Dr. Karl Jansen was born in New Zealand and trained in medicine at the University of Otago. After registering as a medical practitioner, he proceeded to carry out brain research at the University of Auckland as a research fellow of the New Zealand Medical Research Council. At this time he became interested in ketamine and its effects and published his first observations in this area, and also in antipodean use, users and consequences of psilocybin-containing mushrooms. He then went to the United Kingdom, and attended the University of Oxford (New College) were he completed a Doctor of Philosophy in Clinical Pharmacology. He was the Glaxo Fellow at Green College. On completion of his studies at Oxford, he went to the Maudsley Hospital and London Institute of Psychiatry to complete his training as a psychiatrist. He is now a member of the Royal College of Psychiatrists. His current research interests are the ketamine model of the near-death experience and the consequences of long-term, high dose recreational use of Ecstasy (MDMA).
He would like to receive correspondence concening the subject of this paper.
Dr. Jansen has the following to say about the journal article that follows:
'I am no longer as opposed to spritual explanations of these phenomena as this article would appear to suggest. Over the past two years (it is quite some time since I wrote it) I have moved more towards the views put forward by John Lilly and Stan Grof. Namely, that drugs and psychological disciplines such as meditation and yoga may render certain 'states' more accessible. The complication then becomes in defining just what we mean by 'states' and where they are located, if indeed location is an appropriate term at all. But the apparent emphasis on matter over mind contained within this particular article no longer accurately represents my attitudes. My forthcoming book 'Ketamine' will consider mystical issues from quite a different perspective, and will give a much stronger voice to those who see drugs as just another door to a space, and not as actually producing that space'.
There is overwhelming evidence that 'mind' results from neuronal activity. The dramatic effects on the mind of adding hallucinogenic drugs to the brain, and the religous experiences which sometimes result, provide further evidence for this (Grinspoon and Bakalar, 1981). One of the many contradictions which 'after-lifers' can not resolve is that "the spirit rises out of the body leaving the brain behind, but somehow still incorporating neuronal functions such as sight, hearing, and proprioception" (Morse, 1989, original italics).
All features of a classic NDE can be reproduced by the intravenous
administration of 50 - 100 mg of ketamine (Domino et al., 1965; Rumpf
,1969; Collier, 1972; Siegel,1978, 1980,1981; Stafford, 1977; Lilly, 1978;
Grinspoon and Bakalar, 1981; White, 1982; Ghoniem et al., 1985; Sputz,
1989; Jansen, 1989a,b, 1990b, 1993). There is increasing evidence which
suggests that the reproduction of NDE's by ketamine is unlikely to be a
coincidence. This evidence includes the discovery of the major neuronal
binding site for ketamine, known as the phencyclidine (PCP) binding site of
the NMDA receptor (Thomson et al., 1985), the importance of NMDA
receptors in the cerebral cortex, particularly in the temporal and frontal
lobes, the key role of these sites in cognitive processing, memory, and
perception, their role in epilepsy, psychoses, hypoxic/ischaemic and
epileptic cell damage (excitotoxicity), the prevention of this damage by
ketamine, the discovery of substances in the brain called 'endopsychosins'
which bind to the same site as ketamine, and the role of ions such as
magnesium and zinc in regulating the site (Anis et al., 1983; Quirion et
al., 1984; Simon et al., 1984; Benveniste et al., 1984; Ben-Ari,1985;
Thomson, 1986; Coan and Collingridge, 1987; Collingridge, 1987; Contreras
et al., 1987; Rothman et al., 1987; Mody et al., 1987; Quirion et al.,
1987; Westbrook and Mayer, 1987; Sonders et al., 1988; Barnes,1988;
Choi,1988; Monaghan et al., 1989; Jansen et al., 1989a,b,c, 1990a,b,c,
Ketamine administered by intravenous injection, in appropriate dosage, is capable of reproducing all of the features of the NDE which have been commonly described in the most cited works in this field, and the following account is based upon these (Domino et al., 1965; Rumpf, 1969; Collier, 1972; Siegel,1978, 1980, 1981; Stafford, 1977; Lilly, 1978; Grinspoon and Bakalar, 1981; White, 1982; Ghoniem et al., 1985; Sputz, 1989; Jansen, 1989a, b,1990b, 1991c, 1993). Important features of NDE's include a sense that what is experienced is 'real' and that one is actually dead, a sense of ineffability, timelessness, and feelings of calm and peace, although some cases have been frightening. There may be analgesia, apparent clarity of thought, a perception of separation from the body, and hallucinations of landscapes, beings such as 'angels', people including partners, parents, teachers and friends (who may be alive at the time), and religous and mythical figures. Transcendant mystical states are commonly described. Memories may emerge into consciousness, and are rarely organised into a 'life review' (Greyson, 1983).
Hearing noises during the initial part of the NDE has also been described
(Noyes and Kletti, 1976a; Morse et al., 1985; Osis and Haraldsson, 1977;
Greyson and Stevenson, 1980; Ring, 1980; Sabom, 1982). Ring (1980)
classified NDE's on a 5 stage continuum: 1.feelings of peace and
contentment; 2.a sense of detachment from the body; 3. entering a
transitional world of darkness (rapid movements through tunnels: 'the
tunnel experience'); 4. emerging into bright light; and 5. 'entering the
light'. 60% experienced stage 1, but only 10% attained stage 5 (Ring,
1980). As might be expected in a mental state with a neurobiological
origin, more mundane accounts also occur, e.g. children who may 'see' their
schoolfellows rather than God and angels (Morse, 1985). It is clear that
NDE's are not as homogeneous as some have claimed.
Ketamine produces an altered state of consciousness which is very different from that of the 'psychedelic' drugs such as LSD (Grinspoon and Bakalar, 1981). It can reproduce all features of the NDE, including travel through a dark tunnel into light, the conviction that one is dead, 'telepathic communion with God', hallucinations, out-of-body experiences and mystical states (see ketamine references above). If given intravenously, it has a short action with an abrupt end. Grinspoon and Bakalar (1981, p34) wrote of: '...becoming a disembodied mind or soul, dying and going to another world. Childhood events may also be re-lived. The loss of contact with ordinary reality and the sense of participation in another reality are more pronounced and less easily resisted than is usually the case with LSD. The dissociative experiences often seem so genuine that users are not sure that they have not actually left their bodies.'
A psychologist with experience of LSD described ketamine as 'experiments in voluntary death' (Leary, 1983, p375). Sputz (1989, p65) noted:'one infrequent ketamine user reported a classic near-death experience..."I was convinced I was dead. I was floating above my body. I reviewed all of the events of my life and saw a lot of areas where I could have done better". The psychiatrist Stanislav Grof stated: "If you have a full-blown experience of ketamine, you can never believe there is death or that death can possibly influence who you are" (Stevens, 1989, p481-482). 'Ketamine allows some patients to reason that ...the strange, unexpected intensity and unfamiliar dimension of their experience means they must have died..' (Collier, 1981, p552).
Attempts to explain NDE's as hallucinations are sometimes rejected by
spiritualists because many persons insist upon the reality of their
experiences (Osis and Haraldsson, 1977; Ring, 1980). However, 30% of normal
subjects given ketamine were certain that they had not been dreaming or
hallucinating, but that the events had really happened (Rumpf et al., 1969;
see also Siegel, 1978). What is a hallucination ?
" a hallucination has the immediate sense of reality of a true perception
.....transient hallucinatory experiences are common in individuals without
mental disorder" (APA, 1980). The apparently clear sensorium of some
persons who have had NDE's has also been used to argue that the NDE is
'real' and not a hallucination (Osis and Haraldsson, 1977; Ring, 1980). It
is thus important to note that hallucinations in schizophrenia typically
occur in clear consciousness and are believed to be real (APA, 1980). A
personal conviction of the 'reality' of an NDE does not invalidate
scientific explanations. Some users of LSD have claimed that their minds
are clearer than usual, and that the LSD world is real while the 'normal'
world is a veil of illusion (Grinspoon and Bakalar, 1981). Cardiac arrest
survivors have been reported as describing their resuscitation in detail
(Sabom, 1982). Ketamine can permit sufficient sensory input to allow
accounts of procedures during which the patient appeared wholly unconscious
The major neuronal binding site for ketamine is called the PCP receptor, which is itself attached to the NMDA receptor (Monaghan, Bridges and Cotman, 1989). As they are part of the same macromolecular complex, the two terms are sometimes used interchangeably. It was formerly believed that the sigma and PCP sites were the same entity, but it is now clear that sigma receptors are very different, have a unique distribution in the CNS, and are not a form of opioid receptor (Walker et al., 1990; Jansen et al., 1991b) .
There was initially some debate as to whether the hallucinogenic properties of ketamine were due to NMDA or sigma receptors (Jansen, 1990b). These effects are now largely attributed to NMDA receptor blockade (Krystal et al., 1994). Sigma ligands with a high degree of specificity (e.g. (+)pentazocine) do not produce NDE's at doses where most of the binding is to sigma rather than NMDA and/or kappa opioid receptors (sigma receptor ligands frequently have affinity for NMDA and/or kappa opioid receptors at higher doses) (Musacchio et al., 1990; Walker et al., 1990).
When glutamate is present in excess, neurones die via a process called
excitotoxicity. Conditions which have been proven to lead to excessive
release of glutamate include hypoxia/ischaemia, epilepsy and hypoglycaemia
(e.g. Rothman, 1984; Rothman and Olney, 1986, 1987). Blockade of PCP
receptors prevents cell death from excitotoxicity (e.g. Rothman et al.,
1987). The brain may thus have a protective mechanism against a glutamate
flood: release of a counter-flood of substances which block PCP receptors,
preventing neuronal death. Considering the sophistication of the brain's
many known defences, and the vulnerability of neurones to hypoxia, a
protective mechanism against excitotoxicity seems very likely. This is the
only speculation in the process outlined above: the other statements are
strongly supported by experimental evidence (Benveniste et al.,1984; Simon
et al., 1984; Ben-Ari, 1985; King and Dingledine, 1986; Rothman et al.,
1987; Westerberg et al., 1987; Hoyer and Nitsch, 1989). A peptide called
a-endopsychosin, which binds to the PCP receptor, has been found in the
brain (Quirion et al., 1984). Certain ions such as magnesium and zinc also
act as endogenous PCP channel blockers (Thomson, 1986; Westbrook and
Mayer, 1987; Cotman, Monaghan and Ganong, 1988), and it is possible that
these ions are centrally involved in producing NDE's.
A neuroprotective system might become active in any excitotoxic situation including epilepsy. The degree of damage, and the mental state, resulting from a glutamate flood may depend on the final balance in each neuronal pathway between excito-toxic forces and neuroprotective mechanisms. Persons who were oxygen deprived for prolonged periods and had a profound NDE, sometimes survived the episode unimpaired (Sabom, 1982). The lack of apparent brain damage may result from a very effective mechanism for glutamatergic blockade in those individuals.
It is also possible that ketamine has its effects by mimicing some of the
pathological processes seen in temporal lobe epilepsy. Even though ketamine
blocks glutamatergic transmission, and prevents excitotoxic cell death, the
effect of ketamine upon the human electroencephalograph (the EEG) suggests
that it can be epileptogenic - the final result of ketamine acting in the
brain is the result of a complex interplay of forces. There is a reduction
in a wave activity, but b, d and q wave activity are increased (Schwartz
et al. 1974; Pichlmayr et al., 1984). Ketamine acts both as an
anticonvulsant (e.g. McCarthy et al., 1965; Celesia and Chen, 1974;
Taberner, 1976; Leccese et al., 1986; Mares et al., 1992) and as a
pro-convulsant (Bennet et al., 1973; Gourie et al., 1983; Myslobodsky,
1981). Myslobodsky (1981) reported that ketamine could produce epileptiform
EEG patterns in human limbic and thalamic regions, but that there was no
evidence that this affected other cortical regions or that fits were likely
to occur. This is consistent with the NDE model presented by
Saavedra-Aguilar and Gomez-Jeria (1989) involving limited electrical
abnormalites in the limbic system. Thus production of NDE's by ketamine is
not at odds with proposals that NDE's may result from abnormal electrical
activity. Reich and Silvay (1989): " it is hard to draw objective
conclusions regarding the anti-convulsant properties of ketamine...animal
data are particularly difficult to interpret because of interspecies
variations". Ketamine is probably anticonvulsant at NDE producing doses
(Myslobodsky, 1981) suggesting that a PCP receptor blocker is released to
produce the NDE.
Saavedra-Aguilar and Gomez-Jeria (1989) cited animal experiments showing
b-endorphin to be epileptogenic to support an argument that b-endorphins
produce NDE's (e.g. McGinty et al., 1986; Henriksen et al., 1978). While
b-endorphin may have had these effects within the rat paradigms used,
opioids usually produce calming, inhibitory effects in humans - not
excitation or states resembling epilepsy (Meltzer, 1987). Released peptides
probably have protective functions rather than contributing further to
excito-toxicity. The finding of Su, London and Jaffe (1988), that some
steroids bind to sigma receptors, was cited to suggest that steroids could
play a role in NDE's. However, the steroid was progesterone which is not a
hallucinogen. Schwartz et al. (1989) reported that the affinity of
progesterone for the sigma site is insufficient to result in significant
receptor occupancy, except in pregnancy.
2. Hypercarbia: a CO2-enriched breathing mixture can result in typical NDE
phenomena such as bodily detachment and the perception of being drawn
towards a bright light. Diverse personality types produced broadly similar
reports, suggesting a shared neurological substrate (Meduna, 1950).
2. Regression in the service of the ego: confronting death cuts off the external world resulting in regression to a pre-verbal level. This is experienced as mystical ineffability (Greyson, 1983). Losing contact with the external world is one of the most typical effects of ketamine. This is partially due to blockade of NMDA receptors involved in sensory transmission. NMDA receptors play a central role in the transmission of data from all sensory modalities (Davies and Watkins, 1983; Greenamyre et al., 1984; Headley et al., 1985; Cotman et al., 1987; Cline et al.,1987; Monaghan, Bridges and Cotman, 1988; Kisvardy et al., 1989; Oye et al., 1992).
3. State dependant reactivation of birth memories (Grof and Halifax, 1977). Movement through tunnels towards light may be a memory of being born : a 'near-birth experience'. NMDA receptor blockade could be the mechanism for such a reactivation of primitive memories.
4. Sensory deprivation: memories may normally be suppressed by a 'gate' which admits primarily external signals when we are fully conscious and concentrating upon an external task (Siegel,1980, 1981). If this input is dramatically reduced (e.g. by ketamine or a heart attack) in combination with central stimulation (e.g. by excessive glutamate release during hypoxia, epilepsy, or arising without external provocation), stored perceptions are released and become 'organised' into a meaningful experience by psychodynamic forces in the mind in question (Greyson, 1983). The 'white light' may result from CNS stimulation , and also a possible lowering of the phosphene perceptual threshold (Siegel,1980, 1981). Sensory deprivation can produce profound alterations in consciousness (Lilly, 1961,1978).
The hippocampus is the anatomical location of the 'memory gate' described
above. NMDA receptors form the molecular substrate of the gate. NMDA
receptors have their highest concentration in the hippocampus, a part of
the medial temporal lobe where data from the external world is integrated
with internal programs. The NMDA receptor plays an important role in
learning, and in the formation and retrieval of memories. The PCP receptor
is referred to as a 'gated channel'. Whether the gate is open or closed
depends on the degree of excitation - specifically, the position of a
magnesium ion in the channel. In simple terms, ketamine blocks this channel
and closes the gate to incoming data (Monaghan, Bridges and Cotman, 1989;
Morris et al., 1986; Collingridge, 1987; McNaughton and Morris, 1987;
Cotman, Monaghan and Ganong, 1988).
Spiritualists have sometimes seen scientific explanations of NDE's as dull and reductionist. However, the exploration of the mind-brain interface is one of the most exciting adventures which humans have ever undertaken. The real reductionism lies in attempts to draw a mystical shroud over the NDE, and to belittle the substantial evidence in favour of an scientific explanation.
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