The Story of Trendy Psychiatry’s Most Fascinating Molecule

Keith Rasmussen is Professor of Psychiatry on the Mayo Clinic
and the writer of an authoritative textual content on electroconvulsive remedy – Rules
and Observe of Electroconvulsive Remedy. 
I seen the pre-release literature on his guide on ketamine and waited
for months to get a replica.  After studying
it I can say it was among the finest books I’ve learn in psychiatry.

The guide is organized into 9 chapters.  The primary 4 are on the historical past and
pharmacology of ketamine.  That’s
adopted by 4 chapters on scientific purposes together with melancholy, as a
mannequin for schizophrenia, continual ache, different psychiatric issues, substance
use issues, and ketamine assisted psychotherapy.  There’s a last chapter on whether or not ketamine is
a neurotoxin or a neuroprotectant and a number of other experimental purposes are
mentioned.  Many of those chapters might
be freestanding critiques of the literature. In writing these critiques, authors
will usually use desk summaries both as a top level view or within the physique of the
assessment. Rasmussen makes use of one or two paragraph lengthy summaries of analysis papers
and is conscious that may be a tedious method. For that motive, he omits an extended
dialogue of preclinical analysis in a single chapter.

The preliminary chapter is an introduction to the molecule.  We study that it belongs to a category of
arylcycloaminohexanes and that phencyclidine (PCP) was the preliminary drug
synthesized from that class. PCP was invented to be used as a basic anesthetic,
nevertheless it failed due to extreme behavioral reactions.  Extra constructions have been synthesized from that
class and ketamine was finally developed on a preclinical foundation. The molecular
constructions of each compounds are supplied within the guide however the construction of
ketamine on web page 12 is in error (it reveals a chlorine atom in place 2 on a cyclohexane
quite than a phenyl ring however the IUAPC naming within the caption is right).  I’ve posted each constructions under.  The purported mechanism of motion is mentioned
in a number of locations – on the degree of the NMDA receptor and the way pathological processes
like excitotoxicity and apoptosis happen and could also be interrupted.

After I took my first medical faculty pharmacology course in
1984 – the opposed reactions have been famous within the anesthesiology part for each
PCP and ketamine.  Rasmussen writes like
a chemistry main who skilled natural chemistry as an necessary course. He
discusses detailed chemical constructions, reactions, stereochemistry, and the
Grignard response. These explanations have the aim of explaining of how
compounds are named and why the synthesis of ketamine is exterior of the
experience of native meth cookers.  On the
identical time, he doesn’t get too technical in terms of receptor binding
affinities (I didn’t discover a single Ok_i).  Past that he particulars the place ketamine is at the moment produced
(China, India, Mexico) and offers two instances of clandestine operations in
China that have been utilizing 8.5 million tons of ketamine precursor earlier than they
have been shut down by authorities (see Supplementary 1 footnote).

The guide is a radical documentation of the time course of
PCP and ketamine use.  He discusses
landmark papers and factors out analysis papers that have been in all probability the unique
observations and papers which can be extremely cited. 
As I learn the guide, I went to the references and underscored lots of
these papers.  The reference part
alone is 44 pages lengthy.

Every chapter concerning the potential scientific purposes of
ketamine is a by dialogue of the present literature and the constraints
of that literature. He discusses the analysis design of many of those research
and what analysis is required sooner or later. 
He discusses the unanswered questions on ketamine. 

Does the guide have any shortcomings.  A number of reviewers appear to explain needing
to be entertained by the books they’re studying. Nearly every thing I learn is a
scientific paper or guide.  A few of that
content material is thrilling, however typically I might not see it as entertaining.  The closest this guide involves being extra
tough to learn have been lengthy sections that summarize scientific papers. 

Do you have to learn this guide? 
Like all books – lots is dependent upon your degree of experience.  I think about myself to be an knowledgeable in each
ketamine and PCP based mostly on each my pharmacology information and what I’ve seen
clinically. I discovered lots studying this guide and I believe virtually all
psychiatrists and psychiatric residents will discover this guide helpful.  Neurologists are a further viewers for
the sections on neuroprotection in instances of traumatic mind damage, stroke,
subarachnoid hemorrhage, and standing epilepticus.

You will notice info on this guide that you’ll not learn
wherever else.  It’s footnoted to
scientific articles and the dialogue is even handed – the doable good and
the dangerous.  A thread runs by this guide
from the very first web page that every one human drug responses are difficult based mostly on
organic heterogeneity and a few of that may be age based mostly. Meaning there
aren’t any “miracle medicine” for everybody. 
There’s an in depth dialogue of the substance use features of the
drug and it’s introduced as a transparent hazard. 
I believe that every one acute care psychiatrists and residents may gain advantage from
studying this guide and it might type the idea of a journal membership or a resident
seminar in pharmacology. The model of writing jogged my memory of a textual content that I
think about to be probably the most effectively written – Fundamentals of Biochemistry by Voet, Voet, and Pratt.   

What about individuals on the opposite finish of the spectrum of
ketamine information?  There’s loads of
info on this guide that could be helpful to you.  The guide is effectively organized and
researched.  It has a wonderful index
that can include references that you simply wouldn’t have.  The knowledge density within the guide is way
larger than I anticipated from studying the preliminary chapter and introduction.  There are attention-grabbing historic factors
together with a piece of three very well-known ketamine customers, their experiences,
and publications associated to their use. 
If you’re concerned in a analysis challenge involving ketamine or PCP –
this guide is an effective supply of background info.  This guide also can doubtlessly profit
journalists tasked with writing about ketamine and different psychiatric
remedies.  

I actually like all the small print concerning the medicinal chemistry
of ketamine.  It jogged my memory of some
on-line discussions I’ve had with physicians who thought that natural
chemistry was an pointless prerequisite to medical faculty.  If you happen to share that opinion – chemistry at a
extra detailed degree than you usually see in a pharmacology textual content won’t
curiosity you.  It’s nonetheless there in an
accessible type. 

It is a superb guide – effectively researched and written. Dr.
Rasmussen presents a really even method to ketamine.  He presents the analysis and scientific
findings of what actually happens with using ketamine.  No hypothesis is concerned. It took quite a lot of
onerous work and gathered information to jot down this guide and any doctor
studying it can notice that. With a number of modifications the subsequent version of this
guide might develop into a basic textual content in psychiatry.

George Dawson, MD, DFAPA

Reference:

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

Supplementary 1:  The extra I believed concerning the determine quoted for precursor quantities used within the illicit manufacture of ketamine in China – the extra skeptical I grew to become.  The particular quote from the guide is:  “In 2009, Chinese language authorities seized two secret laboratories with a complete of 8.5 million tons of precursor materials, which is just gigantic!” (p. 44).  Since illicit manufacturing estimates based mostly on precursors are typically within the lots of of metric tons – hundreds of thousands of tons actually are gigantic.  From the primary reference (1) listed under:  

“China produces huge quantities of ketamine, dependable estimates for the prevalence of ketamine abuse are usually not obtainable. As of at present, 5 Chinese language factories are formally licensed to supply ketamine, however there are reviews of illicit manufacturing on an industrial scale. In 2009, Chinese language authorities reported the seizure of two illicit laboratories producing 8.5 million tons of the fast precursor of ketamine.”

On this case, the overall precursor was 8.5 million tons and the UN Drug Report (2) was referenced on the head of the paragraph.  From that report (web page 117):

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

Notice that the “mt” designation on this report is metric tons quite than million tons.  A metric ton is often outlined as 1,000 kg decreasing the dimensions of this estimate by about 2 million fold (8,500 kg in contrast with 7.7 million kg), however that’s clearly nonetheless a major quantity of precursor.

Supplementary 2:  This interview of the writer grew to become obtainable within the Psychiatric Information on this date (11/5/2024)  

Ketamine: Miracle Drug or Double-Edged Sword?