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).

Better Living Through Pharmacology

One of the great unspoken biases in psychopharmacology is the belief system about the medication.  What is the medication supposed to do after all?  Is it supposed to be life-changing in terms of positive improvements?  Is it supposed to eradicate all types of depression and anxiety?  Is it supposed to create the perfect cognitive and emotional state?  Is it supposed to turn an average student into an MIT professor?  Is it just supposed to treat a symptom and if so - how many symptoms?  Does it need to address some underlying physiological disturbance or can anyone take it and get the same benefits?  These are all unspoken biases about psychiatric medications that need to be explored with people who are taking the medications.  I don't think that a psychiatrist should even take for granted that a patient knows the difference between depression or anxiety or why thinking that Attention Deficit Hyperactivity Disorder (ADHD)  with essentially no impairment in professional, academic, or social life is not the same as having that diagnosis.

One of the best examples is the myth of the perfect mind.  If ADHD is finally diagnosed and treated, that means the person's mental functioning will either be normalized or be much better than it was in the past.  It should be possible to read entire book chapters and even books for the first time.  That is true isn't it?  It turns out that the effects of most medications for ADHD are modest and rarely life changing.  I have talked with many people who had clear diagnoses of ADHD as children who did not like the side effects of the medication and stopped taking it or even faked taking it in school.  They developed strategies for coping in the world and were able to achieve academic and vocational success.   Even some of the strongest proponents of medical treatment of ADHD will agree that proper care also involves lifestyle and management strategies and in some cases formal therapies in addition to medication.  That does not mean that some people will not do better with medications and worse with lifestyle modification, but it does mean that there is much more latitude in the treatment of this disorder than is commonly assumed.  It is fair to say that in many clinics these days, there are clinicians actively looking fro any treatable psychiatric disorder.  The theory seems to be: "If I treat the social anxiety disorder, bipolar disorder, ADHD, panic attacks, and insomnia this person will be a lot better off."  There is really no evidence that this is true or that there is even a good way to select what disorders should be treated first.

The patient side of this problem seems to be the myth of the perfect mind extended to many conditions.  It is evident in a number of ways.  Some people present with some very basic knowledge of psychopharmacology.  They may suggest that their "serotonin" or "dopamine" is out of whack and that they heard that there are specific medications to correct that.  In some cases they will suggest a medication.  In other cases, a person will not be very stress tolerant and suggest that they need something that will either reduce day to day stress or significant stress from predictable major life stressors like the disruption of a job or relationship.  They seem to think that there is a medication that will both reduce the emotional reaction to this pain but also remove the cognitive elements from their mental life.  Depending on the person's baseline cognitive state, they can become quite demanding if they think that they are not getting adequate relief or it is not happening fast enough.  The risk in these situations is starting to take a number of medications with substantial side effects that frequently precludes them getting back to their baseline conscious state.  There is often a focus on a person's baseline in psychiatry or medicine, but that baseline is almost never adequately characterized.  That is true in the case of blood pressure but more true in the case of mental illnesses.  In the case of severe mental illnesses like bipolar disorder baseline is almost always defined in terms of the presence or absence of a few symptoms.  Wide areas of a person's life like their baseline intellectual functioning, social behavior, and typical stream of consciousness are rarely considered - even in research studies.

Addiction makes everything worse and therefore it also provides the best illustration.  The graphs at the top of the page show two drug response curves with the blue lines showing a good response.  A person who is using an addictive drug and the high risk response to that drug is conditioned to expect the drug response curve on the right - a continued therapeutic response for increasing doses of the medication.  In that case there is no element of safety or toxicity.  True drug responses are represented by the curve on the left - an interval of response followed by toxicity and limited response at the higher levels.  Addictions have a second effect by creating a bias that mental states can be fine tuned within the space of hours by drugs.  Any feeling state can be immediately modified by the addition of benzodiazepines, stimulants, opioids or alcohol.  This is often erroneously referred to as "self-medication" and it is a strong conditioned response that generalizes to the treatment of disorders with non-addicting drugs.

The psychological effects of these patterns are significant.  They can lead to continued addiction and disrupted care.  A person may have the belief: "If this doctor can't give me something that will get rid of the negative way I feel right now - I will take something to get rid of it."  It may lead to disruption of the therapeutic alliance, through anger and open criticism about the lack of immediate effects or minimization of physician concern about side effects and a general lack of concern about toxicity on the part of the patient.  There is often an associated belief: "I have a very high tolerance for drugs and you can give me higher starting doses and higher maintenance doses of drugs than you give most people."  Many people in this situation experience very high levels of anxiety if they are not getting high doses or the physician does not seem to be increasing the medication fast enough.

The thoughts and feelings about medications is one of the most difficult areas in psychiatry.  Contrary to what is written by critics - nobody is complaining about being overmedicated.  Most of the complaints I hear about are about not getting enough medication and not getting to those high doses fast enough.  The solution is rarely to provide the medication and amount requested.  The solution is to spend enough time talking with the patient about these issues.  I generally start with the limitations of the defined treatment and a medication strategy that is risk avoidant.  In that initial conversation I usually tell the person whether or not they have a diagnosis or if I agree with a pre-existing diagnosis.  If I detect signs that unrealistic expectations about the medication are present I move into that area, point out that the medication will not lead to a perfect mind, and what they have to do in addition to taking medication.  If I find that they are really focused on medication issues to the point that they are experiencing anxiety from it - I usually encourage them to think about something else and provide some examples of what else can be done.

There is some literature on psychodynamic issues and medication in the transference that I have not found very useful. I suppose you could say that from what I have written the medication has meaning far beyond its pharmacology.  There is an interpersonal and intrapsychic context.  I think it is addressable in what is usually considered straightforward supportive psychotherapy, but it definitely needs to be addressed.  It is a frequent cause of medication or treatment "failures".


George Dawson, MD, DFAPA