Pharmacology Biochemistry and Behavior, Vol. 60, No. 3, pp. 771–775, 1998 © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/98 $19.00 1 .00 PII S0091-3057(98)00055-0 Discriminative Stimulus Properties of (2)Ephedrine RICHARD YOUNG AND RICHARD A. GLENNON Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0540 Received 14 November 1997; Revised 28 January 1998; Accepted 9 February 1998 YOUNG, R. AND R. A. GLENNON. Discriminative stimulus properties of (2)ephedrine. PHARMACOL BIOCHEM BEHAV 60(3) 771–775, 1998.—Ephedrine, a structural analog of methamphetamine, is one of the major constituents of le- gally available herbal dietary supplements. Although racemic ephedrine and ephedra extract have been previously used as training drugs in drug discrimination studies, there is evidence that the two optical isomers of ephedrine do not produce iden- tical amphetamine-like stimulus effects in rats. Consequently, we trained a group of six male Sprague–Dawley rats to discrim- inate 4 mg/kg of the more potent optical isomer of ephedrine, (2)ephedrine, from saline vehicle. The (2)ephedrine stimulus (ED50 5 0.8 mg/kg) generalized to other central stimulants such as S(1)amphetamine (ED50 5 0.4 mg/kg), cocaine (ED50 5 2.7 mg/kg), methylphenidate (ED50 5 1.2 mg/kg), S(2)methcathinone (ED50 5 0.3 mg/kg), and caffeine (ED50 5 36.7 mg/kg), but stimulus generalization failed to occur to either S(1)methamphetamine or N-methyl-1-(3,4-methylenedioxyphenyl)-2- aminopropane (MDMA). In addition, although we have previously shown that a (1)amphetamine stimulus generalizes to (2)ephedrine but not to (1)ephedrine, in the present investigation the (2)ephedrine stimulus generalized to (1)ephedrine (ED50 5 2.6 mg/kg). From the findings (a) that (2)ephedrine is approximately 10 times less potent than (1)amphetamine in (1)amphetamine-trained rats, whereas it is only half as potent as (1)amphetamine in (2)ephedrine-trained animals; (b) that the (2)ephedrine stimulus failed to generalize to (1)methamphetamine; and (c) that the (2)ephedrine stimulus generalized to (1)ephedrine, it is concluded that the stimulus effects of (1)amphetamine and (2)ephedrine as training drugs, while simi- lar, are not identical. It is also concluded that the stimulus effects of (2)ephedrine and those of the designer drug MDMA, while perhaps sharing some amphetaminergic commonality, are nonidentical. © 1998 Elsevier Science Inc. Amphetamine Ephedrine Methamphetamine Cocaine Methylphenidate Caffeine MDMA Methcathinone Designer drugs Herbal dietary supplements EPHEDRA or ma huang typically refers to the entire above- factured to resemble amphetamine both in physical appear- ground portion of the plant Ephedra sinica. The plant has ance and pharmacological effect (14–16). Typical amphet- been used by the Chinese for several thousand years both for amine look-alikes contained caffeine (37–323 mg), ephedrine its medicinal qualities as an antiasthmatic and central stimu- (12.5–50 mg), and/or norephedrine (phenylpropanolamine) lant (13), and as an intoxicant (14). Its principle pharmacolog- (25–50 mg) (17). Ephedrine and norephedrine are b-hydroxy ically active constituent, (2)ephedrine (13), is still in use to- analogs of methamphetamine and amphetamine, respectively. day. Ephedrine is both an a- and b-adrenergic agonist and an b-Hydroxylation of amphetaminergic agents should reduce agent that releases norepinephrine from sympathetic neurons their lipophilicity and, hence, decrease their ability to pene- (10). Ephedrine is also considered to be a potent central stim- trate the blood–brain barrier; consequently, this would result ulant (10); however, its mechanism of action as a stimulant in agents with decreased central activity. Indeed, amphet- has not been well investigated. amine has been demonstrated to be much more lipophilic The 1970s witnessed the emergence on the clandestine than its b-hydroxylated derivatives (18) and, as central stimu- market of “look-alike drugs” and, in particular, of look-alike lants, it is generally concluded that the rank order of potency amphetamine or pseudospeed, which was deliberately manu- is amphetamine . ephedrine . norephedrine [reviewed in Requests for reprints should be addressed to Dr. R. Young, Virginia Commonwealth University, School of Pharmacy, Department of Medici- nal Chemistry, Richmond, VA 23298-0540. 771 772 YOUNG AND GLENNON (14)]. For example, in rats, (2)ephedrine is about 25-fold less session. For half of the animals, the left lever was designated potent than S(1)amphetamine as a locomotor stimulant; the drug-appropriate lever, whereas the situation was re- (1)ephedrine is even less active than its (2)enantiomer (2). versed for the remaining animals. Data collected during the Although look-alike drugs are not as prevalent as they were extinction session included responses per minute (i.e., re- a decade ago, with the 1990s has come the availability of herbal sponse rate) and number of responses on the drug-appropri- dietary supplements such as, for example, Herbal Ecstacy® (sic) ate lever (expressed as a percent of total responses). Animals (Global World Media Corp., Venice, CA) and Herbal XTC® were not used in the stimulus generalization studies until they (GH Applied Technologies Inc., Fairfield, CT). In addition to made greater 80% of their responses on the drug-appropriate caffeine, both contain ephedrine in the form of ma huang. The lever after administration of (2)ephedrine, and less than 20% amount of ma huang (or ephedrine) is not specified on the of their responses on the same drug-appropriate lever after packaging for Herbal Ecstacy.® However Herbal XTC® con- administration of saline, for 3 consecutive weeks. tains 200 mg of ma huang per tablet and, according to the label- Tests of stimulus generalization were conducted to deter- ing, this represents approximately 18 mg of ephedrine. A com- mine if the (2)ephedrine stimulus would generalize to the fol- panion product, Herbal XTC Enhancer® contains 590 mg of ma lowing agents (doses in parenthesis): (1)ephedrine (1.0, 2.0, huang extract (providing 59 mg of ephedrine) per tablet. 4.0, 8.0 mg/kg), S(1)amphetamine (0.25, 0.5, 0.75 mg/kg), me- Despite the widespread use of these herbal products (ac- thylphenidate (0.75, 1.25, 1.5 mg/kg), cocaine (2.0, 3.0, 3.5, 4.0 cording to the lay press (1), manufacturers of Herbal Ecstacy® mg/kg), caffeine (3.0, 6.0, 12.0, 18.0, 24.0, 30.0, 40.0, 50.0 mg/ alone claim to have sold 150 million dose units), relatively lit- kg), S(2)methcathinone (0.1, 0.25, 0.4, 0.5 mg/kg), S(1)meth- tle is known about the stimulus effects of ephedrine. Huang amphetamine (0.1, 0.3, 0.35, 0.4, 0.5 mg/kg), and MDMA (0.5, and Ho (12) demonstrated that racemic ephedrine produces 1.0, 1.25, 1.5 mg/kg). During this phase of the study, mainte- .80% (1)amphetamine-appropriate responding in tests of nance of the (2)ephedrine-saline discrimination was insured stimulus generalization using (1)amphetamine-trained rats, by continuation of the training sessions on a daily basis (ex- whereas a subsequent study by Holloway et al. (11) reported a cept on a generalization test day; see below). On 1 of the 2 maximum of about 70% (1)amphetamine-appropriate re- days before a generalization test, half of the animals would re- sponding. Racemic ephedrine (10 mg/kg)(5) and crude ephe- ceive (2)ephedrine and half would receive saline; after a 2.5- dra plant extract (4) have been used as training drugs in rats. min extinction session, training was continued for 12.5 min. The (6)ephedrine stimulus generalized to (6)amphetamine Animals not meeting the original criteria (i.e., .80% of total and cocaine (5), and the ephedra-extract stimulus generalized responses on the drug-appropriate lever after administration to S(1)methamphetamine (4). There is, then, evidence for of training drug, and ,20% of total responses on the same le- some similarity between the stimulus effects produced by ra- ver after administration of saline), during the extinction ses- cemic ephedrine and amphetaminergic stimulants. However, sion were excluded from the immediately subsequent general- Young et al. (20) recently have shown that whereas an ization test session. During the investigations of stimulus S(1)amphetamine stimulus (ED50 5 0.4 mg/kg) generalizes to generalization, test sessions were interposed among the train- (2)ephedrine (ED50 5 4.5 mg/kg), it only partially generalizes ing sessions. The animals were allowed 2.5 min to respond un- to (1)ephedrine (maximum drug-appropriate responding 5 der nonreinforcement conditions; the animals were then re- 50% at 12 mg/kg). So, although ephedrine has been previ- moved from the operant chambers and returned to their ously used as a training drug (5), racemic ephedrine, not the home cages. An odd number of training sessions (usually five) more centrally active optical isomer, (2)ephedrine, was em- separated any two generalization test sessions. Doses of the ployed. The purpose of this present investigation was to de- test drugs were administered in a random order, using a 15- termine if (2)ephedrine would serve as a training drug in ani- min presession injection interval, to groups of five to six rats. mals and, if so, to examine several central stimulants in tests If a particular dose of a challenge drug resulted in disruption of stimulus generalization so as to better characterize the of behavior (i.e., no responding), only lower doses would be stimulus properties of this agent. evaluated in subsequent weeks. Stimulus generalization was considered to have occurred when the animals, after a given dose of challenge drug made 80% of their responses on the METHOD (2)ephedrine-appropriate lever.