Ketamine back in the news cycle...

 

The New York Times came out with a report a few days ago describing potential problems that presidential advisor Elon Musk was having with substances (1).  The report included concerns of other observers and his self-report of patterns of use of stimulants, a sedative hypnotic (zolpidem), psychedelic mushrooms, an unknown weight loss drug, and ketamine.  He described bladder complications of ketamine, that do not typically occur with supervised medical use.

The NYT report also includes concerns about erratic behavior by some high-profile individuals and some general concerns about drug use. There are quotes where Musk acknowledges recreational drug use, using ketamine at a frequency of every 2 weeks, and denouncing “traditional therapy” for depression – but it is never clear whether the ketamine is prescribed and supervised by any physician. He is described as having a history of “grandiose statements and a mercurial personality” but some have observed further changes.  All of this occurs on a backdrop of relationship conflicts and a recent goal of maximizing childbirths in the US.

My previously stated adherence to the Goldwater Rule – precludes me from making any armchair diagnoses based on a newspaper article.  But I think it does provide an opportunity for education and ties with some of my previous posts. On the ketamine issues – I reviewed Rasmussen’s book on ketamine and posted a review of it on Amazon.  In the book (p. 45-55) he describes 3 famous “ketamine celebrities” and likens them to modern “influencers”. All three were interested in the altered states induced by the drug.  All three were active from the 1970s to 1990s.  One died by drowning while under the influence of ketamine and another had several close calls with drowning.  The third person may have taken a significant amount of ketamine and wandered into the woods where she died of exposure (although there is an alternate theory of homicide).  In all three cases, these influencers idealized the psychedelic effects of ketamine.  All three had uncontrolled use of ketamine, but only one acknowledged an addiction and warned of that danger.  One of them injected ketamine every hour around the clock for 3 weeks or a total of 500 injections.   

My professional experience with ketamine and the related compound phencyclidine or PCP came at two points in my career.  Initially during my tenure as an acute care inpatient psychiatrist in the late 1980s and early 1990s – I would see people who were acutely psychotic from the effects. The reason why they were transferred to my unit rather than being detoxed in the emergency department was severe agitation, psychosis, and in some cases self-injury.  This represented an acute intoxication delirium and it resolved with symptomatic care and detoxification.  The second point was during my employment at a large substance use treatment center.  Toward the latter half of that employment ketamine was heavily hyped in the press.  There were typically stories about how club drugs were now psychiatric drugs.  I would see people who were using excessive amounts of ketamine often rationalized as a psychiatric treatment or a treatment for chronic pain. Some were using unusual forms of the drug like tablets.  Oral ketamine has a very low bioavailability.  Others were using preparations formulated for sublingual use or the or more typical use by insufflation or inhalation.  I got used to seeing people tell me that many of the substances they were using were for a psychiatric treatment even though they had never been seen or evaluated for a mental health problem.

Supervised medical use of ketamine is necessary because of two risks – hypertension and the neuropsychiatric effects most notably the K-Hole experience.  During that episode of extreme dissociation and delirium – a person has extreme detachment.  Some people feel like it is a near death experience and they are unable to respond to the environment.  In a semi phenomenological study of infrequent, frequent, and former users (3) – more specifically describe the disliked effects as cognitive disorganization, paranoia, dissociation, body/sensation distortion, auditory and visual hallucinations, loss of control, depression, introversion, nausea, vomiting, and restlessness. The subjects who like the experience basically endorsed similar experiences, but felt more relaxed, social and sociable and did not have any of the physical side effects. Half of the frequent users sought medical attention for stomach pain or “K-cramps (30%) and bladder complications (20%).  Half of the frequent users also reported a decline in mental health.  The authors also expressed a concern that there was a signal for compulsive use in their survey question 80% reported using whatever ketamine they had on hand until it was gone rather than saving some for future administration.

As a clinical psychiatrist seeing people who may be using multiple drugs and are often not using the drugs they think they are – the two long term consequences I have seen are severe anxiety and panic attacks and hallucinogen persisting perceptual disorder (HPPD).  The HPPD is technically the result of taking classical psychedelics, but many of these people will also be taking drugs that they think may approximate those effects like ketamine.  Many people compulsively take ketamine and/or stimulants while taking other hallucinogens (Mushrooms or LSD). 

I have included several references on the bladder complications of ketamine (4-9).  Most of them are available online.  In trying to determine the bladder toxic dose of ketamine – the closest I could come was reference 9 at 3 grams/month to 3 grams per week.  Estimates like this assume that the drug ingested is pure pharmaceutical grade ketamine – a likely invalid assumption. I have attended numerous conferences on ketamine infusions administered under medical supervision and have never found any descriptions of bladder complications even though they are listed in the FDA package inserts on ketamine.

In terms of the self-reinforcing property of ketamine – the question is the mechanism.  Many authors write that it causes psychological dependence and those properties may depend on baseline psychological and personality characteristics. There is also the intensity of the spiritual experience if there is a psychedelic experience.  In some studies subjects are asked to rate that experience in terms of similar experiences in their life and in the case of psilocybin they rank it in the top 5 most meaningful (58%) or spiritual significant experiences (67%) in their life (11).  Although ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist it also activates mu opioid receptors and has been suggested as a treatment for opioid use disorder (12) suggesting another reinforcing mechanism. 

Ketamine has several properties outlined so far that highlight its problems and potentials.  It is hyped as an antidepressant but also a general approach to “well-being.”  The influencers of the 1970s emphasized the spirituality and consciousness expanding potential for the drug and they experienced uncontrolled use, medical complications, and deaths and near deaths during periods of intoxication.  Even though many frequent users surveyed required medical help and were concerned about their mental health – the downsides are never mentioned in the media.

This cultural profile is like drugs that people take as performance enhancers believing that their subsyndromal symptoms of anxiety, depression, insomnia, and appetite problems may improve. Beyond that there is an idea that certain drugs may enhance cognition, delay aging, and cause neurobiological changes consistent with both.  As I reported earlier on LSD these effects are unlikely to happen and it becomes a coin toss between whether you are a person who will value any psychedelic experience you get from the drug or not.

For the purposes of the NYT article – it is a fair question to ask if a person making major changes to the federal government affecting millions of people is doing that while using intoxicants and whether that person was screened with the required drug tests according to their policy.   

 

   George Dawson, MD, DFAPA

 

1:  Grind K, Twohey M, On the campaign trail, Elon Musk juggled drugs and family drama.  New York Times May 30, 2025.

2:  Rasmussen KG.  Ketamine: The Story of Modern Psychiatry's Most Fascinating Molecule.  Washington DC.  American Psychiatric Publishing.  2024; 295 pp.

3:  Muetzelfeldt L, Kamboj SK, Rees H, Taylor J, Morgan CJ, Curran HV. Journey through the K-hole: phenomenological aspects of ketamine use. Drug Alcohol Depend. 2008 Jun 1;95(3):219-29. doi: 10.1016/j.drugalcdep.2008.01.024. Epub 2008 Mar 19. PMID: 18355990.

4:  Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007 May;69(5):810-2. doi: 10.1016/j.urology.2007.01.038. PMID: 17482909.

Original series of 9 daily ketamine users with severe ulcerative cystitis.

5:  Meng E, Wu ST, Cha TL, Sun GH, Yu DS, Chang SY. A murderer of young bladders: Ketamine-associated cystitis. Urological Science. 2013 Dec 1;24(4):113-6.

6:  Jhang JF, Birder LA, Kuo HC. Pathophysiology, clinical presentation, and management of ketamine-induced cystitis. Tzu Chi Medical Journal. 2023 Jul 1;35(3):205-12.

This review suggests that conservative measures such as medications may be successful if the patient is able to completely discontinue ketamine.  In refractory cases bladder reconstruction is required.  They describe enterocystoplasty using the ileum to reconstruct the bladder. 

7:  Chen CL, Wu ST, Cha TL, Sun GH, Meng E. Molecular pathophysiology and potential therapeutic strategies of ketamine-related cystitis. Biology. 2022 Mar 24;11(4):502.

Authors suggest 19 possible pathophysiological mechanisms leading to bladder damage from ketamine and reviewed available treatments suggested by other case series.

8:  Jhang JF, Hsu YH, Kuo HC. Possible pathophysiology of ketamine‐related cystitis and associated treatment strategies. International Journal of Urology. 2015 Sep;22(9):816-25.

Authors suggested 7 possible pathophysiological mechanisms for bladder injury including a pathway to neoplastic change.

9:  Chen CH, Lee MH, Chen YC, Lin MF. Ketamine-snorting associated cystitis. Journal of the Formosan Medical Association. 2011 Dec 1;110(12):787-91.

Case series of 4 patients using ketamine by insufflation at a rate of 3 g/week (3 patients) to 3 g/month.  All had severe hemorrhagic cystitis.  Patients typically present with lower urinary tract symptoms (LUTS) including urinary frequency, urinary urgency, straining to urinate, weak stream, and post void leakage. Patients also have bladder pain and may have gross hematuria.  If they are able to stop using ketamine the symptoms can persist for up to one year.  Urinalysis shows hematuria and pyuria, with negative cultures for bacteria. Imaging of the bladder can show a thickened bladder wall with smaller volume. Hydronephrosis and hydroureter can also be present. 

10:  Morgan CJ, Curran HV; Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 2012 Jan;107(1):27-38. doi: 10.1111/j.1360-0443.2011.03576.x. Epub 2011 Jul 22. PMID: 21777321.

11:  Yaden DB, Newberg AB.  The Varieties of Spiritual Experience: 2st Century Research and Perspectives. New York. Oxford University Press. 2022; p. 353.

12:  Levinstein MR, Michaelides M. Exploring the role of mu opioid receptors in the therapeutic potential and abuse liability of (S)-ketamine. Neuropsychopharmacology. 2024 Jan;49(1):315-316. doi: 10.1038/s41386-023-01652-x. PMID: 37438422; PMCID: PMC10700302.

Review of Ketamine: The Story of Modern Psychiatry's Most Fascinating Molecule

 

Keith Rasmussen is Professor of Psychiatry at the Mayo Clinic and the author of an authoritative text on electroconvulsive therapy - Principles and Practice of Electroconvulsive Therapy.  I noticed the pre-release literature on his book on ketamine and waited for months to get a copy.  After reading it I can say it was one of the best books I have read in psychiatry.

The book is organized into 9 chapters.  The first 4 are on the history and pharmacology of ketamine.  That is followed by 4 chapters on clinical applications including depression, as a model for schizophrenia, chronic pain, other psychiatric disorders, substance use disorders, and ketamine assisted psychotherapy.  There is a final chapter on whether ketamine is a neurotoxin or a neuroprotectant and several experimental applications are discussed.  Many of these chapters could be freestanding reviews of the literature. In writing these reviews, authors will often use table summaries either as an outline or in the body of the review. Rasmussen uses one or two paragraph long summaries of research papers and is aware that can be a tedious approach. For that reason, he omits a long discussion of preclinical research in one chapter.

The initial chapter is an introduction to the molecule.  We learn that it belongs to a class of arylcycloaminohexanes and that phencyclidine (PCP) was the initial drug synthesized from that class. PCP was invented for use as a general anesthetic, but it failed because of severe behavioral reactions.  Additional structures were synthesized from that class and ketamine was eventually developed on a preclinical basis. The molecular structures of both compounds are provided in the book but the structure of ketamine on page 12 is in error (it shows a chlorine atom in position 2 on a cyclohexane rather than a phenyl ring but the IUAPC naming in the caption is correct).  I have posted both structures below.  The purported mechanism of action is discussed in several places – at the level of the NMDA receptor and how pathological processes like excitotoxicity and apoptosis occur and may be interrupted.

 

When I took my first medical school pharmacology course in 1984 – the adverse reactions were noted in the anesthesiology section for both PCP and ketamine.  Rasmussen writes like a chemistry major who experienced organic chemistry as an important course. He discusses detailed chemical structures, reactions, stereochemistry, and the Grignard reaction. These explanations have the purpose of explaining of how compounds are named and why the synthesis of ketamine is outside of the expertise of local meth cookers.  At the same time, he does not get too technical when it comes to receptor binding affinities (I did not notice a single K_i).  Beyond that he details where ketamine is currently produced (China, India, Mexico) and provides two cases of clandestine operations in China that were using 8.5 million tons of ketamine precursor before they were shut down by authorities (see Supplementary 1 footnote).

The book is a thorough documentation of the time course of PCP and ketamine use.  He discusses landmark papers and points out research papers that were probably the original observations and papers that are highly cited.  As I read the book, I went to the references and underscored many of these papers.  The reference section alone is 44 pages long.

Each chapter about the potential clinical applications of ketamine is a through discussion of the existing literature and the limitations of that literature. He discusses the research design of many of these studies and what research is needed in the future.  He discusses the unanswered questions about ketamine. 

Does the book have any shortcomings.  A lot of reviewers seem to describe needing to be entertained by the books they are reading. Almost everything I read is a scientific paper or book.  Some of that content is exciting, but generally I would not see it as entertaining.  The closest this book comes to being more difficult to read were long sections that summarize scientific papers. 

Should you read this book?  Like all books – a lot depends on your level of expertise.  I consider myself to be an expert in both ketamine and PCP based on both my pharmacology knowledge and what I have seen clinically. I learned a lot reading this book and I think practically all psychiatrists and psychiatric residents will find this book useful.  Neurologists are an additional audience for the sections on neuroprotection in cases of traumatic brain injury, stroke, subarachnoid hemorrhage, and status epilepticus.

You will see information in this book that you will not read anywhere else.  It is footnoted to scientific articles and the discussion is even handed – the possible good and the bad.  A thread runs through this book from the very first page that all human drug responses are complicated based on biological heterogeneity and some of that can be age based. That means there are no “miracle drugs” for everyone.  There is an extensive discussion of the substance use aspects of the drug and it is presented as a clear danger.  I think that all acute care psychiatrists and residents could benefit from reading this book and it could form the basis of a journal club or a resident seminar in pharmacology. The style of writing reminded me of a text that I consider to be the most well written – Fundamentals of Biochemistry by Voet, Voet, and Pratt.   

What about people on the other end of the spectrum of ketamine knowledge?  There is plenty of information in this book that may be useful to you.  The book is well organized and researched.  It has an excellent index that will contain references that you do not have.  The information density in the book is much higher than I expected from reading the initial chapter and introduction.  There are interesting historical points including a section of three very well-known ketamine users, their experiences, and publications related to their use.  If you are involved in a research project involving ketamine or PCP – this book is a good source of background information.  This book can also potentially benefit journalists tasked with writing about ketamine and other psychiatric treatments.  

I really like all the details about the medicinal chemistry of ketamine.  It reminded me of some online discussions I have had with physicians who thought that organic chemistry was an unnecessary prerequisite to medical school.  If you share that opinion – chemistry at a more detailed level than you typically see in a pharmacology text might not interest you.  It is still there in an accessible form. 

This is a very good book – well researched and written. Dr. Rasmussen presents a very even approach to ketamine.  He presents the research and clinical findings of what really occurs with the use of ketamine.  No speculation is involved. It took a lot of hard work and accumulated knowledge to write this book and any physician reading it will realize that. With a few modifications the next edition of this book could become a classic text in psychiatry.

 

 

George Dawson, MD, DFAPA

Reference:

Rasmussen KG.  Ketamine: The Story of Modern Psychiatry's Most Fascinating Molecule.  Washington DC.  American Psychiatric Publishing.  2024; 295 pp.

Supplementary 1:  The more I thought about the figure quoted for precursor amounts used in the illicit manufacture of ketamine in China - the more skeptical I became.  The specific quote from the book is:  "In 2009, Chinese authorities seized two secret laboratories with a total of 8.5 million tons of precursor material, which is simply gigantic!" (p. 44).  Since illicit production estimates based on precursors are generally in the hundreds of metric tons - millions of tons certainly are gigantic.  From the first reference (1) listed below:  

"China produces massive amounts of ketamine, reliable estimates for the prevalence of ketamine abuse are not available. As of today, five Chinese factories are officially licensed to produce ketamine, but there are reports of illicit production on an industrial scale. In 2009, Chinese authorities reported the seizure of two illicit laboratories producing 8.5 million tons of the immediate precursor of ketamine."

In this case, the total precursor was 8.5 million tons and the UN Drug Report (2) was referenced at the head of the paragraph.  From that report (page 117):

"In 2009, China reported seizing two illicit laboratories processing hydroxylamine hydrochloride, the immediate precursor chemical for ketamine, and seizing 8.5 mt of this substance."

Note that the "mt" designation in this report is metric tons rather than million tons.  A metric ton is usually defined as 1,000 kg reducing the size of this estimate by about 2 million fold (8,500 kg compared with 7.7 million kg), but that is obviously still a significant amount of precursor.

Supplementary 2:  This interview of the author became available in the Psychiatric News on this date (11/5/2024)  

Ketamine: Miracle Drug or Double-Edged Sword?

https://psychiatryonline.org/doi/full/10.1176/appi.pn.2024.11.11.13

References:

1:  De Luca MT, Meringolo M, Spagnolo PA, Badiani A. The role of setting for ketamine abuse: clinical and preclinical evidence. Rev Neurosci. 2012;23(5-6):769-80. doi: 10.1515/revneuro-2012-0078. PMID: 23159868.

2:  UNODC, World Drug Report 2010 (United Nations Publication, Sales No. E.10.XI.13).

Latest on Ketamine

(R,S)-ketamine

Ketamine has been prominent in the psychiatric literature and conferences for the past decade as a potential agent for both treatment resistant depression and a rapid antidepressant response.  In some communities ketamine infusion clinics are available where patient can go for a weekly infusion to maintain depression either in remission or a partial response.  At a cultural level, besides being a dissociative agent for anesthesia, ketamine is also in the collection of drugs known as club drugs and as such it is abusable.  Ketamine is not among the most commonly abused drugs.  The NSDUH survey puts lifetime abuse at about 1%.  In a practice of addiction psychiatry it is less likely to be used than LSD and much less likely to be used than dextromethorphan.  It may be one of many drugs used by polysubstance users at some point in their usage history.  Ketamine is also classified as a psychedelic drug or a drug that can cause hallucinogenic or dissociative experiences.  From the time their use was popularized there was a belief that these experiences could be potentially beneficial from the standpoint of personal growth and creativity, as an agent to enhance psychotherapy, or in some cases as an agent to treat psychiatric problems like alcoholism and depression.  Ketamine is currently a Schedule III non-narcotic drug on the DEA List of Controlled Substances.  My first professional exposure to the pharmacology of ketamine occurred in basic science courses in medical school in about 1983.  It was taught as part of the pharmacology of anesthesia agents.  It was taught as not being a first line drug at that point because of the side effects of dissociation and anesthesia.  Like most old medications there has been a recent revival of interest for rapid sedation of patients in emergency department settings.  In the linked report it had a more rapid onset of action than the usual agents, but also a significantly higher complication rate.

Alan Schatzberg, MD gave a presentation on ketamine at the University of Wisconsin Annual Update and Advances in Psychiatry in October 2013.  He presented data to show that the effects of intravenous ketamine were acute but not sustained.  Depressed unipolar subjects noticed the antidepressant effects within a few hours and they lasted about one week before returning to baseline depression scores on a standard Hamilton Depression Rating Scale.  In bipolar depression the effects last about 12 days.  He presented the results of an NIMH trial of ketamine in treatment resistant depression.  It was a small multisite trial that compared ketamine (N=47) to midazolam (N=25) as an active placebo.  The primary outcome measure was remission of depressive symptoms at 25 hours and the rates were 63.8% for ketamine versus 28% for midazolam.  Dizziness, blurred vision, nausea/vomiting, headache, and palpitations were the most common side effects acutely and at 24 hours.  There were no episodes of psychosis.  Longer term strategies were presented that might sustain the acute ketamine response including an oral form, repeated infusions, memantine, riluzole, lamotrigine, high dose d-cycloserine, and several new oral agents that were antagonists or partial allosteric modulators of the glutamate receptor, or partial agonist of the NMDA receptor glycine site.  Response to ketamine infusion at 2 hours was shown to be predictive of response and there was a 70% chance of relapse after repeated infusion but this sensitization did not occur at 2 week intervals.  Despite these limitations on therapy there is  Ketamine Advocacy Network that includes a quote about the coming ketamine today tidal wave and a page with this very dim view of psychiatric practice and the intellectual interests of the average or most (?) psychiatrists.  It is not clear to me who writes their pages or who their medical consultants are.

Barry Rittberg, MD gave a presentation at the Minnesota Psychiatric Society in May 2014 and reviewed the science, clinical trial data, and local protocols for ketamine infusions in Minnesota.  The major problems were short term benefit, unknown long term risk,  inability to drive that day,  psychotomimetic effects, and the 3-4 hour time commitment for the infusion.  The protocol discussed involved a 40 minute infusion with monitoring blood pressure, pulse and oxygen saturations every 15 minutes.  Treatments were given 3 days a week for three weeks.  In addition, insurance companies did not cover the treatment (and still don't).  The treatment is not FDA approved and therefore considered experimental by insurance companies.  

The main emphasis of research studies on ketamine and other agents is the potential importance of the glutamatergic system in the treatment of depression.  It also has a purported role in schizophrenia.  There was a good review in an excellent journal Clinical Pharmacokinetics that suggested the (S)-ketamine had a more favorable side effect profile than the racemate.  It was with that backdrop of information that I honed in on this article that popped up on my Facebook feed.  After the first few pages I knew that I was not going to be disappointed.

The authors of a Nature article (1) review the information in the above paragraphs as a rationale for their research and rapidly describe their series of experiments.  The animal research done in this paper is all rodent research to test the potential antidepressant, self-administration, drug discrimination, chronic corticosterone induced anhedonia, and motor coordination effects effects of various glutamatergic compounds.  All of these paradigms and much more are detailed in the supplementary and methods section of the online paper.  Tissue distribution and clearance of ketamine and metabolites was determined in both plasma and brain at 10, 30, 60, and 240 minutes post ketamine administration.

In the first set of experiments, the researchers showed that (R)-ketamine had greater antidepressant potency in three antidepressant predictive tasks - the mouse forced swim test (FST), the novelty-suppressed feeding task (NSF) and the learned helplessness task.  They also showed that this was not due to higher brain levels (R)-ketamine versus (S)-ketamine.  The NMDAR antagonist MK-801 was also shown to not exert the same effects as ketamine, suggesting that the mechanism was more complex than inhibition.  The most interesting part of this paper was the examination of ketamine metabolites and their potency as potential antidepressants.  Ketamine is metabolized by CYP3A and CYP2B6 hepatic enzymes mostly to norketamine, but a number of transformations including dehydrogenation, and hydroxylation to a broad array of metabolites as shown in the authors' graphic below (click on the graphic for a more readable version).

The HNK (hydroxynorketamine) metabolites are the major metabolites found in the plasma and brains of mice after ketamine administration and the plasma of humans.  When greater antidepressant effects were noted in female mice, it was determined that the levels of (2S,2S;2R,6R)-HNK were three times higher in females than males.  In order to confirm that this metabolite was the most potent, a deuterated form of ketamine was synthesized.  The deuteration significantly slowed the metabolism of the parent compound and the antidepressant effects were eliminated largely by blocking the formation of  (2S,2S;2R,6R)-HNK.  The (2R,6R)-HNK derived from (R)-ketamine was subsequently determined to be the most potent metabolite (as highlighted in the above metabolic map).

The authors went on to confirm that (2R,6R)-HNK increased glutamatergic signalling in a number of paradigms.  They also demonstrated that administration led to expected changes in AMPARS (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors).  Drug discrimination and self-administration tests showed no tendency for self-administration with the (2R,6R)-HNK as opposed to ketamine.  In the same experiments ketamine was self administered and increased amounts were taken.   The (2R,6R)-HNK metabolite also did not cause motor incoordination or increased locomotion like ketamine did.

The implications of this paper are far reaching in terms of possible therapeutic agents.  It clarifies that the molecule involved in treating depression may be a significantly different structure than ketamine.  Second, that structure seems to have none of the side effects of the parent compound in animal models.  This paper also has implications for human research.  A search on HNK in the medical literature shows no evidence that it has ever been administered to humans.  A search on ClinicalTrials.gov shows no current research with the compound.  People are receiving infusions of ketamine for both chronic pain and chronic depression.  The infusions are done in clinics where patients need to monitored closely largely because of the side effects of ketamine.  The research done in this paper suggests that the administration of the active metabolite of ketamine may open the door for a less invasive and time intensive treatment for chronic depression.  I liked the idea that this paper discussed the relevant chemistry and pharmacology - undergraduate and medical school knowledge that is still relevant.  I also liked the idea that it potentially demystifies a hallucinogenic drug.  I have seen the newspaper headlines: "Club drugs to treat your depression."  I doubt that they will be replaced by: "(2R,6R)-HNK to treat your depression" anytime soon.

But the nullification of another urban drug legend is always a positive from my perspective.


George Dawson, MD, DFAPA      



References:

1: Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016 May 4. doi: 10.1038/nature17998. [Epub ahead of print] PubMed PMID:27144355.

2: Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet. 2016 Mar 30. [Epub ahead of print] Review. PubMed PMID: 27028535.

Supplementary:

1:  The figure labelled Extended Data Figure 1 is from reference number 1 (above) and is used with permission from the Nature Publishing Group - license number 3863110054693 obtained on May 6, 2016.

2:  Shortly after writing this post I came across this reference suggesting the postsynaptic signalling mechanism responsible for the "ketamine" effect.  I have not read the article yet since it is not open access, but if they were really using ketamine to induce the effect it would be more interesting if they compared (2R,6R)-HNK to ketamine and other metabolites in this model.  It could provide confirmatory data on whether (2R,6R)-HNK is in fact the active metabolite.

Harraz MM, Tyagi R, Cortés P, Snyder SH. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry. 2016 Mar;21(3):313-9. doi: 10.1038/mp.2015.211. Epub 2016 Jan 19. PubMed PMID: 26782056.