4-Methylaminorex
4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street names "U4Euh" and "Ice". It is banned in many countries as a stimulant.
4-Methylaminorex has effects comparable to methamphetamine but with a longer duration.
The results of animal experiments conducted with this drug suggest that it has an abuse liability similar to cocaine and amphetamine. One study found that, "stimulus properties of racemic cis, racemic trans, and all four individual optical isomers of 4-methylaminorex were examined in rats trained to discriminate 1 mg/kg of Samphetamine sulfate from saline. The Samphetamine stimulus generalized to all of the agents investigated". A second study in which rats trained to discriminate either 0.75 mg/kg S-amphetamine or 1.5 mg/kg fenfluramine from saline generalized to aminorex as amphetamine stimulus but not to fenfluramine. Rats trained to discriminate 8 mg/kg cocaine from saline generalized 4-methylaminorex to cocaine-stimulus. The reinforcing effects of cis-4-methylaminorex were determined in two models of intravenous drug self-administration in primates. Vehicle or 4-methylaminorex doses were substituted for cocaine. One of the two different doses of 4-methylaminorex maintained self-administration behavior above vehicle control levels.
Chemistry
4-Methylaminorex exists as four stereoisomers : -cis and -trans. The -cis isomers are the form used recreationally.The -cis isomers generally synthesized from dl-phenylpropanolamine in one step by cyclization with cyanogen bromide. Alternate synthesis routes generally involve more steps, such as replacing cyanogen bromide with sodium or potassium cyanate to form an intermediate and then reacting it with concentrated hydrochloric acid. A method reported in microgram replaced the need for a separate addition of hydrochloric acid by starting with the hydrochloride salt of the dl-phenylpropanolamine but side-products are noted. The -trans isomers are synthesized in the same manner above but dl-norephedrine is used as the starting material instead. The cyanate reaction proceeds differently from the cyanogen bromide and transforms norephedrine into trans-4-methylaminorex instead, as noted in the DEA micrograph. The cyanogen bromide, by comparison, transformed norephedrine into the cis isomer and norpseudoephedrine into the trans isomers of the final product.
Dosage
4-methylaminorex can be smoked, insufflated or taken orally.As an anorectic, the ED50 is 8.8 mg/kg in rats for the -cis isomers. The -trans isomers are slightly more potent at 7.0 mg/kg. As a recreational drug, the effective dosage ranges from 5 to 25 mg.
In the 1970s McNeil Laboratories, Inc. was trying to bring 4-methylaminorex to drug market as a sympathomimetic, research name was McN-822, they mention that human dose would have been 0.25 mg/kg of body weight. They mention also LD50: 17 mg/kg
p.o for mice
There is a patent about the use of 4-methylaminorex "as a nasal decongestant which, when administered orally, does not produce adverse central nervous system stimulant effects as experienced with other decongestants and anorexiants." Dose mentioned is 0.25 mg/kg of body weight.
Effects
It produces long-lasting effects, generally up to 16 hours in duration if taken orally and up to 12 hours if smoked or insufflated. Large doses have been reported anecdotally to last up to 36 hours. The effects are stimulant in nature, producing euphoria, increased attention, and increased cognition. Anecdotally, it has been reported to produce effects similar to nootropics. However, there is no research to support the claim that it is different or more effective than other psychostimulants in this respect. Moreover, 4-methylaminorex does not have the established safety profile of widely used clinical psychostimulants such as methylphenidate and dextroamphetamine.| Time | Concentration of 4-methylaminorex in urine |
| 0-6 | 45 |
| 6-24 | 1.0 |
| 24-36 | 0.1 |
| 36-48 | not detected |
There has been one reported death due to 4-methylaminorex and diazepam. Concentrations of 4-methylaminorex were: in blood 21.3 mg/L; in urine 12.3 mg/L. Diazepam concentration in blood was 0.8 mg/L. One experiment on rats has studied excretion of 4-methylaminorex in urine: "The concentration of trans-4-methylaminorex in rat urine following four injections of the trans-4S,5S isomer 5 mg/kg i.p each, at intervals of 12 h in 2 days, as measured quantitatively by GC/MS".
Another study focused on pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in rats.
"Pulmonary hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methylaminorex, was discovered on the property of three individuals with diagnoses of pulmonary hypertension."
Neurotoxicity studies
There have been three studies studying possible neurotoxicity of 4-methylaminorex. First study using quite high doses in rats and studying short-term effects suggested reduction in tryptophan hydroxylase activity but citing study: "No change in TPH activity was observed 30 min after injection; by 8 h the activity of this enzyme appeared to be recovering." and "this agent is significantly less neurotoxic than methamphetamine or MDMA."A study published 2 years later than first one also suggested reduction in tryptophan hydroxylase activity, they used quite high dose too and studied also long-term effects, they found reduction of 20-40% of tryptophan hydroxylase activity and "recovery of TPH activity occurred 18 h after treatment, but was significantly decreased again by 7 days." but "It is noteworthy that, unlike the other analogs, the striatal levels of 5-HT did not decline with TPH activity following multiple 4-methylaminorex treatment"
The latest study was not able to find any long-term effects suggesting neurotoxicity and instead found an increase in serotonin levels, they also used high doses "The dosages used in the present experiments are about 6-10 times than the effective doses of aminorex and stereoisomers inhibition of food intake." Doses were repeated 3 times a day and mice were killed 7 days after last dose. "Since a long-lasting depletion of dopamine or 5-HT appears to be a good predictor of dopamine or 5-HT neurotoxicity, the results suggest that the aminorex compounds except 4S,5S-dimethylaminorex, unlike MDMA or fenfluramine, are not toxic to either dopamine or 5-HT neurotransmitter systems in CBA mice. It was reported that although multiple doses of 4-methylaminorex caused long-term declines in striatal tryptophan hydroxylase activity in SD rats, no changes were found in 5-HT and 5-HIAA levels.
That first study also suggested reduced dopamine levels, but citing study: "However, 8 h after drug administration no differences from control values were seen in DA, DOPAC or HVA levels." and again later studies didn't find any long-term reduction.
Legal status
Australia
In Australia, 4-Methylaminorex is listed as Schedule 9, making it legal only for scientific and medical research.Canada
In Canada, 4-Methylaminorex is listed as Schedule III.Netherlands
In the Netherlands, aminorex is a List I drug of the Opium Law. It is not approved by the CBG, and so it is designated as lacking any medical use.United Kingdom
In the United Kingdom, 4-Methylaminorex is listed as Class A.United States
In the United States, -cis-4-methylaminorex was placed in Schedule I of the Controlled Substances Act shortly after its emergence as a recreational drug in the mid-1980s. Manufacturing the trans isomer required a different process than those encountered when the substance was first scheduled, and was believed less potent than the cis isomer with a much lower abuse potential. However, studies revealing the abuse potential of the 'trans' isomer, coupled with the development of new clandestine synthetic methods that would produce the trans created a potential loophole in the law, which covered only the 'cis' isomer. To clarify the situation, the US Drug Enforcement Administration published a paper in its DEA Microgram Journal, regarding interpretation of the relevant statutory law as it relates to the status of trans-4-methylaminorex. In summary, according to this non-legally binding decision, trans-4-methylaminorex is not currently a controlled substance, but a potential analogue. In fact, the report explicitly states:However, the opinion does say that the agency considers the substance a potential controlled substance analogue, making the substance identical to a Schedule I substance if intended for human consumption, according to the Federal Analogue Act. The report gives an account of a successful conviction under the Federal Analogue Act of an offense involving the trans isomer.