The Ketamine Model of the Near Death Experience

A Central Role for the NMDA Receptor

Near-death experiences (NDE's) can be reproduced by ketamine via blockade of receptors in the brain (the N-methyl-D-aspartate, NMDA receptors) for the neurotransmitter glutamate. Conditions which precipitate NDE's (hypoxia, ischaemia, hypoglycaemia, temporal lobe epilepsy etc.) have been shown to release a flood of glutamate, overactivating NMDA receptors resulting in neuro ('excito') toxicity. Ketamine prevents this neurotoxicity. There are substances in the brain which bind to the same receptor site as ketamine. Conditions which trigger a glutamate flood may also trigger a flood of neuroprotective agents which bind to NMDA receptors to protect cells, leading to an altered state of consciousness like that produced by ketamine. This article extends and updates the theory proposed in 1990 (Jansen, 1990b).

The near-death experience (NDE) is a phenomenon of considerable importance to medicine, neuroscience, neurology, psychiatry, philosophy and religon (Stevenson and Greyson, 1979; Greyson and Stevenson, 1980; Ring, 1980; Sabom, 1982; Jansen, 1989a,b, 1990b). Unfortunately, some scientists have been deterred from conducting research upon the NDE by claims that NDE's are evidence for life after death, and sensationalist media reports which impart the air of a pseudoscience to NDE studies. Irrespective of religous beliefs, NDE's are not evidence for life after death on simple logical grounds: death is defined as the final, irreversible end. Anyone who 'returned' did not, by definition, die - although their mind, brain and body may have been in a very unusual state.

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, 1991a,b,c, 1993).

Characteristic Features of the Near-Death Experience

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 and Phencyclidine

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 (Siegel, 1981).

Glutamate, NMDA and Sigma Receptors, and the Hippocampus

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.

Scientific Hypotheses and NDE's

Temporal Lobe Epilepsy

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.

A Flood of Endorphins

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.

Hypoxia and Hypercarbia

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).

Serotonin

Psychological

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).

Drug-induced hallucinations ?

Conclusions

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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