Neurologic Disorders

1.7.1 Neurologic Disorders

Reports of ephedra-related stroke on file with the FDA have not yet been published in the peer reviewed literature. In some of the FDA cases, massive doses of ephedrine were consumed (as with products intended for abuse, such as "herbal ecstasy," now withdrawn from the market). In other cases, toxicology testing was not performed, and it is not known with any certainty whether ephedrine was even taken. In still other cases, the drug identified was not ephedrine! Many adverse events attributed to ephedrine have actually been due to ephedrine enantiomers, pseudoephedrine (Loizou et al., 1982; Stoessl et al., 1985) and phenylpropanolamine (Johnson et al., 1983; Glick et al., 1987; Lake et al., 1990; Thomas et al., 1991; Ryu and Lin, 1995; Tapia, 1996; Chung et al., 1998), and even methylephedrine (Ishigooka et al., 1991).

In the only large study ever done to assess risk factors for stroke in young people (age 20–49) over a 1- yr period (in Poland, a country where ephedra based products are widely used), nearly half the stroke

cases were associated with preexisting hypertension, another 15% had hyperlipidemia, and 6% were diabetic (Jovanovic, 1996). None of the individuals were ephedrine users.

Sometimes, especially in Japan and the Philippines, ephedrine is taken specifically as a psychostimulant. In Japan, BRON, the OTC cough medication containing methylephedrine, dihydrocodeine, caffeine, and chlorpheniramine is very widely abused and transient psychosis is not an uncommon result (Tokunaga et al., 1989; Ishigooka et al., 1991; Levine et al., 1993).

Psychosis (Herridge and Brook, 1968; Roxanas and Spalding, 1977; Whitehouse and Duncan, 1987; Kalix, 1991; Shufman et al., 1994; Doyle and

Kargin, 1996) and stroke (Stoessl et al., 1985; Yin, 1990; Bruno et al., 1993;Anonymous, 1996a,b; Waluga et al., 1998) are fairly common complications of ephedrine abuse, although rarely, if ever, are these seen when the drug is taken in recommended doses.

More often than not, psychosis occurs in individuals taking ephedrinebased products for asthma and other respiratory conditions. Ephedrine's usefulness as a bronchodilator is somewhat limited by the fact that chronic use leads to a predictable, and fairly rapid, down regulation of β -receptors and decreased bronchial responsiveness (Neve and Molinoff, 1986). As the medication becomes less and less effective, patients tend to increase the dose. If they take enough, psychosis can occur. Of course, ephedrine, and products containing ephedrine enantiomers, can also be taken specifically with the intent of becoming intoxicated.

One of the studies cited by the FDA in its 1997 proposed "rule making" (21 CFR Part 111, Federal Register; 1997:30678–30724) described 44 Japanese polysubstance abusers taking BRON™ which

contains 2 mg/mL of racemic methylephedrine, 1 mg/mL of dihydrocodeine, 2.4 mg/mL of caffeine, and 0.4 mg/mL of chlorpheniramine maleate. Half of the group were also smoking marijuana and/or abusing organic solvents. On average, each of the 44 drug abusers was consuming 1060 mg/d of methylephedrine, along with 1392 mg/d of caffeine, and 580 mg of codeine, along with 232 mg of chlorpheniramine. The FDA did not specify just why psychotic behavior in this group of individuals should be attributed to massive ingestion of methylephedrine, rather than massive ingestion of caffeine, chlorpheniramine, or codeine (Ishigooka et al., 1991). Why the FDA assumes that ephedrine in standard

clinical doses will produce the same toxicity as methylephedrine in particularly massive doses is anyone's guess.

Ephedrine psychosis closely resembles psychosis induced by amphetamines: paranoia with delusions of persecution and auditory and visual hallucinations, even though consciousness remains unclouded. Typically, patients with ephedrine psychosis will have ingested more than 1000 mg/d. Recovery is rapid after the drug is withdrawn (Shufman et al., 1994). The ephedrine content per serving of most food supplements is on the order of 10–20 mg, making it extremely unlikely that, in recommended doses, use of any of the products would lead to neurologic symptoms.