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Drugs frequently abused at dance clubs and circuit parties are known collectively as "club drugs." Club drug use is common among populations with, and at high-risk for, HIV-infection (Colfax et al., 2006). Ketamine, a powerful anesthetic used in veterinary and human medicine, continues to gain in popularity in the drug abuse scene or "Rave Wave" of all-night dance marathons. As the primary analytical laboratory for criminal investigative agencies in the Department of Defense, the Division of Forensic Toxicology Laboratory in the Office of the Armed Forces Medical Examiner at the Armed Forces Institute of Pathology has seen requests for ketamine analysis rise due to increasing abuse (Moore et al., 2001).

Ketamine - which is commonly snorted, smoked, and ingested - has emerged as a parenteral drug of abuse increasingly prevalent among injection drug users who are sharing contaminated drug-injection equipment (Lankenau et al., 2005). Furthermore, data collected from inmates as part of the Transitional Case Management protocol within the Criminal Justice Abuse Treatment Studies cooperative agreement reveals HIV-associated high-risk sexual behaviors (e.g., unprotected anal sex) among ketamine-abusing criminal offenders prior to prison entry (Oser et al., 2008).

There is a prevailing view among abusers that ketamine is not harmful; abusers believe that the drug has a wide-margin of safety and low potential for dependence. However, studies show that most ketamine abusers demonstrate features of physiological dependence after regular ketamine abuse and report withdrawal symptoms on stopping ketamine use. In addition to drug-induced neuropsychological effects, abuse of ketamine causes an array of medical complications including hepatobiliary and urologica! toxicity (Chen et al., 2004; Chu et al., 2008; Felser et al., 1982; Jansen et al., 2000; Selby et al., 2008; Shahani et al., 2007).

Clinical Case 1

A 25-year-old man consulted a physician in order to discuss "issues in his lifestyle that needed expert medical attention." The man disclosed that he was a longstanding devotee of the club scene with a particular preference for "Special K" (i.e., ketamine). He reported that he sought the "near death experience" obtained on the drug - "You just feel like you're really dead," he said, insisting that this was a profoundly spiritual experience - "like meeting God" (Fitzpatrick, 2003).

Clinical Case 2

A 28-year-old man was admitted to an addiction center for treatment of ketamine dependence. His drug abuse history included onset of cannabis use at age 11; he became a dependent user of cannabis at age 1 8. He started drinking alcohol at age 18, and rapidly escalated to 750 ml of distilled spirits daily. At age 24 he began parenteral (injection) abuse of the opioid pentazocine; as tolerance developed, the dose increased over the ensuing 4 years to 500 mg per day in 5 to 6 divided doses. Parenteral abuse of ketamine followed.

He self-injected 2 to 4 ml (100 to 200 mg) of ketamine daily, and was injecting ketamine at home and at work. He described his ketamine-induced experiences: altered perception of time; feeling of floating in air; increase in size of his hand and arm; watching his own body from the outside; and feeling as if his body was made of wood. These experiences would start within 5 to 10 minutes after each injection and would last for 1/2 to 1 hour. Tolerance developed and over a period of 2 to 3 months, he increased the dose of ketamine 5-to-10fold to 20 ml per day (1000 milligrams; 1 gram) divided into 6 or 7 injections per day. At this point he sought in-patient treatment and was admitted to the addiction center for detoxification (Pal et al., 2002).

Clinical Case 3

A 25-year-old man was hospitalized for detoxification treatment of ketamine abuse. The patient had been abusing ketamine for 6 years and his daily use was between 1 and 7 grams per day. He used ketamine by evaporating the liquid down to powder and snorting it.

The patient described a rapid increase in the quantity of ketamine used, with a gaining of tolerance on an hour-by-hour basis. He described several phenomena caused by ketamine intoxication: euphoria; symptoms of depersonalization and derealization; experiencing a combination of senses simultaneously such as sounds and colors; tunnel vision and rising above his body like a near-death experience; a sensation that his hands and feet seemed large and numb; and that objects in the world seemed large and soft. These ketamine-induced effects lasted between 20 to 60 minutes. An observer reported that the patient's speech and ideas were "mixed up and illogical" during the episodes of ketamine intoxication.

The patient described a pattern of behavior in which he had an overwhelming desire to use ketamine that was difficult to control. He had continued abusing ketamine despite evidence that ketamine caused him harm in terms of his health, relationships, and work. He had suffered a perforated nasal septum, abdominal pain, and anorexia with weight loss.

The patient described withdrawal effects experienced following abrupt discontinuation of heavy (4 to 7 grams per day for over 1 week) ketamine abuse:

* 1 to 4 hours after cessation - craving and drug hunting, ransacking his house looking for ketamine.

* 4 to 8 hours after cessation - anxiety, shaking, sweating, palpitations, and depressed mood.

* 24 to 48 hours after cessation - tiredness, poor appetite, and depressed mood (at this point, he would take to bed for 24 consecutive hours).

The diagnosis was ketamine dependence syndrome Internationa! Classification of Diseases version 10 [ICD-10 Dependence Syndrome - other psychoactive substances, F19.25]). After three sessions of motivational interviewing, the patient decided to undergo detoxification. He was abstinent for 3 weeks; his mood, memory and concentration improved, and he gained employment. Nevertheless, there continued to be short periods of ketamine abuse, up to 3 days every 14 days, with a maximum of 2 grams per session (Critchlow, 2006).

Clinical Case 4

A 24-year-old woman was admitted to a psychiatric ward for treatment of depression and ketamine dependence. She had been snorting powdered ketamine for 2 years. The patient reported that during the 6 months prior to hospital admission, she rapidly increased her abuse of ketamine to 2 grams per day, and during this period severe dysuria, urinary frequency, and urgency developed. She visited several gynecologists and urologists, but a series of examinations including urinalysis, urine culture, pelvic examination, and hysteroscopy were all negative; interstitial cystitis was diagnosed. The symptoms subsided significantly within 2 weeks of discontinuation of ketamine in the restricted environment of the psychiatric ward (Chen et al., 2009).

Clinical Case 5

A 21-year-old woman was hospitalized for evaluation of recurrent epigastric pain. She had a history of ketamine abuse for 18 months, and complained of colicky epigastric pain during the past year. Liver function tests snowed elevated alkaline phophatase (ALP; 122 IO /L) and alanine aminotransferase (ALT; 333 IU /L) levels. An ultrasound scan revealed a dilated common bile duct with a normal gall bladder. Computed tomography (CT) showed fusiform dilatation of the entire length of the common hepatic and bile duct up to 9 millimeters in diameter, which tapered smoothly to the pancreatic head. No gross obstructive lesions were seen on the CT scan. A nasobiliary drain was inserted for biliary drainage. During this hospitalization, the patient also reported recent onset of lower urinary tract symptoms.

Her symptoms and liver function gradually improved and the nasobiliary drain was removed. The patient ceased abusing ketamine after discharge. A follow-up magnetic resonance cholangiopancreatogram (MRCP) 3 months later showed resolution of the common bile duct dilatation, with the mid-common bile duct measuring 4 millimeters in diameter. The patient's liver function had also returned to normal.

Unfortunately, the woman resumed abuse of ketamine and was re-hospitalized for epigastric pain. Once again, her blood tests showed abnormal liver function with an elevated ALP (158 IU /L). She was treated conservatively and her symptoms subsided soon after admission (Wong et al., 2009).

Clinical Case 6

During a surgical case in a hospital operating room, the anesthetist was noted to be in an unresponsive "trance-like" state. The anesthetist's vital signs showed elevated blood pressure and tachycardia.

The anesthetist was taken to the hospital's emergency room. Twenty minutes later, his mental status cleared. A medicine consultant suggested that the anesthetist's mental status change had been most likely caused by low blood sugar (hypoglycemia). However, it was subsequently discovered that the anesthetist had intentionally withheld pertinent medical information from the emergency room physicians - he had not disclosed his ongoing abuse of ketamine.

The anesthetist had been snorting ketamine for 2 years; he obtained his supply of ketamine from the operating room. Initially, he began abusing ketamine to alleviate dysphoric feelings related to job dissatisfaction and stress. He snorted just enough ketamine to calm himself, as a small amount of alcohol might do, since larger amounts impaired both speech and motor function. He carefully adjusted his doses so as to not affect his ability to work in the operating room. However, he had to increase his use of ketamine to 3 times a day to obtain the same effect once achieved with a single daily dose (i.e., development of tolerance). He had tried to quit without help, achieved 2 months of sobriety, but returned to ketamine abuse because he found its addictive powers so compelling (Moore, 1999).

Clinical Case 7

An anesthetist was noted to be ataxic and disoriented in the operating room. He was admitted to the hospital's medicine unit for evaluation.

The anesthetist quickly reconstituted and his admission physical examination was unremarkable. Standard laboratory tests were normal and urine toxicology screen and blood alcohol were negative. However, when confronted by the consult team, the anesthetist admitted to injecting himself with ketamine procured at work. He stated that he took ketamine recrea tionally for its "hallucinatory effects." In response to a decreased hallucinatory effect after several months of daily use, he had increased both the dosage and frequency of use (i.e., tolerance).

The anesthetist had a history of experimental drug use in his youth. He also had a previous history of substance abuse at work, having lost his credentials several years earlier for abusing both ketamine and alcohol. After attending a four-week inpatient rehabilitation program followed by a six-week outpatient rehabilitation program, he had been re-credentialed. Nevertheless, despite the rehabilitation programs, the anesthetist was not able to resist reinitiating ketamine abuse and was found ataxic and disoriented in the operating room (Moore et al., 1999).

Clinical Case 8

A 28-year-old male emergency medical technician was found dead in his apartment. The decedent was found wearing lady's panties, net stockings, bra, corset, and high-heeled shoes; leather belts were restraining his wrists and ankles. Under the decedent's hands lay a disposable syringe. Plastic tubing was connected to an intravenous catheter inserted in the right antecubital vein, and a urethral catheter attached to a collection bag was inserted in the penis. The decedent's head was wrapped with an ace bandage, there were covering eye-patches, he was wearing a cervical collar, and his oral cavity was filled with a rubber ball. A bedside table contained syringe needles, and an almost empty bottle originally containing 10 ml of ketamine. Several sex magazines depicting bondage scenes and a vibrator were also found. Investigators concluded that the decedent had sought autoerotic sexual arousal through bondage and intravenous administration of psychotropic ketamine.

Postmortem toxicological examination revealed a high level of ketamine with a concentration of 2.5 ug/ml in femoral vein blood, well within the therapetitic range (1.0-6.0 ug/ml). Autopsy and toxicological findings led the medical examiner to conclude that the man's death was caused by autoerotic asphyxia; lethal hypoxia was induced by a combination of high-dose intravenous ketamine (respiratory depression), and a complex bondageinduced gag-mechanism that produced obstruction of the respiratory tract (suffocation) (Breitmeier et al., 2002).

Discussion

Ketamine was synthesized in 1962, and like its close relative phencyclidine (PCP), was designed specifically to be a dissociative anesthetic, but free of the violent confused behavior patients emerging from PCP anesthesia had often demonstrated.

Although PCP failed to be approved for medical use as an anesthetic agent, it quickly became a popular street drug. Recreational PCP abusers valued it for its psychedelic properties. However, the terrifying hallucinations and sensory numbing PCP induced often led those under its influence to display violent and erratic behavior, including superhuman strength and imperviousness to painful stimuli along with telltale ataxia and nystagmus. Those in a user's path, including emergency and law enforcement personnel, were at considerable risk of serious injury if the paranoid or disoriented user attacked. Ketamine, on the other hand, "comparatively gentle," was initially touted as safe and reliable.

From its first use in humans, ketamine was known to cause dissociation, a disconnection between the sensory system and the limbic/cortical system, resulting in lack of awareness of pain sensations. However, from patient testimony, anesthesiologists soon discovered that ketamine had many psychotropic effects. Patients described bizarre dreams while under ketamine's influence; reported "flashback" phenomena for several days after surgery; and experienced agitation coming out of anesthesia, requiring sedation with benzodiazepines to prevent accidental self-harm. Psychic emergence phenomena of ketamine were described as floating sensations, vivid dreams (pleasant and unpleasant), hallucinations, and delirium. Ketamine was therefore not very different from PCP, except that it has a much shorter duration of action (shorter half-life).

As occurred with PCP, ketamine became a popular drug of abuse. Recreational drug abusers obtained ketamine through underground "medicinal chemists," and pharmaceutical ketamine was diverted from veterinary offices. Street-ketamine refers to the nonpharmaceutical grade ketamine available in the underground market for the purpose of abuse; it is always an impure compound containing variable amounts of ketamine (31%-90%).

Ketamine has various street names including Special K, Vitamin K, Kit-Kat, Keets, Kay, K, Special LA Coke, Super Acid, Super C, Green, Purple, Mauve, Jet, and Cat Valium. Several of the street names for ketamine refer to the green crystalline appearance of powdered ketamine, or the dark red color of Vitamin B12 with which it is often admixed in the belief that this mmLmizes adverse reactions. Ketamine is pharm aceutically manufactured as an injectable liquid but is available on the street in liquid, powder, or pill forms. There are various modes of ketamine administration as it can be ingested, snorted, smoked, injected subcutaneously, injected intramuscularly, or injected intravenously.

The effects associated with ketamine have a rapid onset (30 seconds to 30 minutes, depending on the route of administration used) and last 30 to 180 minutes. Effects begin approximately 30 seconds after an intravenous injection; 2 to 4 minutes after an intramuscular injection; 5 to 10 minutes after intranasal use; and 10 to 30 minutes after an oral dose on an empty stomach or by rectal injection (using a lubricated syringe with the needle removed; ketamine has an unpleasant taste and irritates the nose). Duration of the psychedelic effects varies from 10 minutes (intravenous) to an hour (intramuscular) to 4 hours (oral). Psychedelic doses are about 10% to 25% of anesthetic doses. As tolerance develops, the psychedelic effects have a much shorter duration of action. A club "bump" for intranasal use is 200 mg; psychedelic doses for intramuscular use are 50 to 150 mg; and oral doses are usually 350 to 500 mg.

Abusers seek ketamine-induced near death experiences (i.e., an altered state of being - dissociative mental state). Abusers report the following phenomena: no fear of death; unconcerned whether one lives or dies; departing the physical body with a conviction that one has died; entering a place where everyone who has ever died resides; a sense of energy that everyone who has ever moved-on (died) is there together; seeing God; having telepathic communion with God; inability to feel pain; awareness exits the body and travels through a tunnel towards light; ringing, buzzing, and whistling sounds followed by travel at high speed; perceptions of falling; entering other realities; feeling connected to the cosmos; clarity of thought; emergence of old memories; a life review; euphoria; and visions of landscapes, angels, and religious and mythical figures. However, rather than "Paradise," abusers may emerge into "Hell." They experience a loss of contact with external reality and the sense of being part of other, more fundamental realities may be overwhelming.

Clinicians recognize a spectrum of acute adverse neuropsychological effects of ketamine: ataxia, slurred speech, blurred vision, dizziness, confusion, cognitive impairment, hyperexcitability, unpleasant imagery, anxiety, nausea, and insomnia. Long-term adverse effects include flashbacks, attentional dysfunction, memory impairment, tolerance, and high dependency potential. In 1979, the Federal Food and Drug Administration (FDA) warned of ketamine's abLise potential and considered making it a controlled substance (FDA Drug Bulletin, 1979); however, for unclear reasons, this did not happen for 20 more years. Finally, in 1999, ketamine was classified as a Schedule III drug under the Controlled Substances Act making ketamine possession for nonmedical purposes illegal in the United States.

Adverse effects of ketamine abuse are well known to physicians and nurses who work in emergency rooms and poison control centers. A case series published in the Journal of Emergency Medicine noted that among 20 self-reported ketamine abusers who sought medical assistance in emergency rooms, presenting complaints included anxiety, palpitations, chest pain, confusion, vomiting, and memory loss. Of the 20 patients, 11 patients stated that they had injected the ketamine (at doses of 100-200 milligrams); 9 patients stated that they had inhaled ketamine powder; 1 patient admitted to simultaneous use of LSD; and another stated that he had used methamphetamine before injecting ketamine. In the emergency room, physical examination findings included tachycardia (ranging from 100-140 beats per minute), altered mental status, slurred speech, nystagmus (rotatory), mydriasis, and hypertension; three of the patients were actively hallucinating in the emergency room. Five patients had agitation severe enough to warrant benzodiazepine treatment for sedation. One patient with chest pain and hypertension (blood pressure 180/100 mmHg) was treated with intravenous metoprolol and underwent a stress test 12 hours after presentation (the result was unremarkable). Ketamineinduced cardiovascular toxicity manifests as hypertension, tachycardia, palpitations, and chest pain. Elevated doses of ketamine induce respiratory depression, loss of pharyngeal reflexes, and apnea. Note that Patient 8, who sought autoerotic sexual arousal and orgasm, experienced fatal asphyxia caused by a dual combination of ketamine-induced respiratory depression, and bondageinduced airway obstruction caused by a complicated gag-mechanism inspired by pornographic magazines depicting bondage scenes. No antidote exists for ketamine intoxication; therefore, the cornerstone of clinical management is supportive care with special attention to respiratory and cardiac function (Weiner et al., 2000).

Persons abusing ketamine may develop severe addiction and a withdrawal syndrome requiring detoxification. Dependence on the drug's psychological effects evolves quickly in ketamine abusers. Subjectively positive psychological effects of the drug are so strong that adverse effects are ignored by ketamine abusers; note that both Patient 6 and Patient 7, hospital-based anesthetists, ignored the consequences of ketamine abuse and worked in operating rooms in obviously impaired states. (Moore et al., 1999; Smith et al., 2002)

Ketamine can cause urological and hepato-biliary toxicity. A case series published in the British Journal of Urology International reported 59 ketamine abusers who presented with significant drug-induced lower urinary tract symptoms. All patients had moderate to severe symptoms that included frequency, urgency, dysuria, urge incontinence, and occasional painful hematuria (with no evidence of bacterial infection [abacterial]). Thirty patients (51%) had unilateral or bilateral hydronephrosis, and 8 patients had a raised serum creatinine level (renal insufficiency) (Chu et al., 2008). In addition to urological problems, ketamine abusers may develop hepato-biliary toxicity manifested as recurrent epigastric pain, abnormal liver function, and biliary tree dilatation. The proposed mechanism for ketamine-induced cystitis is direct toxicity of ketamine metabolites on urinary tract mucosa. Because ketamine is metabolized in the liver and excreted in bile, mucosal toxicity has also been postulated as the cause of dilated bile ducts (Chen, 2009; Wong et al., 2009).

The non-medical use of ketamine can clearly place the abuser at increased sexual and parenteral risk for contracting and transmitting infectious diseases such as HTV-infection. Abuse of ketamine can make a user vulnerable to engaging in unprotected sexual intercourse since judgment is often impaired. The current literature highlights ketamine abuse among men-who-have-sexwith-men at circuit parties. Among high-risk youth, ketamine injectors report sharing vials of liquid ketamine and injection equipment. Because the effects of ketamine are short-lived, parenteral ketamine abusers inject multiple times within a short period of time to maintain euphoria (Lankenau et al., 2005; Oser et al., 2008).

Because ketamine is tasteless, odorless, and colorless, it can be surreptitiously added to beverages and used to facilitate sexual assault. Along with reduced awareness or unconsciousness, the victim may develop anterograde amnesia as rapidly as 15 minutes after ingestion. Vivid hallucinations, amnesia, and dreams make it difficult to discern drug-induced effects from reality, rendering the victim unreliable as a witness in court proceedings. The Federal Drug Enforcement Administration (DEA), in response to a Congressional mandate (Public Law 106-172), established a special Dangerous Drugs Unit to assess the abuse of and trafficking in designer and club drugs associated with sexual assault.

Conclusion

Most abusers consider club drugs to pose few if any health or safety risks, but the serious reactions and emergency department visits associated with their abuse suggest otherwise. Because the sources of many club drugs are clandestine laboratories, users may concomitantly ingest other toxic substances in addition to the purported club drug, or may consume doses far higher than purported. The wide availability and illicit marketing of psychoactive drugs like ketamine at circuit parties, raves, and dance clubs present significant public health and drug policy challenges. Correctional facilities have a unique opportunity to educate inmates about club drugs, treat drug-dependent patients, and motivate successfully treated patients to become peer-educators.

References

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Author affiliation:

ABE M. MACHER M. D.

Author affiliation:

Dr. Abe M. Macher is a 30-year veteran of the United States Public Health Service. He retired in 2005 and currently advocates for inmates' access to the standard of care. Dr. Macher may be contacted at abemacher@yahoo.com.