maps • volume xvii number 1 • spring~summer 2oo7 23
Ketamine: Peril and Promise
Those following science news will have noticed some recent
buzz about ketamine. What’s going on?
Carlos Zarate Jr., MD, of the National Institute of Mental
Health (NIMH) recently injected 18 patients who had treatment-
resistant depression with ketamine and found that their depres-
sion significantly improved within hours - an improvement that
R. Andrew Sewell, MD lasted for up to a week after a single dose.1 This is in striking
firstname.lastname@example.org contrast to conventional antidepressants, which have to be taken
every day and need weeks to months to have any therapeutic
effect. The importance of these findings was articulated by the
NIMH director, Thomas Insel, MD: “To my knowledge, this is the
first report of any medication or other treatment that results in
such a pronounced, rapid, prolonged response with a single
dose.” This study corroborates earlier findings by researchers in
2000 who gave ketamine to seven depressed patients and noted a
Veterans began to return remarkable and lasting remission of depression in all of them.2
to the United States
By coincidence, Zarate was an attend- 1). It was invented in 1962 by the phar-
with unusual stories ing physician at the medical center where macist Calvin Stevens and patented in
I did my training, and I remember well 1966 by Parke-Davis for use as an anaes-
about psychedelic the dismay everyone expressed when he thetic in humans and animals. It is a
left for bigger challenges at NIMH, as he neurotransmitter antagonist that blocks
experiences they was renowned for his excellent clinical excitatory glutamate from reaching the N-
skills and teaching ability. Strangely methyl-D-aspartate (NMDA) receptor. In
had experienced enough, I don’t remember his ever higher doses, it also stimulates the mu and
expressing an interest in psychedelic sigma opiate receptors and increases
while on the drugs! epinephrine and endorphin levels. It
Given that this is a major positive affects primarily the hippocampal forma-
operating table… news story related to psychedelic drugs, it tion (responsible for memory) and the
is perhaps worthwhile to step back and prefrontal cortex (responsible for abstract
see what work has been done with this thought), explaining its profound effects
unusual psychedelic and where we might on both.
see ketamine research leading. Ketamine saw initial use in army field
What Is Ketamine? hospitals in Vietnam – where it was
Ketamine is an arylcyclohexylamine, considered useful because it acts quickly,
the same class of drugs as allows rapid recovery, and depresses
dextromethorphan (DXM, “robo”) and consciousness without disrupting breath-
phencyclidine (PCP, “angel dust”) (Figure ing or circulation, unlike most
24 maps • volume xvii number 1 • spring~summer 2oo7
anaesthetics. This means that monitoring Moore, who penned one of the first
and support by an anaesthesiologist is not descriptions of the effects of ketamine in
necessary, and a single surgeon can in her autobiography Journeys Into the
theory perform an operation unaided.3 Bright World, vanished one night under
Veterans began to return to the United the influence of ketamine in 1979, and
States with unusual stories about psyche- her skeleton was found in a tree two years
delic experiences they had experienced later.6 Ketamine slowly acquired a reputa-
while on the operating table, however. tion for insidiously trapping those who
Similar to LSD, ketamine induces vibrant really knew better. The psychedelic was
hallucinations, but unlike LSD, ketamine added to the Drug Enforcement
lasts only an hour or so and induces an Administration’s “emerging drugs” list in
“out-of-body” state similar to that of a 1995, then moved to Schedule III – the
near-death experience. In 1965, professor same class as buprenorphine and anabolic
Unlike most Edward Domino coined the term “disso- steroids – in 1999.
ciative anaesthesia” to describe ketamine’s Medical Use of Ketamine
of the other trancelike effects.4 Interest in the psycho- Why, given ketamine’s evident
logical effects of the new drug spread dangers, was it not put into Schedule I
psychedelic drugs, rapidly. Karl Jansen, MD, PhD, who instead? Schedule I is reserved for drugs
devoted his entire career to understanding with “no currently accepted medical use,”
society never really lost ketamine from the receptor to the social and the medical uses for ketamine are
level, came to believe that ketamine had plentiful. Aside from applications on the
sight of the benefits potent healing powers (see Ketamine: battlefield and in veterinary medicine,
Dreams and Realities, published by lower doses also appear to be helpful in
of ketamine… MAPS). By the mid-1970s ketamine was managing chronic pain conditions. When
being used in Argentina to regress clients pain fibers from an injury site activate,
“back to the womb,”5 and psychotherapeu- they trigger a chain reaction that changes
tic use continues to this day. This use is the structure of the pain neurons them-
even reflected in popular culture. An X- selves. These changes can sometimes
Files episode in 1993 (“Demons”) featured provoke the neurons to fire even more, in
Agent Mulder being given ketamine by a an out-of-control feedback loop called
rogue doctor in order to help him recover spinal sensitization, or the “wind-up”
his lost memory. phenomenon, that creates even more pain.
However, recreational use of ket- Unlike most anaesthetics, ketamine’s
amine also mushroomed over the same NMDA-receptor (and thus long-term
period, together with scare stories in the potentiation) blocking effects prevent this
media. It was immediately dubbed a “date- sensitization. At doses of 0.1 to 0.5 mg/
rape” drug, just as MDMA and GHB had kg/h, ketamine is useful as a local anaes-
been in turn, despite the fact that the drug thetic and as a treatment for chronic pain.
most overwhelmingly implicated in rapes It acts synergistically with opioids to
is alcohol. Alarm started to grow within further improve pain relief and is particu-
the psychedelic community as well, for larly useful in treatment of pain that is
different reasons. Although psychedelic caused by cancer.7
drugs are generally considered to be One form of pain resulting from
nonaddictive, ketamine seemed to be the sensitization is called complex regional
exception. The American researcher Dr. pain syndrome (CRPS), in which a
John Lilly, well versed in other seemingly minor trauma becomes more
psychedelics such as LSD, found his painful with time rather than less and is
ketamine use spiralling beyond his accompanied by changes in the skin and
control, and he nearly drowned once autonomic response in the affected limb.
while under its influence. D.M. Turner, The pain can be severe and is often both
author of The Essential Psychedelics chronic and resistant to conventional
Guide and Salvinorin - the Psychedelic therapy. In 2002, a team in Germany led
Essence of Salvia Divinorum, also became by Ralph-Thomas Kiefer, MD, kept six
addicted and was finally found drowned patients with CRPS unconscious with a
in a bathtub at the age of 34, having continuous ketamine infusion for a week
succumbed during a ketamine trip. Marcia and found that four were cured and two
maps • volume xvii number 1 • spring~summer 2oo7 25
were relieved of their pain for one and Psychotherapeutic Use
three months respectively.8 Mindful that a of Ketamine
week of intensive monitoring in the ICU During the late 1960s, Lilly conducted
is seldom a practical treatment for any- initial research with ketamine as an agent
thing, G.E. Correll’s group at Penn State to induce nonordinary states of conscious-
Hershey Medical Center reviewed the ness. He was the first to characterize the
medical records of 33 patients given low- relationship between dosage and the
dose (subhallucinogenic) ketamine for nature of the ketamine experience.15
CRPS instead and found that three- Jansen has since argued that rather than
quarters had experienced complete pain using ketamine as an adjunct to psycho-
relief and 31 percent were still pain-free therapy, in the way that MDMA is typi-
six months later.9 This was enough to cally useful, the altered state induced by
prompt a prospective trial in which 40 ketamine is in itself therapeutic. Its
patients with CRPS were given resemblance to a near-death experience …ketamine
subhallucinogenic doses of ketamine. can have a similar effect as an actual near-
They reported significant pain relief that death experience. For example, it can might be useful
lasted for weeks in most of the patients supposedly reduce anxiety about death,
and caused a permanent remission in increase altruism, and make people less in the treatment
three.10 concerned with material goals.
There are also suggestions that In 1973, the Iranian psychiatrist E. of heroin
ketamine might be useful in the treat- Khorramzadeh, MD, published the first
ment of heroin withdrawal. In one recent report on the use of ketamine as an withdrawal.
study, 58 opiate-dependent patients were adjunct to psychotherapy.16 His patients
given “ultra-rapid detox” under general reported a number of different effects.
anaesthesia with either ketamine or Many vividly recalled painful childhood
placebo saline infusion.11 The ketamine events. “I always desired to make nasty
group had noticeably better control of remarks but dared not,” said one. “The
withdrawal symptoms, although there injection took away the discomfort in my
was no difference in abstinence between chest,” reported another. “My heavy
the two groups four months later. burden of sin is gone now,” “I now feel
More recently, the Department of care-free, with no worries,” and “As a child
Defense has become interested in devel- I always wanted to shout but they did not
oping an intranasal ketamine spray for let me,” were other responses. Ninety-one
battlefield use.12 Presumably an injured percent of the patients were still doing
soldier on ketamine is more able to guide well six months later. A later study by the
a tank to safety than one sedated with same researcher attempted to predict
morphine! response to ketamine based on personality
Finally, a remarkable case of rabies type (as measured by an Iranian version of
survival mediated by ketamine was the Eysenck Personality Inventory) and
reported two years ago in the New found that pleasant experiences were well-
England Journal of Medicine.13 A 15-year- correlated with high “Extraversion” scores,
old girl did not report that she had been whereas unpleasant trips were had by
bitten by a bat until it was already too those with low scores.17 A decade later,
late. Reasoning that the virus could not Hanscarl Leuner, MD, one of the earliest
multiply in nonfunctioning neurons, pioneers of LSD therapy in Europe and
Willoughby and his team flatlined her on author of the encyclopedic volume Hallu-
ketamine for over a week, halting the cinogens, was using ketamine as a psycho-
spread of the virus and giving the girl’s therapeutic agent at his psycholytic
immune system time to activate and treatment center at the University of
eliminate the disease, thus saving her life. Gottingen.
Initial enthusiasm for this method has Later still, across the Atlantic, a British
been tempered by four subsequent team found that by combining ketamine
attempts that have not been such re- (to block long-term potentiation and
sounding successes, however.14 stimulation of compulsive behavior) with
an opioid blocker (to prevent loss of
consciousness), patients with refractory
26 maps • volume xvii number 1 • spring~summer 2oo7
anorexia nervosa completely lost their first rapid-acting antidepressant. Scientific
compulsive thoughts with repeated merit is clearly in the eye of the beholder.
doses.18 “The speed with which a person But the giant in the field of ketamine
changed from the high arousal, compul- psychotherapy is surely Evgeny Krupitsky,
sive state to the more normal state was MD, PhD, chief of the research laboratory
occasionally fast enough to resemble a at St. Petersburg Regional Center of
change in personality,” they noted. “This Addictions and Psychopharmacology, who
It is gratifying was particularly so with patient 8, whose has been researching the treatment of
husband described her as changing back to alcoholism and addiction with ketamine
to see that NIMH the personality he knew when he first since the 1980s and hopes to extend his
married her. The patient found the speed research to encompass post-traumatic
is following MAPS’ of change difficult to adapt to in the first stress disorder in the near future.
week.” More than half of the patients In 1985, he developed ketamine
lead in supporting showed a return to normal eating behavior psychedelic therapy - which was initially
that persisted long after discharge from merely a method for increasing suggest-
the treatment of the hospital. ibility and enhancing aversive treatment
Ketamine’s effects on depression were for alcoholism - publishing his first report
psychiatric disorders first noticed by a team led by psychiatrist on the method in 1992.21 He found that
John Krystal at Yale, who was studying ketamine induced total abstinence in 66
with psychedelic ketamine as a way of understanding percent of his alcoholic patients (versus 24
schizophrenia by deliberately inducing percent of the nonpsychedelic control
drugs. psychosis. “For many, it was a huge, group) for as long as a year. He observed
obvious effect,” said Krystal. “One of the improvement in personality profile,
patients said, ‘Don’t give me those old positive transformation of self-concept
medications, I want this again’.” At the and emotional attitudes to various aspects
time, this was just an incidental finding, of self, positive changes in life values, and
however. Because the behavioral effects of improved spiritual development in the
ketamine resemble those of schizophrenia ketamine group.
and dissociative states, Krystal reasoned What is the contribution of the
that ketamine administration would be an psychedelic experience to this improve-
ideal way to study such states, which he ment? Krupitsky posited nine factors:22
then proceeded to do, in both normal 1. Stable, positive psychological changes.
controls and schizophrenics, unwittingly 2. Personality growth and self-cognition.
illustrating one of the hazards of psyche- 3. Important insights into existential
delic research. Following a blistering problems and the meaning of life.
expose in the Boston Globe in 1998 4. Transformation of one’s “life value
alleging irresponsible Nazilike administra- system.”
tion of psychedelics to helpless mental 5. A change of view of one’s self and the
patients,19 some advocacy groups, such as world around.
Citizens for Responsible Care in Psychia- 6. Insight into life and death.
try and Research, called for a complete 7. A rise of creative energies.
moratorium on such “challenge” studies, 8. Broadening of spiritual horizons.
and two months later the NIMH re- 9. Harmonization of a person’s relation-
sponded with a shutdown of Krystal’s ships with the world and with other
ketamine research for “lack of scientific people.
merit.” Although the subsequent, more In 1991, another Soviet psychiatrist,
sober debate among the scientific commu- Igor Kungurtsev MD, who had initially
nity ultimately concluded that his studies worked with Krupitsky and later immi-
were in fact conducted ethically,20 and grated to the United States, published a
they were permitted to continue, albeit in summary of his own experiences treating
a more cautious fashion, the episode is a alcoholism with ketamine.23 Although,
sobering reminder of the potential risks of like Krupitsky, he initially felt that
psychedelic research to the researchers ketamine simply made alcohol aversive in
themselves, if not the subjects! Krystal’s a purely behavioral way, he radically
work ultimately led to Zarate’s study, changed his approach following a series of
which could potentially lead to the world’s ketamine self-administrations and instead
maps • volume xvii number 1 • spring~summer 2oo7 27
adopted a transpersonal model for therapy therapy had over twice the rate of
in order to better utilize the profound abstinence of those receiving only a
mystical experiences induced by ketamine. single session. This contradicts the notion
He found that successful treatment of that psychedelic drugs somehow repre-
alcoholism with ketamine was correlated sent a “magic bullet” or “instant miracle
with a changed spiritual outlook in the cure” by showing that a single adminis-
same way that 12-step programs also tration of a psychedelic drug is often not
achieve success by changing addicts’ fully effective.
spiritual outlook, albeit in a Like any powerful drug, ketamine
nonpsychedelic manner. carries with it considerable danger as well
MAPS’ Support for as profound potential for benefit. Unlike
Ketamine Research most of the other psychedelic drugs,
It is gratifying to see that NIMH is society never really lost sight of the
following MAPS’ lead in supporting the benefits of ketamine because its applica-
treatment of psychiatric disorders with tions in anaesthesia were so obvious.
psychedelic drugs. MAPS has long been a Now the psychological benefits of
supporter of Krupitsky’s work, co-funding ketamine at lower doses are becoming
(with the Heffter Institute) his recently apparent also, we can hope to see a
published study on the treatment of renaissance in ketamine research that Figure 1: The structure of ketamine
heroin addiction with ketamine.24 will translate into increased acceptance
Krupitsky and his team found that heroin- for other research with psychedelic
dependent subjects receiving three drugs as well. •
sessions of ketamine-assisted psycho-
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[online]. Available at: http://ir.javelinpharmaceuticals.com/
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