A Review of the non-medical use of Ketamine: Part 1: Use, Users and Consequences
Jansen, K. L. R. (2001) A review of the non-medical use of ketamine: part 1: use, users and consequences. Journal of Psychoactive Drugs (in press)
5. TOXIC EFFECTS
The use of ketamine has been linked with a wide range of mental health problems including anxiety, panic attacks, flashbacks, post-traumatic stress disorder, persistent perceptual changes, mania, depression, suicide, insomnia, nightmares, night terrors, an unpleasant feeling of being unreal or that the world is unreal, paranoid delusions, persistent hallucinations, automatic behaviour, fragmentation of the personality and aggression (Jansen 2000). However, a cause-and-effect relationship has usually not been established in these cases. Some people will develop mental health problems regardless of any drugs they may have used. Establishing that a drug actually causes a problem, rather than being linked with it by chance, can be difficult. Nevertheless, brief case reports often boldly conclude that taking a drug caused a particular condition, and the sufferer aids this process by seeking external explanations and making false attributions. There is a natural reluctance to accept that something would have gone wrong 'internally' in any case, or may have already been wrong. In Victorian times, favorite 'roots of all evil' in this sense, given serious discussion in the medical literature of the time, were railway and bicycle travel and masturbation. Bearing this caution in mind, let us now consider the possibilities.
Freudian theory maintains that anxiety- provoking material unacceptable to the waking mind is repressed into the unconscious. If defenses against this disturbing material are impaired by taking ketamine, the outcome will partly depend on the set and setting. The indirect blockade of NMDA receptors is one reason why so little of a ketamine experience is remembered. The same mechanism is involved in the failure to recall dreams, except that a natural blocker is involved: a 'mental fire wall' which obliterates awareness of 'other realities' incompatible with our ordinary reality. Breaches in these barriers may not wholly self-repair as the acute effects of the drug resolve, resulting in some types material gaining increased access to the conscious mind. This can result in a variety of mental health problems. One of these simply involves an increased level of imagery and some 'lack of focus'. This is called Pandora's box syndrome (Jansen 1997b). The imagery is intensified by anxiety. During a ketamine experience itself, 'breaching the walls' can have results as follows:
I felt excruciating aversion, fear. ... It seemed to me that I would never get out of this nightmare, that I was slowly and painfully dying, that I, my entire self, would melt in this black mass, but my brain would go on working. That I would feel, think, not live, but suffer... Everything I saw resulted from my hopeless life - As if the trash accumulated in me during years and years went out of me during an hour. I do not want it to repeat, I am afraid of this nightmare - I would never forget it - (Krupitsky & Grinenko 1997)
I was alone in my room. Then it was in with the i.v. hit while sitting at my desk. The next thing I remember is extreme panic. I was convinced that I had discovered THE SECRET - that this world we live in now is an illusion and I had seen the Real Universe. The Gods could not possibly let me live with this forbidden knowledge. I knew that I was about to die. This was all very fast, a matter of seconds. I tried to decide if I should rush out of the apartment into the corridor screaming for an ambulance. Fortunately I decided that this was futile. My death was seconds away and I should lie on my bed and wait for it, which I did. My heart must have been going about 200 a minute. 30 seconds later I was perfectly O.K.... (Interview from: Jansen 2000)
The fear of being killed for stealing forbidden knowledge from the Gods is closer to Jungian psychology, an archetypal mythical experience, and can be related to Grof's model of the near-birth experience.
I went to Hell instead. I took the largest dose ever, 200mg as a shot in the buttock, and curled up for the night. Once again I was going through a pipe system, but this time I came out into a small, dimly lit red room, and was filled with terror. I had lost my body and had become something resembling a dwarf's hood hanging on a peg. I know that sounds funny, but I thought that I would have to stay forever in that room on that hook. I was in HELL. I screamed, and screamed...it was my first experience of what ETERNITY really means. I almost became a Catholic the next morning. That experience seriously shook the basis of my disbelief. I thought that people were absolutely mad who wanted to carry on for Eternity without their bodies. It made me fervently hope that the end really is the end...(Interview from: Jansen 2000).
'Depersonalisation' refers to feelings of being unreal, detached and unable to feel emotion. 'Derealisation' is where the setting appears to be unreal, a cardboard stage-set. Both are deeply unpleasant and occur as adverse ketamine effects.
Attention, learning and memory are altered during ketamine experiences (Malhotra et al. 1996; Curran & Morgan 2000). This is partly due to blockade of NMDA receptors (Cotman et al. 1988) but acetylcholine is also important in memory (Bartus et al. 1987) and ketamine has anti-cholinergic properties (Morita et al. 1995; Hustveit et al. 1995). The loss of acetylcholine in Alzheimer's disease is one of the most distinctive features of the condition, as is loss of glutamate (Bartus et al. 1987). Ketamine has been used to produce a model of Alzheimer's disease (Ellison 1995). Research into cognitive problems which persist once the urine is proven to be free of all drugs and their metabolites is rare, and co-existing depression and anxiety (which affect memory and concentration) must be excluded. Curran & Morgan (2000) found a persistent semantic memory problem in a group of 19 people at 3 days after recreational ketamine use, but it is possible that norketamine would still be present in significant quantities at this stage. Norketamine is also an NMDA receptor antagonist (Ebert et al. 1997), with far less tendency to produce hallucinogenic effects. Patients can tolerate prescribed oral ketamine long-term for chronic pain (Humphries et al. 1997). Thus the resolution of hallucinogenic effects does not imply that there is an inadequate level of active metabolites remaining to affect cognitive function. The pharmacokinetics of norketamine in poly-drug using adults aged 20 to 30 is an area requiring further study.
An anaesthetist became dependent on ketamine and had problems with memory, attention and concentration, and a subtle change in visual perception persisting into drug-free periods (Jansen 1990b). Ketamine use would be followed by impaired recall and difficulty with word finding. The visual change involved mildly 'increased graininess', aggravated by fatigue, anxiety and other drugs. This is 'persistent perceptual change', differing from a flashback as it is chronic rather than episodic. Neurons undergo many changes throughout life, forming the basis of some types of memory and of the brain's compensation for ageing. NMDA receptors play a key role in this 'plasticity'. Chronic ketamine in animals blocks this plasticity (Corbett 1990), but there is no evidence that ketamine causes brain damage at the cellular level in primates (human/ monkey), although changes do occur in rat brains. 40mg/kg results in vacuoles (fluid-filled bags) appearing within cells in some parts of the rat brain, such as the cingulate gyrus, which resolve after several days. High, repeated doses of the more toxic PCP or its even more toxic relative MK801 (dizocilpine) can result in some cell death (Olney et al. 1989, 1991). Auer et al. (1996) injected monkeys with MK801, the most toxic drug of this group (never approved for human use) and were unable to produce any toxic changes. Humans and monkeys are not at risk of these changes because of differences in metabolism between rat and primate brains. Ketamine can block excito-toxicity (brain damage due to low oxygen etc.) but it can also excite the brain at low doses by switching off the inhibitory system. This is not damaging in primates because ketamine also binds to a wide range of receptors which shut down this form of excitement before structural damage can result. Ketamine's promiscuity greatly improves its safety relative to MK801, which binds very specifically to the NMDA receptor complex. Rats have rates of brain metabolism which are twice as high as primates to start with. It is because of this higher base rate of excitement that ketamine causes over-excitement in rats at doses below those at which it activates shut-down systems. NMDA receptors must be blocked for at least 2 hours to cause reversible changes and at least 24 hours to produce some cell death, but ketamine has a short half-life (about 20 minutes in rats) so many injections are needed, over a prolonged period, to produce persistent change (Farber et al. 1998). Reversible toxic changes in the rat appear at 40mg/kg of ketamine and stop at 100mg/kg, with no further changes (Sharp et al. 1994). Attempts to produce toxic changes in monkeys were a total failure at 10mg/kg i.m. ketamine (Sharp 1998).
Thus humans and monkeys are protected from toxic changes by the rising anaesthesia, which cuts in above a certain dose and calms cells down. This also happens in rats, hence the 100mg/kg plateau, but it happens too late to completely avoid some toxic changes as rats are already 'running hot' because of their twice as fast metabolic rate. Cell changes do not appear if rats are pre-treated with a wide range of drugs, including LSD and amphetamine-like substances such as DOM (4-Methyl-2,5-dimethoxy-amphetamine) (Farber et al. 1998), all the benzodiazepines and barbiturates, anti-cholinergics (Olney 1994), antipsychotic drugs including haloperidol, clozapine and olanzepine (Farber et al. 1996), nifedipine and other drugs. Some of these block toxic changes in rats by switching inhibitory systems back on again, and ketamine itself activates these inhibitory systems at higher doses. It has been suggested that the process which is neurotoxic in rats is responsible for psychedelic effects in humans, and may be involved in schizophrenia (Farber et al. 1998). However, most of the drugs which block toxicity are not treatments for schizophrenia (e.g. LSD), nor is it proven that these drugs will block ketamine effects in humans. For example, lorazepam reduces emotional distress but not ketamine 'psychosis' (Krystal et al. 1998). Nevertheless, many anecdotes indicate that LSD and amphetamine-like substances (MDMA, 2CB (2,5-dimethoxy-amphetamine) etc.) when taken 90 minutes prior to ketamine, reduce dissociation (e.g. Turner 1994). The resulting state is less intense than either drug taken on its own, differs from either drug, and is much easier to fully recall than a pure ketamine experience.
Although examination by a neuropathologist may find no structural cell changes, there is increasing appreciation of the role of much smaller entities in memory, such as the response of immediate early genes which produce 'third messengers' such as the c-fos protein (Dragunow et al. 1989). Subanaesthetic doses of ketamine induce formation of c-fos (Nakao et al. 1996) but full anaesthetic doses may not (Nakao et al. 1993). The dopamine/glutamate mutual regulation system is involved in this process. Repeated chronic doses of ketamine result in persistent alterations in the dopaminergic system amongst others (Irifune et al. 1991; Lindefors et al. 1997), and these alterations will have feedback effects on glutamate systems (Verma & Moghaddam 1996) that might result in a loss of efficiency in memory systems that is not apparent as a change in cell structure. Thus changes may not only at the receptor level (Morita et al. 1995; Williams et al. 1992) but also at the level of intracellular signalling and nucleic acid activation/deactivation. This has been investigated for cocaine, with which ketamine shares important properties (e.g. Nishimura & Sato 1999). In response to chronic cocaine, induction of Fos-type immediate early genes is downregulated, resulting in persistent changes downstream in such gene products as the AP-1 transcription factor (Hope 1998).
Of a group of women undergoing elective surgery, half had droperidol and fentanyl, and the other half and diazepam and ketamine. The droperidol/fentanyl group complained of restlessness, dysphoria and fatigue after the operation. No complaints were made by the ketamine/diazepam group. At 3 months, the only significant difference between the two groups was that 25 % felt that their memory and concentration were severely affected by the droperidol /fentanyl, versus none for the ketamine /diazepam. There was no difference in dreaming, nightmares, hallucinations or illusions. Does a single dose of droperidol/fentanyl really cause lasting memory impairment? The women disliked these drugs at the time of the surgery, and this dislike made them more inclined to blame the anesthesia for problems they were having 3 months later, rather than considering other causes. (Klausen et al. 1983).
After a binge, there is a gradual return to normal mood over several days as the slow decline in norketamine levels provides a cushioning effect. Being 'too high' is more likely than being 'too low', and ketamine may trigger mania in bipolar disorder (manic-depression), as it has a specific chemical action that reverses that of the mood-stabilising drug lithium (Dixon et al. 1994). However, there are anecdotal indications that, as with other stimulants, a low mood may still follow the high but it does not appear for about a week. Ketamine has antidepressant effects (Berman et al. 2000). However, amphetamine can also be described as an antidepressant, although its use is followed by a period of low mood (a 'crash'), usually the following day, while low mood after MDMA appears mid-week (Jansen 1997b). Suicidal actions while affected by ketamine may not always be due to low mood. In 23 users, half reported a lasting elevation in mood. There was an equal division between positive and negative effects, with 30% noting 'deeper insights' (Siegel 1978).
Ketamine flashbacks have been defined as episodes lasting for a few seconds in which the user re-experiences some mild phenomena (White & Ryan 1996). This differs from the media view that a flashback is a complete, unprovoked re-living of a drug experience. A drug-specific, physical brain effect is an unlikely explanation as a wide range of drugs, with quite different actions in the brain (e.g. LSD, ketamine and MDMA) are implicated (Jansen 1997b), and flashbacks also occur in post-traumatic stress disorder (PTSD). This is a delayed response to an exceptionally stressful event (World Health Organisation 1992). Ketamine experiences can be exceptionally stressful, so some flashbacks following traumatic 'K-trips' may actually be PTSD, which involves a repeated reliving of the trauma in the form of intrusive memories or dreams, may include episodic hallucinations, appears after a latency of a few weeks, and can also involve problems with memory, learning, attention, anxiety and depression (Van der Kolk 1997). Post LSD flashbacks are more likely after traumatic LSD 'trips' (Strassman 1984). Some drug-related flashbacks may be a form of conversion disorder (hysteria), where anxiety and other forms of psychological distress are 'converted' into symptoms such as perceptual change, somatic symptoms, amnesia and others. Dissociative drugs are especially likely to trigger such symptoms, and conversion disorder (hysteria) is classified as a 'dissociative' disorder. This disorder is a partial or complete loss of integration between memories of the past, awareness of identity, immediate sensations and control of movements (World Health Organisation 1992), all of which are major acute effects of ketamine. Ketamine can give rise to dangerous 'automatic' behaviour, with activities continuing out of contact with the observing ego (e.g. repeatedly walking into a wall). Siegel's study of 23 recreational users noted a high incidence of flashbacks (and attentional dysfunction), but the definition of 'flashbacks' used in this study was not stated (Siegel 1978). Large, controlled anaesthetic conclude that ketamine is usually devoid of significant persistent effects once the drug and its metabolites have cleared the body (Schorn & Whitwam 1980; Modvig & Nielsen 1977).
Ketamine use has been linked with sleep disorders such as sleep paralysis and night terrors. The sleeper wakens from deep stage 4 sleep with a loud scream. They may report being either trapped in a small space or in a place without co-ordinates. These are not nightmares as they do not arise during the normal dream REM periods. A woman had 'a trip to Hell' on ketamine, and screamed very loudly. Several weeks after stopping ketamine, the night terrors began. They continued for several years, stopping when she was taking drugs (including alcohol), and restarting when she had been drug free for several weeks. The condition gradually faded. The screaming may not have appeared during periods of drug use as these provided a conduit for buried parts of the psyche to communicate with 'the surface' in other ways. When she stopped using drugs, these parts may have been 'entombed' and only burst through during deep sleep by means of a penetrating scream. Nevertheless, the wall-weakening effect of the initial ketamine may have triggered the condition. There were predisposing personality features and a family history of mental health problems (Jansen 2000). Ketamine may have also disrupted the 'wetware' / 'software' of sleep mechanisms (Feinberg & March 1995).
There are rare reports of prolonged hallucinations following ketamine anesthesia, but as there was no normal period before the onset of the hallucinations, these are not flashbacks. Hallucinations continued for 5 days in a boy who was given ketamine during investigations of brain-based symptoms. He had pre-existing abnormal brain waves over the visual cortex, raised pressure in his brain, severe headaches, loss of appetite, vomiting, fever and nausea. He was then given ketamine without after-effects. 10 days later, he was given ketamine again and had a scan involving injection of air into spaces in the brain. This was followed by 5 days of hallucinations typical of delirium (Perel & Davidson 1986). It seems unlikely that ketamine was responsible, especially as operations are often followed by delirium for a few days.
1,400 patients were given full surgical doses. There were 3 cases of prolonged hallucinations, the longest being for 3 weeks. In no case did hallucinations begin after a period of normality (Fine & Finestone 1973). In over 200 patients, the mental changes following ketamine were compared with other anesthetics. Tests were carried out repeatedly for a year. There were no differences between the groups in mental performance, hallucinations and behavior. Multiple doses did not cause persisting impairment of intellectual function or personality (Abajian et al. 1973). Ketamine or halothane gas was given to 100 children. A month later, there was no difference in emotional disturbances between the groups (Modvig & Nielson 1977). Schorn & Whitwam (1980) concluded that ketamine was unlikely to cause permanent changes in personality or intellect. These anaesthetic studies are much larger and much better controlled that the studies which exist of recreational users (Curran & Morgan 2000, Jansen 1990b, Siegel 1978). However, the patient usually receives the drug at a full anaesthetic dose, possibly with effect modifying drugs such as diazepam, droperidol and propofol, and probably not more than 20 times. Subanesthetic dose have different effects from full anesthetic doses, and are, paradoxically, more likely to have adverse effects on mental health for the reasons discussed previously. Subanesthetic doses produce metabolic hyperfontality like that seen in schizophrenia with positive features (Vollenweider et al. 1997 a, b) rather than a calm brain, and there is actual activation of glutamate (Anand et al. 2000; Moghaddam et al. 1997), while full anaesthetic doses lead to a fall in extracellular glutamate levels (Rozzo et al. 2000). This raises a question mark over the degree of reassurance which can be taken from anaesthetic studies when we shift our attention to psychedelic use.
A ketamine trance can resemble catatonic schizophrenia. The eyes may rove from side to side and limbs move in semi-purposeful ways, while the mind stages an intense inner drama. Some people will suddenly sit up, speak a phrase, and lie down again. Ketamine users often insist that events 'really happened' and that the drug is merely a key for doors to 'other realms'. Most of these people are not insane, just as persons who regard their NDE's as real are not usually insane. However, frequently experiencing these other states of being may result in problems back in 'ordinary reality' if the borders between them become blurred. This lack of boundaries between realities, the inter-penetration of one by the other, may be distressing and can meet diagnostic criteria for psychosis. Marcia Moore repeatedly warned that 'this delusion of grandeur thing has to be watched' and on at least one 'journey' she described herself as 'briefly but certifiably insane'.
In some types of schizophrenia, certain glutamate-releasing cells and/or terminals are missing and there is an excess of dopamine. This is probably due to genetic and pre-birth factors (Moghaddam 1994; Tsai et al. 1998). The net result may be similar to blocking NMDA receptors while stimulating dopamine release, the effects of ketamine. The results of subanaesthetic doses have been interpreted as being similar to the positive (hallucinations, delusions, disordered thinking), and the negative and cognitive (emotionless, apathy, isolation, concrete thinking, absence of thought, impaired memory /attention /concentration / planning/task completion) symptoms of schizophrenia (Adler et al. 1999; Carpenter 1999; Krystal et al. 1994). However, normal subjects did not hear critical voices, also a weakness in LSD models of schizophrenia. The Yale studies used very general terms such as 'conceptual disorganisation' and 'unusual thought content', and it seemed that the 'dream-like states' of the 1960's had been reframed as 'schizophrenia-like symptoms' in the 1990's using very broad criteria. However, ketamine was then given to persons with schizophrenia and a specific, acute worsening of their schizophrenic symptoms was noted, strengthening the theoretical basis for the model although ketamine-induced 'symptoms' in controls were distinctly different from the ketamine-induced symptoms in persons with schizophrenia (Lahti et al. 1995; Malhotra et al. 1997). While the model is flawed, and apparently travelling down tunnels at high speed into Light is not really a feature of schizophrenia, these studies may eventually lead to new and better treatments for people in distress. These studies have already led to new drugs with pro-glutamate 'anti-ketamine' effects (e.g. Arvanov & Wang 1998).
A true drug-induced psychosis is one that is not explained by another underlying condition, and which persists once the urine is clear of drug metabolites (Poole & Brabbins 1996). In some heavy daily users, norketamine can take several days to leave the body. John Lilly rapidly became non-psychotic after being cut off from his drug supply, and was never in hospital for long except when he had serious physical injuries. 'Ketamine intoxication with paranoia' may be a better description for his episodes than 'drug-induced psychosis', which is one where the psychosis starts during intoxication and is still present when the urine is clear of metabolites. It should only recur on re-exposure to the drug and not at any other time, and must have a different course and outcome from schizophrenia, bipolar disorder (manic-depression) and related conditions (Poole & Brabbins 1996). Some doubt that any drug can produce such a condition. Connell's famous report on amphetamine psychosis concluded that this only occurred with intoxication and resolved as the urine cleared of metabolites, a process taking up to a week in some people (Connell 1958). Where it does not resolve, long-term follow-up usually finds schizophrenia, bipolar disorder or a related condition. Lilly had many features of schizotypal disorder existing years before he took ketamine (Lilly 1978). Ketamine increases schizophrenic symptoms while a person with this disorder is affected by the drug, but the symptoms are not increased once the drug and its metabolites have left the body (Lahti et al. 1997; Malhotra et al. 1997). Hence some anesthetists argue that ketamine can be safely used in schizophrenia (Ishihara 1997).