The most common club drugs or party drugs are MDMA, ketamine and GHB. How dangerous is continued use of these substances? Can they cause real damage to the brain?
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Dr. McDowell is assistant clinicalprofessor at Columbia University. He is thesenior medical director of the Substance Treatment and Research Service (STARS)and director of the Buprenorphine Program. Hemaintains a private practice in Manhattanand has been researching and writing about club drugs for over 12 years.
Dr. McDowell has indicated he hasnothing to disclose.
Club drugs are also called "party drugs," and this name conveys thecommonality and situational nature of their use. They consist of a disparategroup of psychoactive substances and usually include, but are not limited to, 3,4-methylenedioxymethamphetamine (MDMA), ketamineand g-hydroxybutyrate (GHB). The drugs differ interms of administration, mechanism of action and effect. The use of thesesubstances is by no means limited to parties and large gatherings, but it isthere that they are most often found and best understood.
Club drugs have been linked inextricably with the rise of the ravephenomenon. Anecdotal reports suggest that raves were "born" in Ibiza, anisland off the coast of Spain(Bellis et al., 2000). Raves have periodically beenconsidered "the next big thing" episodically, but have developed into abackground subculture. However, raves remain a locus where young people areintroduced to and use drugs of all kinds and club drugs in particular.
At raves, groups of young people dance to rapid, electronically synthesized,lyric-free music called techno. Ravestake place in a variety of venues, most of which are not strictly commercial orregulated, such as abandoned stadiums, fields or other out-of-the-way publicspaces. Teen-agers and young adults consider club drugs the perfect match forthis scene. At most of these events, a substantial majority of raveparticipants may be using MDMA, ketamine, GHB orother drugs, such as marijuana and lysergic acid diethylamide (LSD) (Lee etal., 2003; McDowell and Kleber, 1994; Winstock et al., 2001). Polysubstanceuse might be considered the norm at such events, withover 80% of participants using more than one substance (Winstocket al., 2001).
Such rampant drug use has inspired efforts at harm reduction and educationalefforts to promote "responsible" use of the drugs-an approach that remains, notsurprisingly, controversial. Some organizations offer on-site verification ofthe authenticity of drugs. Perhaps the most prominent and well funded of theseorganizations, DanceSafe <www.dancesafe.org>,offers a wide variety of services and advice (Koesterset al., 2002). At times the advice has backfired, such as when the admonitionto drink copious amounts of water to avoid dehydration while using these drugshas resulted in hyponatremia and comas.
Ecstasy is the most popular namefor MDMA. It is sometimes classified as a stimulant, and while it does havesimilar properties to the amphetamines, it also has some unique effects (Hermle et al., 1993; Shulgin,1986). It is usually taken in pill form and has the effect of making the userfeel close and bonded to those around them. Typically, young people takeEcstasy in a dance or rave setting and dance the night away. The acute dangersassociated with MDMA are rare, but serious, and usually involve dehydrationthat may result in coma or death. The long-term effects are more insidious, andinvolve MDMA-use-induced neurotoxicity.
In the United States,MDMA was legal until July 1, 1985, when it was made a Schedule I drug.(Medications are "Scheduled" from I to V, with Schedule I being the mostrestricted and regulated. Schedule I medications are said to have a high abusepotential and no therapeutic value.)
Over the past two decades, MDMA has undergone an almost cyclic flow ofpopularity, with successive generations "discovering" the drug (Cohen, 1998;Morgan, 2000). It is a popular choice because those who take MDMA feel good.This feeling is a dramatic, consistent and profound feeling of attachment andconnection in the user. Many consider the drug misnamed; the Los Angeles drug dealer who coined the term Ecstasy originally wanted to call thedrug Empathy, but asked, "How manypeople would know what [empathy] means?" (Eisner, 1968).
Although there is a minority that disagrees with the conclusion, it hasbecome increasingly apparent over the past decade that MDMA is neurotoxic to humans. It has long been known to damagebrain serotonin (5-HT) neurons in laboratory animals (McCann and Ricaurte, 1993; Montoya et al., 2002). Furthermore, theresulting neurotoxicity has real and functionalimplications (McCann et al., 2000; Montoya et al., 2002; Morgan, 2000; Spragueet al., 1998). Ecstasy use is associated with sleep, mood and anxietydisturbances; elevated impulsiveness; memory deficits; and attention problems.Many of these disturbances appear to be permanent and seem likely to depend onthe overall amount of MDMA consumed over time, but there is evidence that theymay be caused by as little as a single dose (Rodgers, 2000; Turner and Parrott,2000).
History of MDMA
Ecstasy is not a designer drug. The process for the creation of MDMA was patentedin 1914 by Merck & Co., Inc., in Darmstadt, Germany (Shulgin, 1986). Humans probably first used MDMA in the late1960s. It was discovered as a recreational drug by so-called New Age seekers,people who liked its properties of inducing feelings of well-being andconnection (Watson and Beck, 1986). The drug does induce feelings of warmth andconnectedness, and using this rationale, its use was promulgated by therapistsin the 1970s (Shulgin, 1990). Before the compoundbecame illegal in 1985, it was used extensively for this purpose (Beck, 1990).
Ecstasy became increasingly popular, especially in those who used it infestive settings during the early 1980s. In 1984, production reached at least30,000 tablets per month, and, despite its widespread use during the early1980s, the drug did not attract much attention from the media or from lawenforcement officials (McDowell and Kleber, 1994).
Although for an organic chemist, the synthesis of MDMA is reasonably simple,most supplies in the United States are imported and then distributed byorganized crime networks. Its price, usually $25 to $40 for a 125-mg tablet--theamount producing the sought-after effect in most intermittent users (Green etal., 1995)--has remained remarkably stable over the past two decades. This highprice makes adulteration highly tempting--such adulteration can be eitherharmless, with the buyer being duped, or harmful, if the substitute issomething dangerous.
Physiological Effects of MDMA
Ecstasy is almost exclusively available in pill form. Often the pills arestamped with clever images. The usual single dose is 100 mg to 150 mg. Theonset of effect begins about 20 minutes to 40 minutes after ingestion and isexperienced with immediacy. The plateau stage of drug effects lasts three hoursto four hours. The principal desired effect, according to most users, is aprofound feeling of relatedness to the rest of the world around them (Liester et al., 1992). Although the desire for sex canincrease, the ability to achieve arousal and orgasm is greatly diminished inboth men and women (Buffum and Moser, 1986). Thus,MDMA has been termed a sensual, not sexual, drug. Prescription drugs such as sildenafil (Viagra) may be taken in order to counteractthis effect and may be sold along with MDMA (Weir, 2000). The array of physicaleffects and behaviors produced by MDMA is remarkably similar across mammalianspecies (Green et al., 1995) and includes mild psychomotor restlessness, bruxism, trismus, anorexia,diaphoresis, hot flashes, tremor and piloerection (Peroutka et al., 1988).
After-effects associated with MDMA are common and can be pronounced. Peopleusing MDMA once, or on multiple occasions, may experience any number ofsymptoms including lethargy, anorexia, decreased motivation, sleepiness, depressionand fatigue. Severe, immediate effects appear to be rare, but they do occur.Altered mental status, convulsions, hypo- or hyperthermia, severe changes inblood pressure, tachycardia, coagulopathy, acuterenal failure, hepatotoxicity, rhabdomyolysis,and death have all occurred (Demirkiran et al., 1996;Kalant, 2001).
Mechanism of Action of MDMA
Ecstasy is primarily serotonergic, and itsprincipal mechanism of action is as an indirect serotonergicagonist (Sprague et al., 1998). The drug's effects, and side effects (anarbitrary distinction), including anorexia, psychomotor agitation, difficultyin achieving orgasm and profound feelings of empathy, can be explained as aresult of the flooding of the serotonin system (Beck and Rosenbaum, 1994).
Most people who use MDMA on a regular basis tend not to increase their useas time goes on (Cohen, 1998; Peroutka, 1990).Because of its mechanism of action (the drug depletes serotonin stores andinhibits synthesis of new serotonin), subsequent doses produce a diminishedhigh and a worsening of the drug's undesirable effects, such as psychomotorrestlessness and teeth gnashing. People who use MDMA most typically becomeaware of the benefits of periodic, and even rare, use. First-time users areoften instant advocates of MDMA, only to have their enthusiasm dampen withtime. An adage about Ecstasy captures this succinctly: "Freshmenlove it, sophomores like it, juniors are ambivalent, and seniors are afraid ofit" (Eisner, 1993).
The most important individual and public health danger posed by thewidespread use of MDMA is its likelihood to cause the permanent destruction ofserotonin axons in humans who use it. The ingestion of MDMA in laboratoryanimals causes a decrease in the serum and spinal fluid levels of 5-HIAA in adose-dependent fashion (McCann et al., 2000; Shulgin,1990) and damages brain serotonin neurons (Burgess et al., 2000; McCann and Ricaurte, 1993; Montoya et al., 2002). The dosage necessaryto cause permanent damage to most rodent species is many times greater thanthat normally ingested by humans (Shulgin, 1990); innonhuman primates, however, the neurotoxic dosageapproximates the recreational dosage consumed by humans (McCann and Ricaurte, 1993). To date, MDMA has been found to damageserotonin neurons in all animal species tested (McCann et al., 1996), and thesame is likely to occur in humans.
Human studies are, for obvious reasons of safety and ethics, more difficultto execute, and those that are done offer legitimate and ample room forcriticism. The bulk of evidence that MDMA is neurotoxicin humans is indirect, but convincing (Burgess et al., 2000; Green et al.,1995). This evidence includes metabolite studies, which quantify the levels ofserotonin and metabolites in populations of those people who use Ecstasy. Thereare an increasing number of investigations demonstrating that metabolite levelsof serotonin are much lower in chronic users, even when they remain abstinentfor long periods of time. The difficulties of the studies notwithstanding, theavailable clinical evidence suggests that repeated ingestion of high doses ofMDMA produces long-term reductions in serotonergicactivity and degeneration of serotonergic terminalsin humans (Montoya et al., 2002).
Extensive cognitive studies in individuals using MDMA, though rife withmethodological problems, show a consistent pattern of cognitive dysfunctionseen in the frontal cortex and the hippocampus. This phenomenon is consistentwith that found in animals exposed to MDMA (Fox et al., 2001; Montoya et al.,2002). Psychiatric problems, such as depression, anxiety, panic, increasedimpulsiveness and sleep disturbances, are significantly higher in people whohave used MDMA, even while abstinent and when the last use was remote. In asymposium titled "Is MDMA a human neurotoxin?" Turner and Parrott (2000)concluded:
Novel studies ... confirmed and extended the range of cognitive,behavioral, [electroencephalographic], and neurological deficits, displayed bydrug-free Ecstasy users. Moreover, these deficits often remained when otherillicit drug use was statistically controlled. In conclusion: If MDMA neurotoxicity in humans is a myth, then it is a myth with aheavy serotonergic component.
The reader is directed to several excellent and extensive reviews of theparticular subject of MDMA and neurotoxicity (McCannet al., 2000; Montoya et al., 2002; Verkes et al.,2001).
Treatment for MDMA Abuse
The treatment of MDMA abuse may be divided into the treatment of acutereactions to the drug and the treatment of those who abuse the drugchronically.
Urgent treatments.Fatalities from Ecstasy use and overdose, although rare, do occur. Because polydrug use is the norm at many of the venues whereEcstasy is popular (Lee et al., 2003), it is sometimes difficult to ascertainthe contribution of MDMA versus other substances. Fatalities can be caused byhyperpyrexia, rhabdomyolysis, intravascular coagulopathy, hepatic necrosis, cardiac arrhythmias and cerebrovascular accidents, as well as by a variety ofbehaviors associated with confusion and impaired judgment (Kalant,2001).
Ecstasy has many chemical similarities to amphetamine drug detectionproducts and may indicate a positive presence of amphetamine after use.Intoxication or overdose of MDMA may be suspected in any individual withalterations of sensorium, hyperthermia, musclerigidity and/or fever. Because the drug is used in specific settings and byspecific subgroups, the level of suspicion should be proportional to the userand the circumstance involved. In addition, the clinician should have a highdegree of suspicion that the patient may have taken multiple drugs. Drugs thatmay have been substituted for Ecstasy tablets, such as ephedrine, Ma-Huang(herbal Ecstasy; Ephedra sinica) and caffeine,should be considered.
Ecstasy overdose would most likely involve the ingestion of multiple dosesand would also most likely occur in an environment that induced dehydration.Overdose or toxic reaction to MDMA is a diagnosis by exclusion. Supportivemeasures, such as effective hydration using intravenous fluids and lowering thetemperature of the patient with cooling blankets or an ice bath, are oftennecessary. Standard gastric lavage should be employed(Ajaelo et al., 1998; Schwartz and Miller, 1997).Physical restraint may be necessary for agitated patients but should be usedsparingly. Benzodiazepines are the preferred choice of sedating agent (Shannon, 2000). Hypertension often resolves withsedation. If it persists, nitroprusside (Nitropress) or a calcium-channel blocker is preferred overa β-blocker, which may worsen vasospasm and hypertension (Holland, 2001).
Nonurgent treatment.Ingestion of MDMA may be associated with a number of adverse psychiatricsymptoms, notably anxiety, panic and depression. These symptoms usually subsidein a matter of hours or days. Support and reassurance are often all that isneeded. If the symptoms are of a more serious nature, brief pharmacotherapy toalleviate symptoms is recommended.
Although classical physiological dependence on MDMA does not occur, someindividuals use the drug compulsively. For these people, the standard array oftreatments, based on a thorough assessment of internal and external resources,should be employed. Clinicians are cautioned against adopting a knee-jerknegative attitude. People, in particular the young, use drugs for validreasons, often because the drugs temporarily make them feel better. Automaticnegativity may inadvertently preclude the initiation of a therapeutic alliance.
Ketamine is usually taken as a gray powder that isinhaled through the nose. The results are dose dependent and cause a feeling ofaltered reality and a feeling of being removed from one's body.
History of Ketamine
Ketamine was first manufactured in 1965, as theresult of a search for an anesthetic that would not compromise respiration norcause the same negative side effects as phencyclidine (PCP), specificallypsychosis and violence, after administration. Veterinarians and pediatricsurgeons still legally manufacture it, primarily for therapeutic use; recentcrackdowns on the illegal distribution of ketaminefrom these sources have led to the increased smuggling of it from foreignsources. Special K, Super K, Vitamin K, or just plain K,are all names for the nonanalgesic anesthetic.
Physiological Effects of Ketamine
Ketamine is classified as a dissociativeanesthetic. As this classification implies, the drug causes a dose-dependent dissociative episode with feelings of fragmentation,detachment and what one user has described as "psychic/physical/spiritualscatter." Use of ketamine imparts a disconnectionfrom awareness of stimuli from the general environment. These stimuli include,but are not limited to, pain.
Ketamine is a close chemical cousin of PCP, alsoknown as angel dust. Ketamine produces minimalcardiac and respiratory effects, and its anesthetic and behavioral effectsremit soon after administration (Moretti et al.,1984; Pandit et al., 1980). In addition, ketamine does not cause the same type of behavioralproblems associated with PCP. The medication continues to have therapeuticusefulness, principally with children and animals.
Ketamine is a noncompetitive N-methyl-D-asparate (NMDA) antagonist (Curran and Monaghan, 2001). Itsubstantially disrupts both attention and learning. In human research subjects,ketamine affects the ability to modify behavior, tolearn new tasks and to remember (Curran and Monaghan, 2001; Krystalet al., 1994). Overdose from ketamine is very rare. Asingle dose of ketamine creates a "trip" that lastsabout one hour (Dalgarno and Shewan,1996); larger doses last longer and have a more intense effect (Malhotra et al., 1996). The user feels physical tingling,followed by a feeling of removal from the outside sensory world. Tolerancedevelops rapidly, and dependence, though rare, is well documented. Flashbackshave been reported, and their incidence may be higher than with many otherhallucinogens (Siegel, 1984). Mild doses induce an autistic stare and adiminishment of thought. Higher doses result in the phenomena of the "K-hole,"which is characterized by social withdrawal, autistic behavior and an inabilityto maintain a cognitive set. Individuals experiencing such conditions may be describedas zombie-like (Gay Men's Health Crisis, 1997).
Treatment for KetamineAbuse
The most dangerous effects of ketamine arebehavioral. Individuals may become withdrawn, paranoid and physically awkward.An individual who is intoxicated on ketamine shouldbe placed in a part of the clinic or emergency department with the least amountof light and stimulation--the less stimulation the better. If necessary, thepatient may be given benzodiazepines to control the associated anxiety (Graeme,2000); however, antipsychotics should be avoidedbecause their side-effect profile may cause discomfort, which could possiblyexacerbate the patient's agitated state.
Ketamine is an addictive drug. Numerous reportsexist of individuals becoming dependent on the drug and using it daily(Galloway et al., 1997; Jansen and Darracot-Cankovic,2001). Such dependence should be treated in the manner of any other chemicaldependency. Treatments such as group therapy or manualizedrelapse prevention are recommended.
Gamma-hydroxybutyrate (GHB) is a largelytasteless, clear liquid. Individuals taking it describe feelings similar tointoxication from alcohol, but with increased stimulation. The effects are dosedependent with small doses (about a teaspoon) resulting in mild disinhibition and larger doses resulting in even higherlevels of disinhibition. Even larger doses, but stillquite small amounts (not much more than a tablespoon), may result insomnolence, unresponsiveness, respiratory depression, coma and death.
History of GHB
First synthesized in the mid-1970s (Vickers, 1969), GHB was popular withbodybuilders and readily available in health food stores during the 1980s. Itcame to the attention of authorities in the late 1980s as a drug of abuse, andthe U.S. Food and Drug Administration banned it in 1990, after reports ofseveral poisonings (Chin et al., 1992). In the past decade, it has become morewidely known as a drug of abuse associated with nightclubs and raves. Inaddition, it has achieved notoriety as a "date-rape drug."
Gamma-hydroxybutyrate can be found occurringnaturally in many mammalian cells. In the brain, the highest amounts are foundin the hypothalamus and basal ganglia (Gallimberti etal., 1989). It is likely that it is a neurotransmitter, although its preciserole is unclear (Galloway et al., 1997). Closely linked to γ-aminobutyric acid (GABA), GHB is both a precursor and ametabolite of GABA (Chin et al., 1992).
With an extremely small therapeutic index, as little as double the euphorigenic dose of GHB may cause serious central nervoussystem depression. In recent years, it has been associated with numerousincidents of respiratory depression and coma, and an increasing number ofdeaths have been linked to GHB (Li et al., 1998).
The legal status of GHB is complicated. In 2001, GHB, which is classified asa Schedule III controlled substance, was given an FDA approvable letter withspecial regulations under the brand name Xyrem. It isavailable only from a single specialty pharmacy (Tunnicliffand Raess, 2002). Most of the GHB sold in the United Statesis of the bootleg variety, manufactured by nonprofessionals. In fact, it isrelatively easy to manufacture, and Internet Web sites devoted to explainingthe process can be readily found. Of course, there is clever concealment andsubterfuge in most of these sites.
Physiological Effects of GHB
Ingested orally, GHB is absorbed rapidly and reaches peak plasmaconcentrations in 20 minutes to 60 minutes (Vickers, 1969). The typical dose isabout a teaspoon, but the effects are dose dependent. The high lasts aboutthree hours and reportedly has few lasting effects, but repeated use of thedrug can prolong its effects.
Users of GHB report that it induces a pleasant state of relaxation andtranquility. A frequently reported effect is calmness, accompanied byloquaciousness. Like MDMA, GHB has also been described as a sensual drug. Itseffects have been likened to alcohol, another GABA-like drug (McCabe et al.,1971). Users report a feeling of mild numbing and pleasant disinhibition,which accounts for the reports that GHB enhances the experience of sex. Thedose-response curve for GHB is exceedingly steep. The LD-50 is estimated atperhaps only five times the intoxicating dosage (Vickers, 1969). Furthermore,the drug has synergistic effects with alcohol and other drugs. Therefore, smallincreases in the amount ingested may lead to significant intensification of theeffects and to the onset of central nervous system depression. Coma andpersistent vegetative states and death may result from overdose (Chin et al.,1992; Gallimberti et al., 1989; Takaharaet al., 1977; Vickers, 1969).
Mechanism of Action of GHB
The drug has several different actions in the CNS, and it has a variety ofeffects on dopamine and growth hormone, as well as naturally occurring opiates(Galloway et al., 1997; Hechler et al., 1992). Theconsequences of these physiological changes are unclear, as are the overallhealth consequences for individuals who use GHB chronically.
Treatment for GHB Abuse
linicians are advised tokeep GHB in mind when confronting a patient with somnolence or loss ofconsciousness. In cases of acute GHB intoxication, physicians should providephysiological support and maintain a high index of suspicion for intoxicationwith other drugs. Most patients who overdose on GHB recover completely if theyreceive proper medical attention. A recent review suggested the followingfeatures for the management of GHB ingestion with a spontaneously breathingpatient (Li et al., 1998):
If the patient's breathing is labored, they should be managed in the intensivecare unit.
Prolonged GHB use results in physiological dependence. The symptoms aresimilar to that of alcohol withdrawal and include anxiety, tremor, insomnia and "feelings of doom," which may persist forseveral weeks after cessation of use (Galloway et al., 1997). Benzodiazepinesare likely the treatment of choice for acute GHB withdrawal (Green et al.,1995). Because data are lacking, clinicians must exercise their most prudentjudgment regarding what will be most helpful in a given situation.
Ecstasy, ketamine and GHB are the most emblematicof the drugs found at raves and clubs. Often used concomitantly with thesedrugs, attendees also use more traditional drugs, such as LSD and otherhallucinogens. In addition, marijuana is perennially popular, and alcohol useis also common. The evidence that MDMA causes neurotoxicityis compelling, and GHB has been the cause of substantial numbers of overdose.The younger individuals are when they first use drugs, the more likely theywill go on to use more drugs. This is cause for a call for effective educationand prevention measures.
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