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).