Ketamine The Story of Modern Psychiatry's Most Fascinating

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 i

KETAMINE
The Story of Modern Psychiatry’s
Most Fascinating Molecule

By

Keith G. Rasmussen, M.D.

Professor of Psychiatry, Mayo Clinic, Rochester, Minnesota
 ii

Note: The author has worked to ensure that all information in this book is accurate at the time of
publication and consistent with general psychiatric and medical standards, and that information
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Library of Congress Cataloging-in-Publication Data
Names: Rasmussen, Keith G., author. | American Psychiatric Association Publishing, issuing body.
Title: Ketamine : the story of modern psychiatry's most fascinating molecule / by Keith G.
Rasmussen.
Description: Washington, DC : American Psychiatric Association Publishing, [2024] | Includes
bibliographical references and index.
Identifiers: LCCN 2024003272 (print) | LCCN 2024003273 (ebook) | ISBN 9781615375448
(paperback ; alk. paper) | ISBN 9781615375455 (ebook)
Subjects: MESH: Ketamine | Phencyclidine | Mental Disorders--drug therapy | Phencyclidine Abuse
Classification: LCC RD86.K4 (print) | LCC RD86.K4 (ebook) | NLM QV 81 | DDC 615.7/81--
dc23/eng/20240228
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British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
 iii

For Gemma and Sigrid – Salamat

 v

Contents

About the Author

1 Ketamine’s Precursor: The Discovery of PCP

2 The Birth of Ketamine

3 Recreational Use of Ketamine: The World Discovers the K-

Hole

4 Pharmacology of Ketamine

5 The Ketamine Model of Schizophrenia

6 Ketamine for Chronic Pain

vi

7 Ketamine for Depression

8 Other Uses of Ketamine in Psychiatry: Anxiety Disorders,

Substance Use, and Psychotherapy Augmentation

9 Is Ketamine a Neuroprotectant or a Neurotoxin?

References

Index
 vii

About the Author

Keith G. Rasmussen, M.D., is Professor of Psychiatry at the Mayo Clinic,
Rochester, Minnesota.

Disclosure
Dr. Rasmussen stated that he had no competing interests during the year
preceding manuscript submission.
1
 Chapter 1

Ketamine’s Precursor: The Discovery

of PCP
KEY POINTS IN THIS CHAPTER:
PCP was synthesized in 1956 by Harold Maddox.

PCP was developed as an anesthetic drug, but it caused emergence

agitation.
Most eventual uses of ketamine were presaged by PCP.

What is ketamine? To Calvin L. Stevens, Wayne State University chemistry

professor and consultant to the Parke-Davis pharmaceutical company, it
was one of the compounds he synthesized in his laboratory in 1962. To his
bosses, the Parke-Davis executives, it was a potentially profitable
medication. To Edward Domino, a University of Michigan pharmacologist,
it was a drug with interesting psychological effects. To John Krystal, Yale
University psychiatry professor, it is a neuropharmacological probe to study
the neurobiology of schizophrenia. To anesthesiologists, it has proved to be
an excellent anesthetic that does not suppress respiration or blood pressure.
To the field of psychiatry, it is a simple-looking molecule that has breathed
new life into a stale and anemic psychopharmacopeia. To modern practicing
psychiatrists, it is much-needed relief from the grinding drudgery of
prescribing pills that don’t work very well. To some entrepreneurial doctors
who oversee ketamine clinics, it is a precious commodity with which to
enrich themselves. To chronically depressed people, it is hope that they
don’t have to spend their lives thinking about suicide. To the psychedelic

2
connoisseur, it is a pathway to enlightenment. To the ketamine addict, it is a
pathway to hell.
Like no other compound, whether prescribed by doctors or used
recreationally, ketamine has a perplexing duality about it. Does it protect
the brain or damage it? Does it cause addiction or treat addiction? Does it
worsen psychiatric disorders or cure them? Does it lead to philosophical
insight or just a fool’s drug high? Some people who take this drug love it;
others hate it.
Of all the molecules in modern psychiatry, ketamine is the most
fascinating. Think about it—what other molecules could be considered
more charismatic? Are any of the other drugs we introduce into people,
such as antidepressant, antipsychotic, antianxiety, antimanic, stimulant, and
hypnotic agents, really that engrossing? Most of them are weakly active at
best and barely distinct from placebo. Thus the intense interest in ketamine.
And then of course there are all the innumerable molecules inherent in the
human brain. Dopamine, serotonin, and norepinephrine captured the
imagination of psychiatry for three decades but seem rather tired now,
yesterday’s news. The old notions that psychosis is caused by “too much
dopamine” and depression by “too little serotonin or norepinephrine”—
hypotheses that seemed so sophisticated in the 1970s—now seem
ludicrously simplistic. All the other neurohormones and neuromodulators
have caused but the barest ripples of interest.
No, in modern times it is ketamine that stands head and shoulders above
the others in fascination. Just open an internet browser, enter “ketamine,”
and appreciate the media and scientific interest in this compound.
In this book, the story of ketamine is told. It is the author’s wish that, as
he has been captivated by this story, so too will the reader. Since its first
synthesis in 1962, ketamine has generated a great deal of excitement and
has traversed several pathways. These include anesthesiology and pain
medicine; psychedelic drug use; the neuropharmacology laboratory to study
psychotic processes such as schizophrenia, brain damage, and
neuroprotection; and most recently, psychopharmacology to treat
depression and other psychiatric disorders. It is on a steep trajectory, and it
is not clear where—to a revolution in psychiatry, perhaps? Or a dead end
like lobotomy?
 In this book, the various ways in which scientists and others have
studied and used this drug are reviewed. But first, as a launching point, we
cover the backstory—how did this versatile molecule come about?
Biographies of people begin with a description of the main character’s
parents. In like manner, seeing this book as a biography of ketamine, we
begin with ketamine’s “parent,” an interesting, unusual, and even legendary
compound: phencyclidine (aka PCP, aka angel dust). Virtually all of the
pathways traversed by

ketamine over the decades really begin with phencyclidine. So, where did
PCP come from?

The Discovery of Phencyclidine

The story begins with a chemist born in 1871 in Cherbourg, France, with
the regal-sounding name of François Auguste Victor Grignard (pronounced
roughly “greenyar”). Dr. Grignard won the Nobel Prize for chemistry in
1912 for discovery of a type of chemical reaction that now bears his name.
The Grignard reaction allows the formation of carbon-carbon bonds, which
is enormously helpful in the chemical synthesis of thousands of useful
compounds. Grignard reagent refers to organometallic halides (an organic
moiety attached to usually magnesium bromide), which are used to effect a
wide variety of chemical syntheses.
In the early part of the twentieth century, Grignard reagents turned out
to be critical for the synthesis of a type of compound at the beginning of the
pathway that led to PCP and ketamine. This class of compounds, known as
the arylcyclohexylamines, consist of three parts: an aryl group, a cyclohexyl
group, and an amine group. An aryl group is aromatic, a cyclic structure
that is planar and very stable. A cyclohexyl group is based on cyclohexane,
a six-membered ring of carbon atoms that is not aromatic, meaning the six
carbon atoms are not coplanar. An amine group contains a nitrogen atom,
which may be part of a ring of carbon atoms, or attached to two hydrogen
atoms, or a carbon-based group such as a methyl or ethyl group.
 Arylcyclohexylamines have interesting biological activity. In 1956, Dr.
Harold Maddox, a chemist working for Parke-Davis in Detroit, Michigan,
was looking into this class of compounds as possible analgesics or sedatives
(Maddox 1981). Using an old reagent with the barely pronounceable name
of piperidinocyclohexanecarbonitrile, he added “phenyl Grignard,”
otherwise known as phenylmagnesium bromide, a Grignard reagent. After a
few more steps, the final product was the arylcyclohexylamine compound
now known as phenylcyclohexylpiperidine—or phencyclidine. The aryl
group of PCP was a phenyl group, with the amine group being a piperidine
ring, of course with the cyclohexyl ring that is always present in an
arylcyclohexylamine. The molecular structure of PCP is outlined in Figure
1–1. Note that the phenyl and amine groups are geminal, which in
chemistry means they are bonded to the same carbon atom on the
cyclohexyl group. Several names for this new compound emerged over the
years: CI-395 (as denoted by the drug company before a common name was
agreed on), Sernyl, Sernylan, and, on the street, the notorious angel dust.

FIGURE 1–1. The molecular structure of PCP (phenylcyclohexylpiperidine or

phencyclidine)

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So the year is 1956, and chemist Maddox, relying on Grignard reactions,
has synthesized this new compound, phencyclidine. What next? Maddox of
course had no preexisting idea what clinical applicability PCP might have.
It was synthesized in the hope of finding a better sedative or analgesic drug,
hot chemical commodities in those days. In pharmacological drug
development, before a compound can be used in humans, it is first used in
animals to test for basic safety and see whether there is a signal for efficacy.
Thus, CI-395 was handed over to animal pharmacologists for
experimentation.

Animal Testing: The Rise of PCP

The first person to take custody of the newly synthesized PCP was expert
animal pharmacologist Dr. Graham Chen, a Parke-Davis employee. When
Maddox synthesized PCP, he was looking for a sedative or analgesic. Thus,
Chen started experimenting to see whether PCP had such properties in
various animal species, and also of course to see whether it was safe (Chen
1981). He and his colleagues published an initial detailed description (Chen
et al. 1959). They studied PCP in rats, mice, rabbits, guinea pigs, dogs, cats,
hamsters, monkeys, pigeons, frogs, and fish. The investigators noted that
PCP caused either behavioral stimulation (usually at high doses) or
depression (mainly at low doses), effects that varied by species. For
example, rats and mice tended toward excitation, and other species tended
toward depression or a cataleptoid state, an expression that appears
frequently in the PCP and ketamine literature of the 1960s. Derived from
the term catalepsy (when an organism assumes a fixed posture and does not
respond to stimulation, used to describe humans who are catatonic), a
cataleptoid state was considered the analogous phenomenon in animals. As
described by

Chen et al. (1959), PCP commonly caused a cataleptoid state in which the
animal would lie still and unresponsive and could be handled and even
surgically operated on without becoming agitated. That made PCP attractive
as a potential anesthetic drug. From low to high doses, Chen et al. (1959)
noted the following general progression of animal behavioral effects of
PCP: 1) being able to be handled; 2) cataleptoid state; 3) deep surgical
anesthesia; and 4) convulsions. At lower doses, PCP also prevented
pharmacologically or electrically induced seizures, thus raising the question
of whether it could be an antiepileptic drug. (The latter finding from the late
1950s progressed all the way to the present with PCP’s progeny, ketamine,
but that story is explored later.)
At PCP doses sufficient to induce anesthesia for surgery in animals,
respirations and blood pressure were not suppressed as happened with the
anesthetic agents then in use, mostly barbiturates. This finding was
enormously important: for some patient populations, it is desirable to
perform a procedure without having to give manual respirations or agents to
keep blood pressure from falling. Thus, the finding that PCP did not
suppress respirations or blood pressure was critical in instilling interest in
human trials. Although the Chen et al. (1959) paper focused on animals, the
authors did make the cryptic comment that PCP causes humans to react
“similarly as monkeys and cats.”
In a later publication, Chen and Weston (1960) focused on the effect of
PCP in monkeys. The animals would assume a “far-away look” with lack of
responsiveness, so that a procedure could be done. Upon awakening from
PCP, the animals remained calm. There was no behavioral toxicity with
PCP—the animals went into and out of the cataleptoid state without
agitation. Thus, to Parke-Davis executives, it appeared as though they may
have a blockbuster anesthetic drug on their hands, and they approved it for
experiments in humans. Little did they know what was about to be
unleashed.

Human Testing: The Fall of PCP

Filled with excitement and enthusiasm about this potential anesthetic, and
reassured about safety and efficacy in animals, Parke-Davis executives now
ordered human trials. They named the drug Sernyl.1 In those days of

6
relatively easy Food and Drug Administration (FDA) approval for new
drugs, Sernyl was granted approval in 1957, almost before human data were
even gathered. The drug company enlisted anesthesiologists at Detroit
Receiving Hospital to use PCP for anesthesia. The results were published
by Greifenstein et al. (1958). In initial dose-finding work, it was found that
0.5–1.0 mg/kg produced excitation or even convulsions, but doses of 0.25
mg/kg produced good analgesia.
At this point, some definition of anesthesiologic terms is in order.
Analgesia means lack of pain perception. Anesthesia means lack of any
sensation, which can be local (such as with lidocaine) or general. There are
no general anesthetic agents that do not also cause unconsciousness, or at
least a diminution of conscious awareness. Theoretically, in surgical or
other procedural work, what is needed is analgesia, so that the procedure
can be conducted without the patient having pain. Most true analgesics,
such as aspirin, acetaminophen, or even narcotic opioids, are not strong
enough for invasive procedures to be done comfortably. Thus, for surgeries,
general anesthetic agents are needed, and as noted, all of them cause
unconsciousness—or at least all of them until PCP.
What Greifenstein et al. (1958) discovered was that some of the patients
undergoing surgery (there were a total of 64) did obtain enough analgesia
with PCP that the procedure could be done, but some of the patients were
not completely asleep. The dose of 0.25 mg/kg was enough to cause
patients not to respond to auditory or painful stimuli. In about one-fourth of
the patients, some degree of excitation occurred during the surgery.
Postoperative euphoria, what seemed like an intoxicated state, was common
and lasted for many hours. Ten of the 64 patients were frankly agitated and
behaviorally unmanageable upon recovery from anesthesia, a phenomenon
called emergence delirium or emergence agitation (in this context,
emergence referring to emerging from the state of general anesthesia, or
regaining consciousness). Some had hallucinations. Interestingly, despite
the emergence agitation being quite prolonged (e.g., into the next day),
some patients had no memory of it or of the surgery. That was important,
because anesthesiologists do not want their patients to recall any aspect of
surgery, as such memories are quite traumatic and emotionally distressing.
Thus, amnesia (a gap in one’s memory) is a goal of anesthesia in addition to
analgesia.