Stimulant Psychosis Page 1 of 20

Virtual Hospital: Clinical Psychopharmacology Seminar : Stimulant Psychosis Page 1 of 20

Clinical Psychopharmacology Seminar Stimulant Psychosis

Original Author: Paul Perry, Ph.D, BCPP Latest Revisers: Paul Perry, Ph.D, BCPP, Brian C. Lund, Pharm.D. Creation Date: 1996 Last Revision Date: March 2001 Peer Review Status: Internally Peer Reviewed

INTRODUCTION

This lecture concentrates its comments on those agents having the amphetamine-type configuration including d-amphetamine, l-amphetamine, racemic mixtures of amphetamine, and methamphetamine as well as cocaine. Other stimulants such as methylphenidate, phenmetrazine, and diethylpropion have similar actions and abuse problems. Thus patients who experience mental status changes when concomitantly ingesting these drugs must have stimulant intoxication ruled out as a possible cause of their mental disturbances.

AMPHETAMINES

Amphetamine psychosis is a toxic reaction closely resembling schizophrenia that may occur after chronic, short-term, or single large-dose amphetamine use. Onset of symptoms with IV usage can occur within 30-75 minutes. With oral ingestion, the syndrome may be seen within hours in apparently sensitized subjects by as little as 55 to 75 mg of dextroamphetamine. Characterized as a paranoid psychosis, the syndrome was first described by Young in 1938, six years after the introduction of amphetamine as a decongestant and narcoleptic (Young and Scoville 1938).

Presentation

In 1958, Connell (1958) published his classic study of amphetamine psychosis in 42 patients (27 males, 15 females) which represented the first large sample that described this syndrome. He conducted a structured psychiatric and drug history interview of these patients, who had been hospitalized because of violence, suicide attempts, and requests for police protection. Twelve patients reported being chased by a gang; another ten complained of persecution of one kind or another. All patients provided extremely detailed information about their paranoia. Importantly, Connell noted that it was difficult to nearly impossible for an experienced psychiatrist to differentiate between amphetamine psychosis and paranoid schizophrenia. Over a third of the patients on whom drug histories were available received the drug from their physicians for indications that included fatigue, depression, "pep," and obesity. The doses that produced the reactions were coarsely estimated as ranging from 50 to 1687 mg. Among this group, doses of greater than 500 mg/day were common. Although the majority of the patients developed the reactions after prolonged drug use, nine (21%) developed psychotic reactions after a single dose or a large dose divided over a three-day period. The entire series consisted of patients ingesting the drug orally. The most important clinical sign of the toxic psychosis was the lack of disorientation in these individuals and positive schizophrenic-like symptoms. Delusions of persecution, in 34 (81%); hallucinations, in 29 (69%); ideas of reference were present in 26 (60%); auditory visual hallucinations,

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in 21 (50%); tactile hallucinations, in 5 (12%); and olfactory hallucinations, in 4 (10%). In the 35 patients on whom information was available, 77% recovered in six to seven days. The most obvious symptoms of withdrawal were dysphoria followed by sleepiness.

Angrist and Gershon (1969) described 60 amphetamine-related admissions to Bellevue Psychiatric Hospital in New York City. The patients had been using oral or IV amphetamines for a mean of 3.7 years (once to 20 years) at a mean dose of 166 mg/d (20-800 mg/d). Table 1 shows the primary presenting symptomatology in the patients.

Table 1. Presenting symptomatology of 60 amphetamine psychosis admissions. Paranoid-hallucinatory 19 (32%) psychosis Paranoid psychosis 13 (22%) Hallucinosis 4 (7%) Suicide attempts or 4 (7%) gestures Bizarre behavior 4 (7%) Exhaustion 3 (5%) Barbiturate overdose 3 (5%) Emotional lability 3 (5%) Destructive outbursts 2 (3%) Assaultiveness 2 (3%)

Bell (1973) was able to produce an amphetamine psychosis in 12 of 14 patients dependent on amphetamine within usually 30-75 minutes of the start of an IV infusion. The dosing endpoint was when the blood pressure increased by 50% of its resting level. All except four of the injections were concluded within an hour while the remainder were terminated within 75 minutes. Total doses of 55-640 mg produced paranoid delusions in 12/14 (86%) of the subjects. The paranoia was mild in most subjects. Many tried to conceal the fact that they were experiencing a psychosis. The constant features were paranoia in a setting of clear consciousness, ideas of reference and ideas of influence. The psychosis lasted from 1-2 days in 9 cases and for 6 days in 2 cases and 26 days in a patient who was actually covertly ingesting his own amphetamine "stash" while in the hospital. Auditory hallucinations were reported in eight (57%) while visual hallucinations were reported in five (36%) patients. On recovery all except two of the 12 who had become psychotic described auditory and/or visual hallucinations. Interestingly, all 12 while intoxicated attempted to conceal their psychotic symptoms, even when it was clearly evident from their abnormal behavior and speech that they were psychotic. Importantly, no evidence of delirium was noted in any of these cases. This is of forensic importance in that intoxicated patients may be paranoid and hallucinating but not disoriented, confused or having memory difficulty.

Differential Diagnosis

The clinical similarities and differences between amphetamine psychosis and schizophrenia were delineated by Angrist (1974). He noted that hallucinations, delusions, flattening of affect, and depression are observed in both conditions. They differ, however, in the severity of the thought disorder present. Depression occurs in some schizophrenics and is also frequently observed in amphetamine psychosis. This may seem paradoxical since amphetamines are commonly thought of as euphorigenic agents. The

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drug does produce an euphoric mood initially, but as the activity of the drug begins to wane the euphoria is usually replaced by withdrawal dysphoria. This experience of dysphoria accompanied by insomnia causes many amphetamine abusers to use sedative-hypnotics or opiates, or both, to alleviate their distress. Smith (1969) described amphetamine psychosis in terms of an "action-reaction" phenomenon. With the onset of the drug effect, one sees the "action phase" or "high". During this phase the individual is hyperactive and continues either "shooting" or "popping" amphetamines many times during the day, to perpetuate the "high" as it begins to subside. The individual is unable to sleep and because of the amphetamine-induced anorexia effect may not eat. As the body becomes saturated with amphetamine, a point is reached where the individual becomes extremely suspicious and then overtly paranoid. The high energy level associated with the paranoia precipitates unpredictable and sometimes violent behavior. Because of fatigue, paranoia, or lack of drug, the individual eventually stops taking the drug and the "reaction phase" begins. As the effects of the amphetamine abate the individual experiences exhaustion and may sleep constantly for one or two days. Following this exhaustion phase, the individual often has a prolonged and severe depression, which can last for days to weeks. At this point, the abuser may start another "run" since withdrawal effects, particularly depression, can be reversed by readministration of the drug.

Assessment of the severity of the thought disorder may be of some value in the differential diagnosis of paranoid-hallucinatory psychosis. Although amphetamines can cause disruption of the thought process, they do not usually cause the severe degree of disruption generally observed in the acutely schizophrenic patient (Angrist 1974). The quantitative difference between the severity of the psychoses in the two syndromes was also delineated by Kalant and Kalant (1975). Visual hallucinations or frightening visual pseudohallucinations are the most common types of hallucinations in amphetamine-induced psychosis. Their occurrence is substantially less frequent in paranoid schizophrenics, who are more likely to experience auditory hallucinations. Further, paranoid schizophrenics rarely experience tactile hallucinations or olfactory hallucinations, which are more frequently seen in drug-induced psychotics after an amphetamine "run". In addition, abrupt onset of the psychosis, stereotypic behavior, hyperreflexia, and sympathetic effects such as hypertension and mydriasis can aid in the differential diagnosis.

The differential diagnosis with amphetamine psychosis is complicated by two factors. First, many patients refuse to admit use of amphetamines on admission even though they may be taking the drug in high doses. Snyder describes case histories of patients with amphetamine psychosis in which a misdiagnosis of paranoid schizophrenia was maintained for up to three years, during which time patients received ECT and insulin coma therapy, all the while covertly ingesting amphetamines while in the hospital (1973). Secondly, if a patient did not admit to use of amphetamines, it was not until the early 1970's that urinalysis procedures were developed which could accurately detect the drug.

Because of these problems, many clinicians utilize a practical approach in making a differential diagnosis. They hospitalize the patient. If the patient shows remission of paranoid symptomatology in five to seven days following admission, the diagnosis of amphetamine psychosis is made. If, however, the symptomatology is chronic even with the addition of neuroleptic drug treatment, the patient is diagnosed as paranoid schizophrenic. Additional confusion is generated by reports of spontaneous recurrence of methamphetamine psychosis after several months of stimulant abstinence. This phenomenon was attributed to a type of "post-traumatic stress" during the original methamphetamine induced psychosis (Yui et al 1998).

Despite these problems, a number of investigators made efforts to assess the role of amphetamines in psychiatric hospitalizations. Askevold (1959) reported that at least 2% of the patients admitted to a Swedish hospital from 1947-1957 were there because of amphetamine abuse. Richards et al (1985) found that 10.7% of 300 admissions to the Iowa City VA Hospital Psychiatry Service admitted to use of

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CNS stimulants within six months prior to admission with 2.7% of these subjects' urines being positive for the psychostimulants, amphetamine or ephedrine. Interestingly, 21% of the schizophrenic and antisocial personality disorder admissions admitted using stimulants within six months prior to admission versus only 8% of all the other non schizophrenic admissions (Richards et al 1985). Thus, stimulant abuse can partially contribute to schizophrenic readmissions.

Today, amphetamine psychosis is considered a "model psychosis" for schizophrenia. Hanson (1967) has shown that amphetamines increase the concentration of catecholamines in the synaptic cleft by stimulating their release from the interneuronal storage vesicles. Also, numerous investigators have demonstrated that amphetamines block the reuptake of catecholamines from the synaptic cleft (Carlson et al 1966, Rutledge 1970, F awcett et al 1972, Maas 1975). Investigation of the behavioral changes and neurotransmitter alterations produced by chronic amphetamine intoxication has lead to a postulated correlation between these two variables. Ellinwood (1973) has described a three-layered psychotic model induced by chronic amphetamine intoxication. Initially, stereotypic behavior such as repetitious examining, searching, and sorting behavior occurs. Next, a sustained pleasurable suspiciousness develops in which the individual will be looking for meanings and minutiae. F inally, ideas of reference and persecutory delusions and hallucinations manifest themselves. Additionally the patient may appear fearful, panic-stricken, agitated, and over-reactive. Snyder (1974) postulated that different areas of the CNS stimulate each phase. He has suggested that stereotypic behavior, equivalent to the "core" schizophrenic behavior, is induced by an excess of dopamine at specific receptor sites in the CNS. An excess of norepinephrine in other receptor causes the alerting effect and euphoria produced by amphetamine intoxication sites in the CNS. This activity is hypothesized to be responsible for the paranoid delusions seen in amphetamine psychosis.

Urine Screens. Because of paranoid leading usually to denial of amphetamine obtaining a urine drug screen is an indispensable element of the diagnosis. Amphetamines will be positive on a urine screen for 2-4 days after the last usage. Since the majority of patients clear within 24 to 48 hours after discontinuing the amphetamines, the urine screen ought to be positive in a paranoid patient if amphetamines are the cause of the psychosis.

MDMA or Ecstasy

3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") was first synthesized 80 years ago (Green et al 1995). It has recently received prominence as a recreational drug of abuse. U sers typically report an euphoric effect while on the drug, with a rebound dysphoria lasting several days after ingestion (Parrott and Lasky 1998). There is a common belief among users that it is safe. However, in the last 2-3 years there have increasing reports of severe acute toxicity and death and there are concerns that it may cause long term toxic damage to 5-hydroxytryptamine (5-HT) nerve terminals. Administration of MDMA to rodents and non-human primates results in a long term neurotoxic decrease in 5-HT content in several brain regions and there is clear biochemical and histological evidence that this reflects neurodegeneration of 5-HT terminals. These serotonergic neuron damage findings have been confirmed in humans by McCann et al (1998). U sing PET imaging using a carbon-11 radioligand that selectively labeled the 5-HT transporter they contrasted the images of 14 chronic MDMA users and 15 MDMA- naï ve control subjects. They found significant global and regional decreases in 5-HT transporter binding in the MDMA group. F urthermore, there was a significant positive correlation between decreases in 5- HT transporter binding and the extent of MDMA use. While these data support the theory that MDMA use leads to destruction of 5-HT nerve terminals, the clinical impact of this observation is not yet clear.

Potentially severe adverse medical effects associated with MDMA include hyponatremia/SIADH, seizures, cerebral hemorrhage, fatal arrhythmias and asystole, aplastic anemia, and hepatotoxicity (at least 2 requiring transplant and 1 death) (McCann et al 1996). Although not widely studied, MDMA is

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metabolized by hepatic demethylation and therefore has the potential for drug interactions (Lin et al 1997, Tucker et al 1994). There is one published case of a fatal interaction with ritonavir, a clinically significant CTP4502D6 hepatic enzyme inhibitor that presented with a grand mal seizure and a cardiorespiratory arrest (Henry and Hill 1998). The recent increase in the number of reports of MDMA toxicity probably results from the widespread use of the drug at all night dance parties or "raves". When used in this setting, MDMA is associated with a typical cluster of symptoms including dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure (McCann et al 1996). The phenomenon of amphetamine aggregation toxicity in mice was reported 40 years ago. If applicable to MDMA-induced toxicity in humans, all the conditions necessary to induce or enhance toxicity are present at raves: crowded conditions (aggregation), high ambient temperature, loud noise and dehydrated subjects.

Specific psychiatric disturbances associated with MDMA abuse include panic attacks, visual illusions, paranoid psychosis, aggression, flashbacks, and memory and cognitive impairments (McCann et al 1996).

Suggestions for the rational treatment of the acute toxicity are made on the basis of both pharmacological studies in animals and current clinical practice. Cases presenting clinically are usually emergencies and unlikely to allow carefully controlled studies. Proposals include decreasing body temperature (possibly with ice), the use of dantrolene and anticonvulsant and sedative medication, particularly benzodiazepines.

A 1996-1997 survey of 12th graders in Massachusetts reported a 14% usage rate among males and 7% among females. U sage is reported to be on the increase, especially in larger cities such as Chicago, Minneapolis/St Paul in the midwest. Currently the tablets are being for $ 20 to $ 30 (see NIDA Web page).

Treatment

The treatment of acute amphetamine psychosis centers on the management of agitation and the reversal of psychotic symptoms. Fatalities associated with amphetamine intoxication are often a result of indirect causes, but deaths due to direct drug effects have been reported. In a case series of 146 deaths in which methamphetamine was detected post-mortem, the majority of deaths (63%) were due to indirect effects of methamphetamine intoxication (e.g. traffic accidents, suicide) (Logan et al 1998). Of the 52 deaths believed to be "drug-caused", 25% (9% overall) were related to methamphetamine-only intoxications. The authors also evaluated blood methamphetamine concentrations and cumulative fatality rates. Risk factors for fatality at lower methamphetamine levels included the co-administration of other substances and relevant underlying disease states (e.g. atherosclerotic disease).

The management of acute agitation and psychosis secondary to amphetamine toxicity primarily involves the use of antipsychotics. Most of the phenothiazine or butyrophenone antipsychotics have been shown to increase the rate of dopamine turnover in the dopaminergic terminals of the CNS. The mechanism of action of these agents is usually attributed to an interneuronal feedback process initiated by their blockade of the postsynaptic dopaminergic receptors (Glowinski 1974). Because of their ability to act as dopamine antagonists, primarily, and norepinephrine antagonist secondarily, the antipsychotics have been found to be effective in reversing the effects of amphetamine psychoses (Angrist et al 1974, Snyder 1973, Angrist et al 1974, Lemberger et al 1970, Espelin and Done 1968).

Espelin and Done (1968) successfully treated 22 children ranging in age from 11 to 48 months with acute poisoning secondary to amphetamines or related compounds with doses of chlorpromazine that varied from 0.4 to 4.0 mg/kg. From his experience with these patients, he recommends an initial

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pediatric dose of 1 mg/kg. The peripheral sympathomimetic effects responded satisfactorily within two to three hours while the central nervous system effects usually subsided within a matter of minutes. The course without chlorpromazine therapy was characterized by 24 to 96 hours of persistent excitation.

In eight patients, haloperidol was effective in reversing amphetamine-induced symptoms of paranoid ideation and excitement following acute ingestions (Angrist et al 1974). He gave a dose of 5 mg IM immediately and noted patients beginning to clear within an hour after the haloperidol administration. He noted some patients exhibited dysphoric moods after receiving haloperidol and he therefore postulated that antipsychotic medication may accelerate the amphetamine "crash" dysphoria and thereby produce an increase in suicidal potential. A single dose of haloperidol should not be used as an alternative to hospitalization because amphetamine psychosis can last for a week or more even with proper treatment.

Richards et al (1997) conducted a large, prospective, randomized trial of a benzodiazepine versus a butyrophenone in agitated methamphetamine users in the ER. One hundred forty-six (146) patients with agitation requiring chemical restraint and a positive urine toxicology for methamphetamine were enrolled in this study. The patients randomly received either lorazepam or droperidol in an unblinded fashion. The suggested dosing schedule for lorazepam was 2mg (<50kg) to 4 mg IV (>50kg) and 2.5mg (<50kg) to 5.0mg IV (>50kg) for droperidol, but dosing was ultimately a clinical decision. Agitation was assessed with a 6-point sedation scale (6-combative, violent, out of control; 1-deep sleep) at baseline and at 5, 10, 15, 30 and 60 minutes after sedative administration. A second dose was given at 30 minutes if sedation was inadequate. Droperidol administration resulted in more rapid and profound sedation. Following droperidol, mean sedation scores dropped from 5.5 at baseline to 2.8 at 10 minutes and 1.6 at 60 minutes. On the other hand, the lorazepam group went from 5.1 at baseline to only 4.0 at 10 minutes and 2.3 at 60 minutes. Furthermore, the lorazepam patients required more repeat administrations at 30 minutes (26 versus 6 with droperidol). Somewhat surprisingly, both drugs resulted in similar reductions in systolic blood pressure and pulse. Significant blood pressure drops have been reported with higher doses of droperidol, but the average dose given in this study (5.2mg) appears reasonably safe. The lowest systolic blood pressure reported was 90 mm Hg at 60 minutes. One patient had a dystonic reaction with droperidol, which responded to IV diphenhydramine. Therefore, droperidol is the drug of choice at moderate doses in the chemical restraint of acutely agitated methamphetamine users. Haloperidol and lorazepam are reasonable alternatives.

Beyond behavioral control, acidification of the urine is a potential method of hastening reversal of amphetamine psychosis. Anggard found that with an acidic urine (pH < 6.6), renal elimination of unchanged amphetamine (67% to 73%) produced a plasma half- life of 7 to 14 hours and rapid clearing of psychotic symptoms (Anggard et al 1973). With an alkaline urine (pH > 6.6), plasma half-life was 18 to 34 hours. The urine can be adequately acidified by giving ammonium chloride 8 to 12 gm daily, in divided doses at mealtime. The drug is only effective for a 1- or 2-day period because of renal compensatory mechanisms (Kunin 1972). Because ammonium chloride is not always available from hospital pharmacies, ascorbic acid may be the only other urine acidifier available. In adults, 4-12 g/d of ascorbic acid in divided doses has been recommended. Because of questionable efficacy of the drug for this purpose, urinary pH should be confirmed with pH paper.

Treatment recommendations include:

The acute psychosis should be treated with a dopamine antagonist such as droperidol at an initial dose of 2.5 (<50kg) to 5 mg IV (>50kg). Haloperidol or lorazepam given IV or IM are reasonable alternatives. Acceleration of the renal elimination of amphetamines may be accomplished by acidification of the urine with ammonium chloride with a dose of 8 to 12 gm po daily for two days or 4 -12 g/d of

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ascorbic acid. Complete clearing of amphetamine psychosis may require up to a week. Because amphetamine "crashing" is associated with dysphoria and sometimes suicidal ideation, the patient should remain hospitalized until completely free of the signs and symptoms of intoxication.

COCAINE

Pharmacology (Loper 1989)

Cocaine blocks the initiation or conduction of nerve impulses following local application by blocking depolarization via sodium influx inhibition. For this reason it was used by ophthalmologists but no longer because it causes sloughing of the corneal epithelium.

Central Nervous System. In the CNS cocaine demonstrates a biphasic pattern of intense stimulation followed by depression. Cortical stimulation is manifested as euphoria, accompanied by restlessness and excitement. Medullary stimulation causes respiratory tachpnea marked by a rapid, shallow breathing pattern. Emesis may result from stimulation of the vasomotor and vomiting centers. Stimulation of the lower motor centers and enhancement of cord reflexes produce tremors and convulsions. Respiration may deteriorate into a Cheyne-Stokes pattern as the vital medullary centers are depressed. As hypoxemia supervenes, the patient becomes comatose and death may result from ventricular fibrillation or asystole. In man, the initial CNS effect is a feeling of well-being and euphoria, although, sometimes dysphoria may result. Garrulousness, restlessness and excitement may accompany these effects. However, as the dose is increased tremors and tonic-clonic seizures may occur. Central stimulation is followed by depression and death resulting from respiratory failure or cardiac arrhythmias.

Cardiovascular System. Small doses of cocaine may slow the heart as a result of central vagal stimulation, but moderate doses produce tachycardia, an increase in blood pressure, hyperpyrexia, and PVCs. A single large IV dose of cocaine may cause immediate death from cardiac failure due to ventricular fibrillation. Like amphetamines, cocaine potentiates the action of norepinephrine, serotonin, and dopamine.

Skeletal Muscle. Cocaine does not increase the intrinsic strength of muscle contraction. The relief of fatigue results from CNS stimulation masking the effects of fatigue.

Body Temperature. Cocaine has markedly hyperpyrexic activity. Increased heat production resulting from increased muscular activity cannot be compensated for because of the vasoconstrictive effects of the drug. Additionally, cocaine may have a direct effect on the heat-regulatory centers of the diencephalon, because the onset of fever is often accompanied by a chill, thereby indicating that the body is adjusting its temperature to a higher level. Cocaine fevers are often a striking feature in cocaine overdoses.

Sympathetic Nervous System. Cocaine blocks the reuptake of catecholamines presynaptically.

Absorption, Fate and Excretion (Loper 1989)

The drug is absorbed from all sites of applications, including the GIT and mucosal membranes. Absorption is enhanced in the presence of inflammation, and therefore the systemic effects can be significantly enhanced. As an example, absorption increases in cystoscopy if the bladder is inflamed. Following absorption, the cocaine is metabolized by plasma pseudocholinesterases, plasma esterases and hepatic esterases to ecognine while the drug is hydrolized and esterified to benzoylecognine. Only small

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amounts are excreted unchanged in the urine. A genetic pseudocholinesterase deficiency (1 in 3000 patients) could lead to increased cocaine levels. This may explain why fatal reactions have been reported from extremely small doses. Cocaine metabolism can also be blocked by inhibitors of that enzyme, such as neostigmine or physostigmine (Chow et al 1985).

Pharmacokinetics (L oper 1989)

Following intranasal administration, cocaine hydrochloride salt is approximately 50% bioavailable whereas the free-base is 100% bioavailable. Cocaine is reported to have a half-life ranging from 48 (Wilkinson et al 1980, Chow et al, 1985) to 87 (Cook et al, 1985) minutes with the shorter half-lives occurring in the chronic abuser of the drug. The half-life is not affected by the route of administration (Cook et al 1985). Practically speaking this means that 8 hours following cocaine inj ection or inhalation 98 to 100% of the drug has been metabolized by the liver or has excreted in the urine. Following nasal inhalation, IV inj ection, or smoking less than 1% of the cocaine hydrochloride salt is recovered in the urine as cocaine over the next 72 hours. Instead mostly metabolites are recovered, i.e., ecgonine (2-3%), ecgonine methyl ester (18-22%), and benzoyl ecgonine (25-38%). The half-life of ecgonine methyl ester is four hours and benzoyl ecgonine is about 6 hours (J avid et al 1983, J atlow 1987). An additional metabolite, cocaethylene is formed only when ethanol is present in the body. U nlike the other metabolites, cocaethylene is CN S active. The mean half-life is estimated to be 109 minutes (Cami et al 1991). Overall, regardless whether the drug is taken intravenously, intranasally, or smoked still approximately 65-70% of the drug will be recovered in the urine within 72 hours. Fecal excretion accounts for only 4 to 11% of the drug' s elimination. Additional pharmacokinetic parameters include a clearance rate of 35 + /- 9 ml/min/kg, and volume of distribution of 2.1 + /- 1.2 l/kg.

The maj or urinary metabolite, benzoylecgonine, may be detected up to 36 hours after cocaine use by thin layer chromatography. Enzyme immunoassay may reveal cocaine metabolites up to 96 hours after use, while chromatography and mass spectroscopy may detect the metabolites up to 1 week after cocaine use (L oper 1989). Typical urine screens can detect the drug for 1to 3 days after the last ingestion.

Administration

Cocaine is most commonly self-administered intranasally, i.e., snorted, but sometimes is administered IV. The drug is sold as a powder, often diluted with procaine, and varies greatly in purity. For snorting, the powder is arranged on glass in thin lines 3 to 5 cm long, each containing about 25 mg. The line is then inhaled into the nose through a straw or rolled paper. Heavy users sniff up to 10 g/d although most users take significantly less. A common usage pattern in social settings involves sniffing into each nostril 25-30 mg (a line) of cocaine. Administration is 2-3/hr over several hours. When smoked with tobacco only 1% cocaine hydrochloride reaches the body whereas when smoked in a glass pipe 44% reaches the system (Cook et al 1989). Fifty mg is a typical smoked dose. Cocaine hydrochloride inj ected IV as a 50 mg dose produces a peak level of approximately 200 ng/ml within minutes whereas when smoked peak levels range from 75-100 ng/ml occurring 30-90 minutes later (Cook et al 1989).

While the cost of the drug limits daily use, users with sufficient funds or special access engage in "runs" or "sprees" similar to amphetamine or "speed freaks." Cocaine free base is both more volatile and chemically more stable than the hydrochloride salt, and therefore can be "smoked" (i.e. vapor inhaled) after heating in a free base pipe. This conversion, which involves extraction with appropriate organic solvents, i.e., ether, also serves to eliminate many of the adulterants. Because the solvents used are highly inflammable, the whole process is dangerous. A new free base preparation has become available called "crack" or "rock". This is made simply by adding baking soda to a solution of cocaine hydrochloride and heating the mixture. The dried residue is sold in the form of small lumps which are then "smoked" in a free -base pipe. When smoked, absorption of the free base from the lungs is rapid and

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efficient, producing plasma concentrations in excess of 900 ng/ml whereas the hydrochloride salt reaches peak values of only 150-200 ng/ml 30-40 minutes after inhalation (J acobs and Fehr 1987). Because of the extremely rapid onset of action of "crack", cocaine' s addictive potential is enhanced. This can be demonstrated by the fact that the use of cocaine was actually decreasing until "crack" started to be sold on the "street" in 1984 (Kleber 1988).

Abuse

Introduction. Abusers describe the euphorigenic effects of cocaine in terms that are indistinguishable from amphetamines. In the laboratory, cocaine users cannot differentiate between effects of dextroamphetamine 10 mg IV and cocaine 16 mg IV (Fischman and Schuster 1982). Cocaine psychosis or intoxication is qualitatively indistinguishable from amphetamine intoxication. Both produce a paranoid psychosis. Transient or "binge" paranoia is common among heavy users. One study calculated the incidence at nearly 70% (Satel and Gawin 1990). The cocaine -associated syndrome differs from the amphetamine paranoia in that the former lasts for only a brief period. The development of paranoia in this group of abusers is unpredictable and is not dose-related. Although it is assumed that cocaine is unique among the local anesthetics in its euphorigenic properties, this is not actually the case. Animals will self-administer procaine and chlorprocaine but not lidocaine. Experienced cocaine users cannot distinguish between the stimulant effects of intranasally administered cocaine and lidocaine (Van Dyke et al 1979). However, they can distinguish between the euphorigenic effects of the local anesthetics, procaine, lidocaine, and cocaine, when administered IV because of the more clear cut "high" produced by the latter (J acobs and Fehr 1987). It is not surprising because of the stimulant properties that procaine is utilized as counterfeit stimulant in street-drug products although only having 10% of the potency of cocaine.

Crack remains relatively inexpensive in all Community Epidemiology Workshop Group (CEWG) cities, ranging from $ 3 to $ 25 per dosage unit, depending on the size and purity of the rock. Marijuana joints containing crack are being sold as fireweed. (see NIDA webpage)

Incidence. In the U .S., the number of persons who tried cocaine at least once in 1974 was 5.4 million. This figure increased to 25 million by 1985. The number of persons with current use (within the past 30 days) has increased from 1.6 million in 1977 to 6 million in 1985. It is estimated that in 1985 3 million people were considered as dependent on cocaine (Kleber 1988).

Behavior. Perceptual changes and pseudo-hallucinations similar to the amphetamines occur with cocaine. The most common of these are tactile, i.e., "cocaine bugs" in the skin and visual, i.e., "snow lights." The user may be fascinated or preoccupied with their own thinking processes and with philosophical concerns about "meanings" or "essences." Stereotypical, repetitious behavior is common. Intoxicated patients may exhibit a compulsion to take apart mechanical objects but cannot put them back together because their thinking is too disorganized. Chronic use may lead to reverse tolerance, to the anesthetic and convulsive properties, i.e. increased effect after repeated administration of the same dose (J ekel and Allen 1987). Post (1975) has suggested a clinical continuum of euphoria, dysphoria and paranoid psychosis that occurs with regular cocaine use that is related to dosage, genetics and previous exposure. With chronic use, euphoria can be followed by insomnia, apathy and melancholia (Post 1975). The user may develop paranoid psychosis accompanied by auditory, visual or olfactory hallucinations. The sensorium is clear and violent behavior may occur in response to the paranoid delusions.

Siegel (1978) studied 85 "recreational" cocaine users for cocaine psychosis. All participants had used a minimum of one gram of cocaine (intranasally) a month for at least 12 months. Thirty-seven subjects (44%) experienced some perceptual phenomena such as increased sensitivity to light and difficulty focusing the eyes. All 37 reported an inability to concentrate. Fifteen (18%) subjects reported

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hallucinations in several modalities (ocular, olfactory, audio, and gustatory). These hallucinations were reported after 6 months of cocaine use and usually during periods of intense use. Thirteen subj ects reported visual hallucinations. These hallucinations were reported after 6 months of cocaine use and usually during periods of intense use. Thirteen subj ects reported visual hallucinations. These hallucinations were generally reports of obj ects moving in the periphery of the visual field. With the eyes closed, the subj ects also reported flashes of lights. Several subj ects called this phenomenon "snow lights." Four subj ects reported occasional diplopia. They also experienced visual illusions such as real obj ects appearing to move or pulsate. Eleven subj ects reported tactile hallucinations. This extreme hallucination occurred only after several days of intense use. The symptoms included itching of the skin; and sensations of foreign particles moving under the skin (Magnon' s sign or "cocaine bugs"). Six subj ects reported olfactory hallucinations. Reports included smelling smoke, gasoline, natural gas, feces, urine, and garbage. Three subj ects experienced gustatory hallucinations. The gustatory hallucinations were all negative in that they failed to detect the strong food or drink present.

Brady et al (1991) interviewed 55 subj ects consecutively admitted for treatment of cocaine dependence (DSM-III-R). A transient cocaine psychosis was reported by 53% (29/55) of the patients. The psychotic group had used more cocaine in the year prior to admission and had a longer duration of use. Males were more likely to become psychotic than females. The mental status presentation of the psychotic group included: paranoid delusions 90% (26/29), and hallucinations 96% (28/29) which included 83% (24/29) auditory hallucinations, 38% (11/29) visual hallucinations, 21% (6/29) tactile hallucinations. Transient sterotypies were experienced by 27% (15/55) subj ects.

Serper et al (1995) contrasted the admission presentation of 37 schizophrenics (DSM-III-R). The patients differed in that 15 were cocaine-abusers and 22 were cocaine-abstainers. Patients were rated with the BPRS and SAN S rating scales at admission and following four weeks of treatment. At admission the cocaine abusers presented with more anxiety and depressive symptoms and fewer negative symptoms than the cocaine abstainers. Following four week of treatment these differences were no longer apparent. Amphetamines combined with neuroleptics in controlled trials have also been shown to reduce negative and positive symptoms (G oldberg et al 1991). However, it seems foolhardy to combine stimulants with neuroleptics to improve negative symptoms since too large a dose could well results in the patient relapsing.

Morbidity and mortality. The degree of violence associated with cocaine intoxicated individuals is legendary. Honer et al (1987) described the presentation of 80 cocaine users who required attention in N ew Y ork City emergency rooms. The data demonstrate the greater morbidity associated with crack cocaine use compared to the cocaine HCl salt. Of the crack users, 29% required hospitalization versus 13% of the other users. Additionally, the Crack users had higher rates of auditory hallucination (36% versus 14-32%), paranoia (50% versus 14-37%), and violent behavior characterized as suicidal ideation (57% versus 26-43%), suicide attempts (29% versus 5-26%), and assaults (19% versus 5-7%).

Miller et al (1991) conducted an extremely interesting telephone interview of the users of the 1-800 cocaine hotline. During one month (452 males in 10/88 and 200 males and females in 10/89) subj ects who made self-referred inquires for themselves regarding cocaine problems were given a structured interview over the telephone. The selection was random and consecutive. Table 2 presents the responses of the male users. Table 3 presents the types of violent behavior. There were no differences according to route of administration. The crack users were spending $ 200-300/week on their habit. Actually the rates for violent crimes of legal importance was low in contrast to other studies. However, the design of the study would suggest these paranoid subj ects may have been less likely to tell the truth because they may have thought their phone was taped. The authors concluded that suspiciousness and paranoia is common among cocaine users; 2) violent behaviors and crimes are associated with cocaine use; and 3) paranoid thinking and the need to get money for cocaine may be the precipitant of the violent behaviors in crimes

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by cocaine users

Table 2. Telephone questionnaire results from 452 males respondents with an mean age of 28 years (Miller et al 1991). Administration intranasal 35% intravenous 7% free base 30% crack 15% combination 66% Does cocaine make you Y es I 42% angryG Does cocaine make you Y es I 32% violentG Does cocaine make you Y es I 84% suspicious/paranoidG Have you or the person you are calling for ever committed a violent Y es I 46% crime while high on cocaine or crackG Has your cocaine use caused you to carry a Y es I 17% weaponG Do you think that crack Y es I 83% causes violenceG Do you think that violence is caused by the Y es I 82% need to get money to pay for crackG

Budd (1989) conducted a study to establish the relationship between homicide and cocaine usage. He discovered that in Los Angeles County in 1987 one of every five homicides in the county were positive for cocaine at autopsy. Of these 114 homicides, 70 (61.4%) died a violent death--over 68% of these as shootings and stabbing. Fourteen of the violent death victims (20%) were found to have been behaving in a violent manner just prior to their death. Table 4 presents the mode of the violent deaths in these 114 homicides. Violence seems to be clearly connected to the use and abuse of cocaine. Thus there seems to be a strong association between cocaine and violent death. There was a significantly higher usage of alcohol in the violently behaving sub-population, which seems to indicate a strong potentiating effect of the two together toward violence and violent death. Table 5 presents the mean cocaine plus benzoylecgonine levels in the victims plus their mean blood alcohol levels for the different groups. The levels do not different the violent deaths from the non-violent deaths.

Table 3. Crimes you are familiar

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with or were associated with involving cocaine (Miller et al 1991). Physical fights 23% Attempted 1% Murder Armed robbery 22% Verbal arguments 33% Child abuse 1% Wife abuse 7% Murder 4% Rape 1% Robbery 14%

Table 4. Modes of violent deaths (70/114, 61%) (Bud 1989). Shot 30 42% Stabbed 18 26% Fell/Jumped 6 9% Auto accident (driver) 5 7% Head Trauma 4 6% Strangled 2 3% Drowned 2 3% Auto vs. pedestrian 2 3% Fire 1 1.4%

Table 5. Drug usage data (Bud 1989). [Cocaine] (ng/ml) Category [Alcohol] (cocaine + metabolite) Violent Deaths 1390 (± 1460) 0.59 (n=70) Nonviolent Deaths 2140 (± 4080) 0.34 (n=44) Violent behaving victims 910 (± 1170) 0.71 (n=14)

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Finally, Tardiff et al (1989) examined all autopsy and toxicology reports of person dying in New Y ork City from 1/1/86 to 11/1/86 that were reported to the Office of the Chief Medical Examiner. There were 935 cases in which cocaine was detected. Table 6 shows the cause of death in these individuals.

A number of models have been suggested to account for the relationship between cocaine and violence. The psychopharmacologic model hypothesizes that the violent behavior associated with the drug is a direct result of the ingestion of cocaine. A systemic model refers to the violent interactions resulting from the production and distribution of an expensive and illicit drug. The economic-compulsive model proposes that the violence is the product of the behavior necessary to support the use of a habituating drug. Only the psychopharmacologic model has data to support its validity. Licata et al (1993) administered oral cocaine (1 or 2 mg/kg) or placebo to 30 normal volunteer subjects. The subjects were then placed in a pseudo-competitive situation in which they could administer electrical shocks of varying severity to their opponent. The severity of the shock (subject aggressiveness) was directly proportional to the cocaine dose. The authors concluded that cocaine-induced aggression is mediated by changes in arousal. Arousal as measured by blood pressure measurements was directly proportional to the cocaine dose. Thus these data suggest that cocaine intoxicated individuals do not need to be psychotic (paranoid) to be more aggressive.

Table 6. Causes of death of 935 persons with cocaine in their body at autopsy (Tardiff et al 1989). Cause of Persons Percentage Death Cocaine 39 4 overdose Acute 112 12 narcotism Chronic 14 2 narcotism Acute 2 0.2 alcoholism Chronic 31 3 alcoholism Occlusive coronary 45 5 artery disease Cerebral 19 2 hemorrhage Ruptured 6 1 aorta Other natural 104 11 causes Homicide 350 38 Suicide 62 7 Motor vehicle 33 4 accident

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Other accident 37 4 Pending or 81 9 unknown Total 935 100

Withdrawal

G awin and K leber (1986) described a three phase withdrawal syndrome that cocaine abusers ex perience following the abrupt discontinuation of the drug. The first phase is the " crash" which is initially characterized by symptoms of agitation, depression, and anorex ia that can occur even before the cocaine is discontinued and can continue for up to 20 hours after the abrupt discontinuation of the drug. The middle stage of the " crash" includes fatigue, depression, no cocaine craving, and insomnia with increased desire for sleep. The late stage of the crash includes ex haustion, hypersomnia, hyperphagia, and no cocaine craving. Substantial craving only returns after the individual has been free of the drug for at least five days. Phase I I is termed the withdrawal phase and can last from one to ten weeks. I t is characterized by symptoms that initially include normalized sleep cycle, euthymic mood, low craving, and low level anx iety while the later stage is marked by symptoms of anhedonia, anergia, anx iety, and high cocaine craving that is ex acerbated by the individual' s condition cues such as seeing a needle. I t is during this ten week period that individuals are most likely to relapse. The last stage is termed the ex tinction phase and it lasts indefinitely. Symptoms include a normal hedonic response, euthymic mood, epi-sodic craving that are triggered by the conditioned cues.

Treatment of Crash and Withdrawal Phase

The increasing abuse of cocaine necessitates the development of a detox ification treatment protocol. With acute use cocaine enhances dopaminergic neurotransmission. I nvestigators have found that when cocaine is chronically used, dopamine concentrations in the brain are reduced. This probably occurs through impaired dopamine vesicle binding (enhances dopamine intracellular metabolism) and increased numbers of dopamine binding sites. This dopamine supersensitivity phenomenon coupled with dopamine depletion is believed responsible for the physiological cocaine craving.

Most of the pharmacologic efforts have been directed at the amelioration of cocaine withdrawal/abstinence syndrome, emphasizing the reversal of cocaine withdrawal dysphoria/depression and decreasing cocaine craving during withdrawal. Antidepressants, amino acid supplements, anticonvulsants, stimulants, and opioid, serotonergic, and dopaminergic agents have been used, mainly in open trial studies to treat cocaine the abstinence syndrome and cocaine craving/addiction. Only amantadine, bromocriptine, carbamazepine, and desipramine have been shown to be effective in double- blind trials of early withdrawal and the positive results have not always been replicated in subseq uent studies.

Dopamine Antagonists. Animal models have suggested that pretreatment with a dopamine antagonist causes a decrease in the self-administration of cocaine. To test the clinical feasibility of this observation, G awin et al (1989a) treated outpatient " crack" abusers with the x anthene, depot neuroleptic (q 2-4 week administration), flupenthix ol decanoate. The 10 flupenthix ol patients were retained in treatment 260% longer and reported less craving compared to an untreated control group. Since neuroleptics block dopamine receptors, the dopamine agonist effect of the stimulants is being effectively neutralized. Although flupenthix ol is not available in the U S there is no reason to suspect that haloperidol decanoate and fluphenazine decanoate would not produce a similar result. The depot dosage formulation is critical in the use of these agents since compliance is a cocaine craving patient cannot be assumed. The usual

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dose of flupenthixol decanoate is 20 -40 mg every 2 -4 weeks. These patients were administered a single 10 or 20 mg dose. It does not seem unreasonable to consider administering depot neuroleptics to outpatient committed cocaine abusers especially in those who have had legal difficulties.

Transgenic mice in whom the D1 receptor has been knocked out are insensitive to cocaine (Xu et al 1994). In a controlled double-blind single dose study Romach et al (1999) administered the D1 receptor antagonist, ecopipam (SCH 39166) 100 mg, 50 mg, 25 mg and placebo to 15 cocaine dependent patients. The drug blocked the stimulating and craving effects of cocaine were attenuated in a dose dependent manner.

Dopamine Agonists. The rationale for using dopamine agonists such as bromocriptine, amantadine, pergolide, or methylphenidate to treat cocaine withdrawal is analogous to the use of methadone for heroin withdrawal and benzodiazepines for alcohol withdrawal. In all three cases a short-acting agent of abuse is replaced by a cross-tolerant agent with a much longer half-life. This pharmacologic substitution strategy results in a decrease in the severity of withdrawal symptoms. The half-life of amantadine ranges from 10-28 hours, while the half-life of bromocriptine is even longer with a mean of 50 hours, amantadine. Although the half-life of pergolide is unknown its duration of action exceed both amantadine and bromocriptine. Thus all of these drugs except methylphenidate with a 2-4 hour half-life, would be a reasonable choice for the treatment of cocaine withdrawal. However, long-term administration of bromocriptine has not resulted in decreased craving (Krantzler and Bauer 1991). However, amantadine 100 mg po bid for 10 days did reduce cocaine use (Cornish et al 1992). Pergolide has a longer duration of action than either amantadine or bromocriptine and a more tolerable ADR profile. An open pilot trial in 21 patients reduced craving and improved sleep in abstaining cocaine abusers (Malcolm et al 1991). However, a placebo controlled cross-over study of pergolide versus placebo found no change in cocaine use and an increase in cravings associated with pergolide (Haney et al 1998). Malcolm et al (2000) in a second controlled trial involving 358 cocaine dependent patients (confirmed this finding. Pergolide 0.1 and 0.5 mg/d was of no clinical value in the treatment of dependence. Methylphenidate with its extremely short half-life has been found not to be of any value in the treatment of cocaine withdrawal with the one exception of cocaine abusers who have ADHD. There are underground reports that high schoolers are now starting to snort methylphenidate.

Antidepressants. Desipramine has been the most commonly studied antidepressant associated with the treatment of cocaine withdrawal (Tennant and Tarver 1984, Giannini et al 1986, Gawin 1988, Gawin et al 1989b, Pickett et al 1991). Regarding SSRIs, there is one small placebo controlled trial (N=17) with fluoxetine in depressed alcoholic cocaine abusers (Cornelius et al 1998). Fluoxetine 20-40mg/d demonstrated a potentially clinically significant, but not statistically significant advantage (10.6 points) over placebo in Beck Depression Index scores. However, there was no change in the significant rate of suicidality (71%) in these patients. In general the controlled trials conclude that

depression/dysphoria associated with cocaine withdrawal is benefited by desipramine cocaine craving overall is not benefited by desipramine although the duration of the craving is shortened by desipramine further evaluation of SSRIs is needed before these agents can be recommended in this setting

Typically, desipramine is dosed at 100-150 mg/d.

Treatment of Intoxication

Since cocaine is also a local anesthetic, acute intoxications and deaths are more frequently characterized by convulsions, cardiac arrhythmias, and/or respiratory depression. Death from acute intoxications with cocaine is no longer unusual and can occur after either inhalation or IV use. In non -human primates,

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dopaminergic antagonists substantially block the convulsive and lethal effects of cocaine. Clinically, dopamine antagonists such as chlorpromazine and haloperidol have been used to treat acute cocaine intoxication although some clinicians prefer propranolol (Loper 1989).

Treatment recommendations for managing severe cocaine intoxications or overdoses marked by tonic- clonic seizures and/or arrhythmias. With regard to seizures, diazepam 5-10 mg/ml IV infused over 2-3 minutes and may be repeated every 10-15 minutes to a total dose of 30 mg. In patients with intractable seizures, pancuronium, a skeletal muscle relaxant, is utilized to prevent myoglobinuria and metabolic acidosis resulting from the excessive skeletal muscle contraction. Propranolol 1 mg IV push every 5 minutes to a maximum of 5 doses is recommended in life-threatening arrhythmias (Cox et al 1983).

Neuroleptics have been used to treat the hallucinations, paranoia and hyperactivity of cocaine psychosis (Colpaert et al 1972). Lithium has been reported to antagonize the effects of cocaine when subjects were pre-treated with lithium. Scott and Mullaly (1981) have reported 3 cases of successful treatment of cocaine psychosis with lithium, though the case reports were not detailed enough to make a positive conclusion.

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