumshoe,” is a longtime medical writer (not a doctor) who shares his mostly non-investing-related thoughts with the Gumshoe community a couple times a month. You can see all of his columns here.]