feussner2

Studies using self administration paradigms to evaluate the reinforcing effects of MPH in animals are summarized in Table 3. MPH maintains self-administration behavior in monkeys trained to self-administer intravenous cocaine20-23 and in rats trained to self-administer intravenous d-amphetamine.24 In these studies, MPH substituted for the cocaine or d-amphetamine training dose and continued to maintain self-administration behavior. The reinforcing effects of MPH are potent. Drug naive animals readily acquire self-injection of MPH.25-29 In rats, the rates of acquisition of MPH are faster than those of d-amphetamine, nicotine or caffeine. In monkeys, unlimited access to MPH produces a higher rate of mortality than the other drugs; 75% of the monkeys self-injecting MPH died, compared to 66% and 25% of the monkeys self-injecting cocaine and d-amphetamine, respectively. In dogs and monkeys, MPH, cocaine, d-amphetamine and phenmetrazine produces a cyclic pattern of self-administration, as well as weight loss, stereotypy and death; this pattern of behavior and profile of effects is characteristic of psychomotor stimulant abuse. In a choice procedure paradigm using rhesus monkeys, MPH and cocaine were chosen over saline in >75% of the monkeys,30 higher doses of each drug were chosen over lower doses and the preference for cocaine decreased as the dose of MPH increased. At the highest dose of MPH vs. cocaine, MPH was chosen by individual monkeys on 85-94% of the trials.

Preclinical studies have also shown that chronic administration of MPH produces tolerance to its disruptive and stimulus effects and shows cross-tolerance with d-amphetamine and cocaine.10,31-36 Like d-amphetamine and cocaine, chronic administration of MPH produces psychomotor stimulant toxicity, including aggression, agitation, disruption in food intake, weight loss, stereotypic movements and death.27-37 These same effects have been well documented in humans.38-45 These case reports demonstrate that high doses of MPH often produce euphoria as well as agitation, tremors, tachycardia, palpitations and hypertension. Psychotic episodes and paranoid delusions characteristic of amphetamine-like toxicity are associated with chronic MPH abuse. The pattern of abuse is characterized by escalation in dose, binge use followed by severe depression and an overpowering desire to continue the use of/his drug despite negative medical and social consequences. In addition, the Food and Drag Administration (FDA) Spontaneous Reporting System (SRS) shows that the administration of MPH can he associated With a number of CNS effects including: twitching, personality disorder, hyperkinesia, hostility, insomnia, nervousness, hallucination and psychosis. Other serious adverse drug effects reported to FDA include drug abuse, dependence, addiction and death.

Medical consequences associated with parenteral abuse of MPH are well documented. Pulmonary hypertension brought on by repeated intravenous injections of MPH was strongly implicated in the deaths of numerous individuals in Oregon and Washington.46 Other fatalities associated with intravenous MPH abuse have been reported.47,48 Brooks et al.49 provided case reports of MPH abusers who presented on the medical-surgical services for eikenella abscesses at injection sites. Problems created by intra-arterial injection of MPH were discussed by Lindell et al.50 Chillar et al.51 presented two eases of hemiplegia brought on by intracarotid injection of MPH. Amett et al.55 presented a case of a patient with staphylococcal tricuspid valve endocarditis with septic embolic pneumonia resulting from intravenous MPH abuse. Elenbaas et al56 and Zemplenji and Colman57 reported abscess formation as a complication of parenteral MPH abuse. Other serious complications of intravenous MPH abuse have included osteomyelitis,58 precocious emphysema,59 severe eosinophilia,60 multiple organ failure,61 retinopathy62 and hepatic injury.63

In summary, MPH produces d-amphetamine and cocaine-like reinforcing effects in both humans and nonhuman animals. Preclinical self-administration studies show that MPH is self-administered by animals under a variety of conditions, including when substituted for cocaine or d-amphetamine in drug-experienced animals or when initiated in drug-naive animals. MPH has reinforcing efficacy similar to cocaine and d-amphetamine. In nonhuman primates, MPH can maintain high rates of self-injection in progressive ratio studies and is chosen over cocaine in preference studies. MPH is self-administered by humans and the pattern of abuse is similar to the abuse pattern of other potent psychostimulants including amphetamine, methamphetamine and cocaine. Clinical data demonstrate that MPH abuse is associated with a number of CNS effects and may result in dependence and addiction.

Manufacture and Distribution/Use:

Each year, the DEA establishes an aggregate production quota (APQ) for MPH to meet the legitimate medical, scientific and industrial needs for the U.S. Since 1990, there has been a dramatic increase in the APQ for MPH: from 1,768 kg in 1990 to 14, 442 kg in 1998. Domestic sales reported by the manufacturers increased nearly 5-fold during this same time period (Figure 1 .). Prior to 1991, domestic sales of MPH reported by the manufacturers remained stable at approximately 2,000 kg per year. In 1997, domestic sales reached nearly 10,000 kg. This increase can be attributed to the increased use of MPH in the treatment of ADHD. According to IMS Health, National Disease and Therapeutic Index m, about 90 percent of all MPH prescriptions are for children diagnosed with ADHD although the use of MPH for adults with attentional problems has been escalating. IMS Health, National Prescription Audit Plus m data suggest that prescriptions for MPH have leveled off in the past two years after significant increases earlier this decade (Figure 2). However, stimulant treatment for ADHD continues to rise as amphetamine products take a greater share of the market. Recent increases in the APQ for
MPH reflect increased product development and new manufacturers entering the market. In 1990, there were only two bulk manufacturers for MPH; in 1998 there are seven. It should be noted that the use of psychostimulants in the treatment of ADHD in the U.S. is not in keeping with medical trends in other countries. According to the United Nations the U.S. produces and consumes about 90 percent of the entire world's supply of MPH ( Figure 3.). The International Narcotic Control Board (INCB) has expressed concern about this disparity.