Disorders relating to the use of ecstasy, other ‘party drugs', and khat. Topics covered:
- Ecstasy (3,4-methylenedioxymethamphetamine)
- Mechanism of action
- Absorption and metabolism
- Clinical features
- Psychological effects
- Physical effects
- Patterns of use
- Evidence for 5-HT disruption in humans
- Acute psychological problems associated with MDMA use
- Physical complications from MDMA
- g-Hydroxybutyrate (GHB)
- Khat (qat)
- Tryptamine derivatives
‘Ecstasy' (MDMA, 3,4-methylenedioxymethamphetamine) is a ring-substituted amphetamine derivative that has become increasingly popular since it first became associated with the ‘rave' music scene during the late 1980s. (1) Incorrectly termed a designer drug, MDMA was first synthesized in 1912 by the Merck Pharmaceuticals as a product of ongoing research, although it never reached the commercial market. It was relatively ignored until the 1950s when United States Army experiments investigated its potential to assist espionage during the Cold War, and it was not until the late 1960s and early 1970s that drug users on the west coast of America began to popularize its recreational use. Although ecstasy is the drug most frequently associated with the term ‘party drug' most users of MDMA are polysubstance abusers with experience of cannabis, LSD, amphetamine, amyl nitrate, and cocaine. This article is concerned with ecstasy, ketamine, g-hydroxybutyrate (GHB), khat, and tryptamine derivatives.
Unlike most illicit substances of abuse, MDMA is sold in either tablet or capsule form (very occasionally as powder), the composition of which can never be certain. Indeed only half of all tablets sold as ecstasy in the United Kingdom actually contain MDMA, with the rest being either analogues of MDMA, such as methylenedioxyamphetamine (MDEA), N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), and methylenedioxyethylamphetamine (MDEA), or combinations of stimulants such as ephedrine or amphetamine and hallucinogens such as LSD or ketamine. (2) The average dose of an ecstasy tablet containing MDMA is about 70 mg (range 50–150 mg).
Mechanism of action
MDMA ingestion leads to an acute increase in central serotonergic effects by causing the calcium-dependent release of serotonin from nerve terminals. To a lesser extent there is also dopamine reuptake blockade. MDMA also results in a rapid inhibition of tryptophan hyrdroxylase, the rate-limiting enzyme in serotonin synthesis, although the mechanism of inactivation in uncertain. This is followed by acute depletion of central serotonin levels which may contribute to the fall in mood that some users notice after use.
Absorption and metabolism
Taken orally the onset of action begins after 30 to 60 min, peaks at between 90 and 120 min with significant effects persisting for a further 3 to 6 h followed by a gradual ‘come down' over the subsequent 6 to 12 h. The drug is primarily metabolized by demethylation by the hepatic cytochrome P-450 enzyme, debrisoquine hydroxylase coded for by CYP 2D6.(3) Two phenotypes predominate in the population with 9 per cent being ‘poor metabolizers'. The consequence of metabolizer status on patterns of use and toxicity is as yet unknown. The drug may also be taken intranasally (snorted), rectally, and (rarely) intravenously.
Being structurally related to both amphetamine and mescaline, (4) MDMA possesses both stimulant and hallucinogenic properties and is said to ‘evoke an easily controlled altered state of consciousness with emotional and sensual overtones' (5) which allows it to be discriminated from other related substances. Some have suggested a new term for this group of drugs ‘empathogens' and suggest that the substance's appeal rests in its ‘dramatic and consistent ability to induce in the user a profound feeling of attachment and connection' (6) which would be in keeping with its popularity as a social drug within the club scene. It was also these qualities that led to the enthusiasm of a small number of physicians and therapists in the United States who held that it could enhance the therapeutic process. (7) Indeed, it is reported that the Los Angeles dealer who coined the street name ‘ecstasy' for MDMA would have preferred the name ‘empathy' but he did not feel that his clients would know what it meant.
As with any psychotropic drug the effects of the drug on a given individual at a particular time are not predictable, depending as it does on the complex interaction of drug dose and type, cognitive set, and environmental setting. As such a wide range of negative psychological effects may also be experienced in addition to the sought-after effects, including anxiety, panic, and paranoia. (Table 1)
Table 1 Psychological effects associated with MDMA
- Increased empathy and emotional expressiveness
- Reduced ability and desire to perform mental tasks
- Increased anxiety and restlessness
- Increased energy, euphoria with periodic rushing (periodic surges in euphoria)
- Reduced defensiveness and decreased aggression
- Disinhibition and increased awareness of emotions
- Perceptual distortion and hallucinations at higher doses
Physiologically sympathomimetic properties similar to amphetamine predominate including tachycardia, anorexia, increased respiratory rate, blood pressure, increased motor activity, mydriaisis, increased temperature, and sweating. Jaw tightening (bruxism), teeth grinding with molar erosion, and tremor may also be seen.
Patterns of use
The typical pattern of use is a half to two tablets per evening (although the time of use often extends into the next morning) with a usual frequency of between once or twice a week to less than monthly. There has been increasing recognition of a minority of users who take the drug in a binge fashion, consuming up to 30 tablets in a weekend. Although primarily a social drug, MDMA may be used while alone and is not confined to clubs, with use extending to public houses, bars, and football terraces as well as occasional solitary use.
The prevalence of illicit drug use, especially MDMA (ecstasy) and other stimulants, is increasing. For example, recent studies among the younger section of the British population show that 54 per cent of 20- to 22-year-olds had been offered ecstasy at some time and 15 per cent had tried it at least once. Almost twice as many men as women had taken it.(9) In a study of over 3000 second-year university students in the United Kingdom, 13 per cent reported that they had tried MDMA. (10) The number of seizures of MDMA in the United Kingdom rose from 39 000 doses in 1989 to 1 564 000 doses in 1994, and the number of persons found guilty, cautioned or dealt with rose from 286 in 1990 to over 3500 in 1994. (11) Similar findings have been reported from Denmark, (12) Germany, (13) Spain (14) and The Netherlands (15) among others. Australia (16) and America have also seen a rise in use the drug with prevalences of up to 25 per cent having been reported among students in the US.
An association between drug use and musical/subcultural preference has been recognized for many years: cannabis and heroin with jazz and blues, LSD with the ‘hippie' movement, and amphetamine sulphate with the punk era.(17) MDMA is associated with the ‘dance and club scene'. The particular association between stimulant drugs and the ‘dance scene' can be partly explained by the energetic and prolonged dancing that accompanies such music. Stimulants may enhance enjoyment and ability to perform to such music.(18)
Over the last 10 years there has been increasing animal evidence of MDMA's neurotoxicity upon serotonergic neurones with consequent worry over the possible functional implications in humans (for reviews see Steele et al. (4) and Green et al. (19)). After administration of MDMA, animals have reduced levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid, and tryptophan hydroxylase. Abnormal 5-HT regrowth has been reported after MDMA-induced damage (20) with a decrease in 5-HT terminal density, suggestive of what has been termed a ‘chemical axotomy'. Pathological investigations suggest that 5-HT nerve terminals arising from the dorsal raphe nucleus are specifically involved. The duration and magnitude of these neurotoxic effects are dose dependent and are followed by differential rates of recovery, with 5-HT damage persisting for up to a year in the rat, and dopaminergic damage for up to 3 years in the rhesus monkey. (21) These changes appear to be species specific with primates being more sensitive to the neurotoxic damage than rodents.
Early findings suggesting dose-dependent damage led some to believe that human consumption was at such a level as to make such extrapolations to humans inconsequential. More recent research taking into account species scaling indicates that the average single dose size consumed by humans is indeed near to those levels found to be neurotoxic in animals. Early optimism regarding the risks of use were accompanied by initial expectations of low abuse potential. Subsequent reports suggest that although the majority use low levels of the drug, a significant minority use up to five tablets a night with a lifetime consumption of more than 1000 occasions.n(2) With such levels of self-administration and some users reporting a binge pattern, the cumulative doses are certainly reaching the levels found to be neurotoxic in animals and a dependence syndrome similar to that seen with other stimulant drugs remains a possibility. Since the dopaminergic system is influenced by MDMA, the ventral tegmental dopaminergic reward pathway may underlie any reinforcing potential.
Factors other than dose have been implicated in the pathogenesis of neurotoxicity associated with MDMA and some of these have practical relevance for the social context of human use. Core ambient temperature and hydration status have been implicated as key factors in the development of neurotoxicty and malignant hyperthermia respectively. The drug is usually taken during relentless hours of energetic dancing in crowded and poorly ventilated venues. The users sweat excessively and often make inadequate or inappropriate efforts at rehydration. (Studies on amphetamine aggregation toxicity may be relevant: mice grouped together had enhanced toxic and behavioural effects from amphetamine compared with mice housed alone.) These findings have influenced both public health messages (advising regular isotonic fluid replacement) and the dance club environment with access to ‘chill out' rooms and to free water.
The neurochemical mechanism underlying neurotoxicity seems to be dependent upon intact dopaminergic and serotonergic systems since disruption of monoamine transmission in either system protects against MDMA-induced neurotoxicity. Recent studies implicating free radicals in the development of neuronal damage suggest that prior consumption of vitamin C could be protective.
Evidence for 5-HT disruption in humans
Markers for 5-HT damage may be sought either by direct assessment of metabolite levels or indirectly by assessing those functions thought to be dependent on an intact 5-HT system. Subjects with prior exposure to MDMA had lower cerebrospinal fluid 5-hydroxyindole acetic acid than matched controls and lower levels of impulsivity, indirect hostility, and harm avoidance. The 5-HT system is implicated in cognition, sex, sleep, and appetite, as well as mood. Uncontrolled human studies have reported cognitive deficits such as impaired immediate and delayed recall in those with a history of MDMA use, and recent work suggests acute mood and cognitive deficit in the days following use.
Further evidence for disruption of the 5-HT system comes from blunted neuroendocrine responses (cortisol and prolactin) to D-fenfluramine in former users of the drug. A study of former users (22) suggested associated personality traits of novelty seeking, depression, and aggressive–impulsive behaviour. The frequency of polysubstance abuse in this population confounds these findings, and the direction of causality in the neuroendocrine, neurochemical, and personality findings is uncertain. Krystal et al. (23) have shown mild to moderate impairment on subtests of the Weschler Memory Scale in nine users, none of whom met clinical criteria for affective disorder. Positron emission tomography studies using novel 5-HT ligands have found results compatible with a decrease in a structural component of brain 5-HT neurones. (24) However, most studies have been of polysubstance users and rely on self-reported histories of drug use, and the control groups were not matched for use of other substances.
Acute psychological problems associated with MDMA use Increased anxiety (25,26) and panic (27,28) have been described, with the three cases of the latter study complicated by prolonged agorophobia which responded to serotonergic antidepressant drugs. Major depressive disorder (29) and prolonged depersonalization with panic and suicide following ingestion (30) have also been described. Numerous cases of MDMA-related psychoses have also been reported (31,32) as well as flashbacks (33,34) and even craving for chocolate. (35) It has been suggested (13,21,22) that such idiosyncratic disturbances are more likely to occur in those already predisposed to psychiatric disorders. It is possible that people predisposed to mood disorders may experience their first episode of psychological disturbance earlier than they would have done had they not taken MDMA. Controlled long-term cohort studies of users, with baseline measures of risk factors, are needed to assess this.
More common adverse effects associated with the use of MDMA are more directly related to the psychostimulant effects of the drug, such as increased restlessness, headaches, and bruxism. Weekend use of MDMA has been shown to be associated with depressed mood midweek (36) which could reflect depletion of serotonin following the acute elevation that follows ingestion of MDMA. This could be a parallel to the ‘crash' reported after abstinence of cocaine use (37) or as a hangover effect.
Physical complications from MDMA
Most users of MDMA use other drugs. Concurrent administration of cocaine and amphetamine will potentiate the stimulant effects of MDMA and may increase the likelihood of hyperthermic and cardiac problems. Some users take benzodiazepines and other depressant drugs to treat insomnia and restlessness. Stimulant drugs reduce the individual's awareness of intoxication by alcohol and may lead to higher alcohol consumption and hence increase the risk of accidents.
Other serious physical complications include hepatocellular failure, arterial aneurysms, and cerebral hemorrhages. Of the 70 or so deaths in the United Kingdom reported in association with MDMA use over the last 10 years, most have been from malignant hyperthermia and dehydration, with the remainder secondary to idiosyncratic organ failure involving the heart, liver, and, in several cases, cerebral oedema, possibly linked to the syndrome of inappropriate ADH secretion. (38) The severity of symptoms and potential outcome appear unrelated to dose consumed, suggesting an idiosyncratic response possibly related to genetically determined metabolizer status. The serotonin syndrome and neuroleptic malignant syndrome have also been described. Concurrent consumption of selective serotonin reuptake inhibitors may potentiate the harmful neurochemical and behavioural effects of MDMA. Similar interactions have been noted with monoamine oxidase inhibitors. (39)
Ketamine, a non-barbiturate anaesthetic/analgesic structurally related to phencylidine was developed in the 1960s when it was promoted as an anaesthetic. Unlike inhalational and opiod anaesthetics which work via supresssion of the reticular activating system, ketamine causes functional and electrophysiological dissociation between the thalamocortical and limbic systems. The dissociation results in higher centres being prevented from perceiving auditory, visual, or painful stimuli, i.e. ‘a lack of responsive awareness'. The effect has been described as somataesthetic sensory blockade with amnesia and analgesia.
The major clinical use of ketamine is in veterinary surgery and anaesthetic induction, especially in the young and in emergency situations such as at crashes or war zones where its ability to induce a cataleptic state of muscle rigidity (i.e. a patient placed in one position cannot subsequently move until the drug effects have worn off) is desirable. It has also been reported useful in the management of uncontrollable patients and may augment analgesia with opiates.
In the United Kingdom the drug is not controlled under the Misuse of Drugs Act (being a prescription-only medicine under the Medicines Act) and hence possession is not a criminal offence. It appears that most abused ketamine is obtained through diversion from legitimate sources.
The first reports of ketamine as a drug of abuse appeared in the 1970s. In recent years the drug has become associated with the ‘rave' music scene. The drug sold as powder or capsules (average dose 70–150 mg) may be marketed as itself ‘Special K' or may be a constituent of tablets purportedly sold as ecstasy, in combination with stimulant drugs.
Ketamine is a potent N-methyl-D-aspartate receptor antagonist but also demonstrates stereospecific binding at opiate receptors. The most common routes of administration outside clinical practice are oral and intranasal. After oral administration, effects appear after 20 min, lasting up to 3 h. The onset of action is more rapid and the duration shorter when the drug is snorted. Sought-after effects include a general stimulating effect (‘being put into overdrive'), euphoria, depersonalization, out-of-body ‘floating' experiences, perceptual distortion, and hallucinations.
As with all psychoactive drugs the adverse effects result from the interaction between the individual's genetic and physiological makeup, the dose and route of administration, other consumed drugs, the cognitive set, and the environmental setting. Adverse effects include the following:
- ‘emergence phenomena' (as awakening from anaesthesia) such as vivid dreams, hallucinations, synaesthesia, and delirium
- tachycardia and hypertension
- nausea and vomiting, hypersalivation, and nystagmus
- numbness (with risk of accidental burning or other traumatic injury), ataxia, and slurred speech
- raised intracranial and intraocular pressure.
Flashbacks have also been reported.
Tolerance to ketamine occurs on repeated administration and a small minority may become ‘psychologically' dependent on the experience. There are also reports of psychosis following use as well as chronic memory impairment.
g-Hydroxybutyrate is a naturally occurring fatty acid derivative, derived from g-aminobutyric acid, which may function as an inhibitory chemical transmitter in the central nervous system. It was synthesized for use as an anaesthetic, although trace amounts may be found in certain fruits such as guava. It has been described as an anabolic steroid since it promotes the secretion of growth hormone during slow-wave sleep and has been abused by body builders. Other recently suggested therapeutic uses include the treatment of narcolepsy and the withdrawal from alcohol and opiates. It is colourless and odourless with an insipid taste, and is available as a liquid or occasionally in powder or capsule form. Concentrations of the drug in these preparations are variable and therefore precise dosing is difficult.
Although not controlled in the United Kingdom under the Misuse of Drugs Act, unauthorized manufacture and sale can be an offence under the Medicines Act.
The sought-after effects are sedative and euphoric as opposed to the stimulant effects described with other dance drugs. The effect begins after 10 to 40 min and lasts 8 to 24 h. At low doses euphoria and disinhibition predominate; with increasing dosage, sedative effects become more evident and there may be nausea and vomiting. There have been several reports of acute physical complications following consumption of the drug, with respiratory depression, seizures (usually petit mal type), and coma (usaully with full recovery). g-Hydroxybutyrate is not detected on routine toxicological screens. Complications are likely to be enhanced when the drug is taken with other substances, especially alcohol. A withdrawal syndrome has been described (40) characterized by insomnia, tremor and anxiety.
This perennial shrub, indigenous to Yemen, Ethiopia, and surrounding areas, is used in cultures where alcohol is prohibited. Outside its area of propagation, khat is most commonly used among immigrant Somali communities in the United Kingdom, and elsewhere in Europe and the United States. Concern has grown over recent years regarding possible adverse effects that use of this stimulant herb may have upon both individuals and their societies. For a review of the literature and use in the United Kingdom see Griffiths. (41)
The fresh bitter leaves are usually chewed for their stimulant effect with the extracted juices swallowed and the residue kept within the cheek for some time after. This is a relatively slow mode of administration, requiring prolonged chewing to provide a relatively mild stimulant effect. Less often the leaves may be smoked or infusions prepared. Khat is primarily a social drug and its mild stimulant effects appear to promote social interaction. Users report loquacity, disinhibition, and improved concentration. As with other stimulants, use is associated with anorexia and reduced need for sleep. Although originally used more commonly by men, its use is becoming more common among women.
Khat is a central stimulant, considerably less potent that amphetamine, although it has a similar mechanism of action through the release of presynaptically stored catecholamines. The main stimulant psychoactive components, cathine and the more potent cathinone (both phenylpropylamines), are found in combination with other alkaloids and tannins. Because cathinone is very unstable, fresh leaves are used within a day or two of harvesting.
In the countries in which it is used, assessment of the impact on health is confounded by the poor socio-economic status of many users, and the anorexic effects of use. Reported adverse physical effects include oral problems, constipation, and hepatic and cardiac disturbances. Accidents may occur whilst intoxicated. Khat use has been associated with compulsion to use and dependence, but there does not appear to be a physically characterized withdrawal syndrome. There have been several case reports of short-lived amphetamine-like psychoses among users of khat, although there is little to suggest longer-term psychiatric morbidity among users.
Cathine and cathinone are controlled in the United Kingdom under the Misuse of Drugs Act 1971, as well as under international conventions. However, sale of unprepared khat is not prohibited in the United Kingdom and where legislation does exist it has been difficult to enforce.
Because cathinone decomposes rapidly, the effects are modest, and the drug is usually taken by chewing, unprepared khat is unlikely to enter Western drug use. Cheaper more potent synthetic preparations are better suited and more familiar to groups not culturally associated with its use. A refined preparation of cathinone could be used and there has been an isolated outbreak of use associated with localized manufacture of the derivative methylcathinone in the United States.
Tryptamine (1H-indole-3-ethanamine) is a naturally occurring metabolite of tryptophan. It forms the parent nucleus of a wide range of hallucinogenic drugs, some entirely synthetic (LSD, N,N-dimethyltryptamine) but many naturally occurring in plants, fungi (psilocybin—the psychoactive component of ‘magic mushrooms'), and occasionally animals. It seems unlikely that many tryptamines other than LSD and psilocybin will be used unduly in dance clubs because they possess few stimulant properties, and need to be smoked or injected because most are inactive by mouth unless taken with a monoamine oxidase inhibitor. An example of the latter is the combination of N,N-dimethyltryptamine (the hallucinogen) and harmine (the activator) in the hallucinogenic drink ayahuasca or caapi used in rituals by South American Indians. Drugs such a N,N-dimethyltryptamine may have adverse effects upon both the cardiovascular system and on temperature regulation. They may induce unpleasant hallucinogenic experiences.
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