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Peripheral adrenergic and serotonergic effects of the “ legal highs” α -methyltryptamine (AMT) and 5-methoxy-α -methyltryptamine (5-MeO-AMT) suggest risks of long term use. AMT and 5-MeO-AMT are recreational drugs which online user reports (http://www.erowid.org) suggest have mixed stimulant, hallucinogen and empathogenic properties. Such effects are likely to be harmful due to acute cardiovascular toxicity associated with blockade of the norepinephrine transporter (NET), direct vasoconstrictor effects (via 5-HT2A receptors, which elicit central hallucinogenic effects as well as peripheral vasoconstriction) and long term effects such as cardiac valve fibrosis (as agonists of 5-HT2B receptor; (1)). We have examined the activity of these compounds at these targets using in vitro smooth muscle preparations from male Wistar rats (200-300g). Segments of tail artery were mounted in wire myographs and stimulated with short bursts of electrical field stimulation (EFS; 10 Hz, 1 sec trains every 5 min) to produce adrenergic contractions. These preparations were used to detect effects on the NET as well as direct vasoconstrictor activity. Longitudinal strips of gastric fundus smooth muscle were used as an assay for 5-HT2B receptor activity. Statistical analyses were made using paired or un-paired t-tests, as appropriate AMT potentiated EFS-evoked contractions of tail arteries at low concentrations (0.1-1.0 µM) and produced contraction from baseline tone at higher concentrations (1-10 µM). The effect on EFS-evoked contractions was abolished by prior addition of the NET inhibitor desmethylimipramine (50 nM; n=5). The direct contractile effect of AMT (318 ± 67% increase above baseline; pEC50 5.314 ± 0.38; n=6) was largely attenuated by the 5-HT2A receptor antagonist ketanserin (10 nM; 103 ±46%; n=5). In the presence of ketanserin, it was possible to establish the full effects of AMT on EFS-evoked contractions (maximal 162 ± 61% increase above baseline; pEC50 5.910 ± 0.50; n=6). AMT also produced concentration-dependent contraction of gastric fundus preparations (30 ± 2% of a methacholine (100 µM)-induced maximum contraction; pEC50 6.337 ± 0.15; n= 5) which were inhibited by the 5-HT2B antagonist RS-127144 (10 µM; 7 ± 4% contraction; pEC50 5.525 ± 0.70; n=5). 5-MeO-AMT produced similar effects but was more potent and efficacious. The effects of 5-Meo-AMT on EFS-evoked contractions and smooth muscle tone were more difficult to distinguish, because 5-MeO-AMT had superior efficacy at 5-HT2A receptors. In the presence of ketanserin, contractions were reduced so that a pEC50 of 6.910 ± 0.93 could be estimated (maximal effect 71 ± 27%; n=6). Augmentation of EFS-induced responses by low concentrations of AMT were inhibited by desmethylimipramine (n =5). Ketanserin caused a rightward shift of the concentration-effect curve for the direct vasoconstrictor effects of 5-MeO-AMT (pEC50 6.55 ± 0.27; maximal contraction 656 ± 115%; compared with reduced pEC50 5.52 ± 0.21; similar maximal response 694 ± 109%; n=6). 5-MeO-AMT also produced contractions of gastric fundus preparations (pEC50 7.08 ± 0.19; maximal response 30 ± 2%) which were sensitive to the 5-HT2B antagonist RS-127445 (10 µM; pEC50 6.41 ± 0.13; maximal response 17 ± 1%; n=5). AMT and 5-MeO-AMT appear to inhibit the NET. Both drugs act as 5-TH2A receptor agonists, which may not be anticipated by users who seek only stimulant effects. The difference in potency between the two compounds and the tendency of online supplies and users alike to confuse them or substitute them for one another may lead to unexpected experiences. Most worrying, though, is that the most potent activity that both compounds possess is agonist activity of the 5-TH2B receptor, suggesting that prolonged use would lead to heart valve fibrosis and subsequent heart failure. (1) Dawson, P & Moffatt, JD, Prog Neuropsychopharmacol Biol Psychiatry, 39: 244, 2012
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