A scoping review of home-produced heroin and amphetamine-type stimulant substitutes: implications for prevention, treatment, and policy.

Several home-produced substances such as krokodil and boltushka are prevalent in many Eastern European countries. Anecdotal reports of its use have been circulating in Germany and Norway; however, this has not been confirmed. Its use has also been reported by the media in the USA, although only one confirmed report of its use exists. Home-produced drugs are associated with high levels of morbidity and a number of complex health issues such as the spread of blood borne viruses, gangrene, and internal organ damage. The high incidence of HIV rates amongst people who inject home-produced substances is a public health concern. The resulting physical health consequences of injecting these crude substances are very severe in comparison to heroin or amphetamine acquired in black markets. Due to this fact and the increased mortality associated with these substances, professionals in the area of prevention, treatment, and policy development need to be cognisant of the presentation, harms, and the dangers associated with home-produced substances globally. This scoping review aimed to examine existing literature on the subject of home-produced heroin and amphetamine-type stimulant substitutes. The review discussed the many implications such research may have in the areas of policy and practice. Data were gathered through the use of qualitative secondary resources such as journal articles, reports, reviews, case studies, and media reports. The home production of these substances relies on the utilisation of precursor drugs such as less potent stimulants, tranquillizers, analgesics, and sedatives or natural plant ingredients. The Internet underpins the facilitation of this practice as recipes, and diverted pharmaceutical sales are available widely online, and currently, ease of access to the Internet is evident worldwide. This review highlights the necessity of prevention, education, and also harm reduction related to home-produced drugs and also recommends consistent monitoring of online drug fora, online drug marketplaces, and unregulated pharmacies.

Synthesis and in vitro toxicity of 4-MTA, its characteristic clandestine synthesis byproducts and related sulfur substituted alpha-alkylthioamphetamines.

4-Methylthioamphetamine (4-MTA) is recognised as a 3,4-methylenedioxymethamphetamine (MDMA)-like drug of abuse. Such amphetamine-type drugs often contain byproducts of uncontrolled, illegal clandestine synthetic processes. We report the isolation and structural identification of a number of novel pyridines, dihydropyridone and N,N-di(1-aryl-2-propyl) amines as route-specific byproducts associated with clandestine synthesis of 4-MTA and related amphetamines. We report the in vitro cytotoxicity of 4-MTA, its synthesis byproducts together with some structurally related sulfur substituted alpha-alkyl phenethylamines in cell lines overexpressing human monoamine transporters as well as in a primary neuronal cell line model and a dopaminergic neuroblastoma cell line. 4-MTA along with a number of other structurally related amphetamine derivatives and synthetic impurities were found to be cytotoxic to these cells within pharmacologically defined concentrations implying that 4-MTA is a cytotoxic agent in vitro and therefore might have the potential to be a neurotoxic agent in vivo.

Identification of specific markers for amphetamines synthesized from glycidic acid pre-precursors and retrospective search in German profiling database.

The pre-precursor market and the clandestine production of amphetamine-type stimulants (ATS) has become more diverse in recent years. Besides α-phenylacetoacetonitrile (APAAN) and α-phenylacetoacetamide (APAA), glycidic acid derivatives and methyl α-phenylacetoacetate (MAPA) are gaining importance. This conclusion is based on seizure data of police and customs. However, analytical data are needed to confirm and quantify the actual prevalence of new pre-precursors by elucidating the percentage of seized ATS that have been produced from them. A recent study showed that APAAN use is currently declining, which supports the view that new pre-precursors are being used. In this study, several conversion procedures using different batches of glycidic acid derivatives and a complete Leuckart reaction to produce amphetamine were carried out. The resulting organic phases were analyzed using gas chromatography - mass spectrometry to identify possible marker compounds. Three marker compounds were discovered and characterized using mass spectra and nuclear magnetic resonance spectroscopy. They were identified as phenyl-1-propanone, N-(1-phenylpropyl)formamide and 1-phenylpropan-1-amine. Their prevalence was investigated by searching the markers in an amphetamine impurity profiling database to determine to what extent they occurred in amphetamine samples from recent years. Data from the central German amphetamine profiling database of more than 250 cases were used for this purpose. The yearly occurrence of the three glycidate marker compounds was determined going back as far as 2009, revealing an increasing trend from 2016 on. This article presents experimental proof that APAAN is currently being replaced by other pre-precursors, such as glycidic acid derivatives.

Detailed investigations into the Akabori-Momotani reaction for the synthesis of amphetamine type stimulants: Part 2.

The Akabori-Momotani reaction can be used to synthesise pseudoephedrine in 50% yield from N-methylalanine and benzaldehyde. This paper investigates electronic effects of substituted benzaldehydes on the reaction to synthesise amphetamine type stimulants and identifies several new Akabori-Momotani by-products, 1-[(4-methoxybenzyl)(methyl)amino]ethanol (11c), 2-(4-methoxyphenyl)-3,4-dimethyl-1,3-oxazolidine (12c), 1,2,3,4-tetramethyl-5,6-di-(4-methoxyphenyl)piperazine (13c) and 1,2,4,5-tetramethyl-3,6-di-(4-methoxyphenyl)piperazine (14c). This paper also investigates pseudoephedrine and methamphetamine isomeric distribution from the Akabori-Momotani reaction with the aid of molecular modelling to understand why more pseudoephedrine than ephedrine is produced.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Home Manufacture of Drugs: An Online Investigation and a Toxicological Reality Check of Online Discussions on Drug Chemistry.

Emerging trends in market dynamics and the use of new psychoactive substances are both a public health concern and a complex regulatory issue. One novel area of investigation is the availability of homemade opioids, amphetamines and dissociatives, and the potential fueling of interest in clandestine home manufacture of drugs via the Internet. We illustrate here how online communal folk pharmacology of homemade drugs on drug website forums may actually inform home manufacture practices or contribute to the reduction of harms associated with this practice. Discrepancies between online information around purification and making homemade drugs safer, and the synthesis of the same substances in a proper laboratory environment, exist. Moderation and shutdown of synthesis queries and discussions online are grounded in drug websites adhering to harm-reduction principles by facilitating discussions around purification of homemade drugs only. Drug discussion forums should consider reevaluating their policies on chemistry discussions in aiming to reach people who cannot or will not refrain from cooking their own drugs with credible information that may contribute to reductions in the harms associated with this practice.

Locomotor activity and discriminative stimulus effects of a novel series of synthetic cathinone analogs in mice and rats.

RATIONALE: Recent years have seen an increase in the recreational use of novel, synthetic psychoactive substances. There are little or no data on the abuse liability of many of the newer compounds. OBJECTIVES: The current study investigated the discriminative stimulus and locomotor effects of a series of synthetic analogs of cathinone: α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinohexiophenone (α-PHP), α-pyrrolidinopentiothiophenone (α-PVT), 3,4-methylenedioxybutiophenone (MDPBP), and ethylone. METHODS: Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine or methamphetamine from vehicle. RESULTS: Each of the compounds produced an inverted-U dose-effect on locomotor activity. Maximal effects were similar among the test compounds, but potencies varied with relative potencies of MDPBP > α-PPP = α-PHP > ethylone > α-PVT. Each of the test compounds substituted fully for the discriminative stimulus effects of methamphetamine. α-PPP, α-PHP, and ethylone fully substituted for cocaine. α-PVT produced a maximum of 50% cocaine-appropriate responding, and MDPBP produced an inverted-U-shaped dose-effect curve with maximum effects of 67%. CONCLUSIONS: These data provide initial evidence that these structurally similar, emerging novel psychoactive substances demonstrate potential for abuse and may be utilized for their stimulant-like effects, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of the classical psychostimulants cocaine and/or methamphetamine.

Discriminative and locomotor effects of five synthetic cathinones in rats and mice.

RATIONALE: Synthetic cathinones continue to be sold as "legal" alternatives to methamphetamine or cocaine. As these marginally legal compounds become controlled, suppliers move to other, unregulated compounds. OBJECTIVES: The purpose of these experiments was to determine whether several temporarily controlled cathinone compounds, which are currently abused on the street, stimulate motor activity and have discriminative stimulus effects similar to cocaine and/or methamphetamine. METHODS: Methcathinone, pentedrone, pentylone, 3-fluoromethcathinone (3-FMC), and 4-methylethcathinone (4-MEC) were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, i.p.) or methamphetamine (1 mg/kg, i.p.) from saline. RESULTS: Methcathinone, pentedrone, and pentylone produced locomotor stimulant effects which lasted up to 6 h. In addition, pentylone produced convulsions and lethality at 100 mg/kg. 4-MEC produced locomotor stimulant effects which lasted up to 2 h. Methcathinone, pentedrone, pentylone, 3-FMC, and 4-MEC each produced discriminative stimulus effects similar to those of cocaine and methamphetamine. CONCLUSIONS: All of the tested compounds produce discriminative stimulus effects similar to either those of cocaine, methamphetamine, or both, which suggests that these compounds are likely to have similar abuse liability to cocaine and/or methamphetamine. Pentylone may be more dangerous on the street, as it produced adverse effects at doses that produced maximal stimulant-like effects.

Substituent branching in phenethylamine-type hallucinogens: a comparison of 1-[2,5-dimethoxy-4-(2-butyl)phenyl]-2-aminopropane and 1-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]-2-aminopropane.

Two novel hallucinogen analogues related to 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP) were synthesized and evaluated in the two-lever drug discrimination paradigm by using 0.08 mg/kg of LSD as the training drug stimulus. The two compounds differ from each other only with respect to the point of branching in the 4-alkyl group. However, pharmacological evaluation revealed a clear difference in difference in potency and degree of LSD generalization for the two isomers. Branching adjacent to the ring, as in the 4-(2-butyl) analogue, may provide steric interference to the formation of the drug-receptor complex, while branching one methylene unit removed from the ring, as in the 4-(2-methylpropyl) analogue, poses less of a steric problem for the drug-receptor interaction. This is consistent with the idea that formation of a charge-transfer complex between the hallucinogen molecule and the receptor may be one of the features of this drug-receptor interaction.

Monomethylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane.

Regiospecific syntheses of the three monomethylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane are described. The three isomeric amines were evaluated for potential psychotomimetic potency using the rabbit hyperthermia assay. Enantiomeric compositions and time-concentration curves in rat brains were determined following intraperitoneal administration of each compound. The biological data are contrasted with the corresponding results obtained with the potent human psychotogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM).

Steric effects of substituents on phenethylamine hallucinogens. 3,4-(Methylenedioxy)amphetamine analogues alkylated on the dioxole ring.

The compounds 1-(2-methyl-1,3-benzodioxol-5-yl)-2-aminopropane and 1-(2,2-dimethyl-1,3-benzodioxol-5-yl)-2-aminopropane were synthesized and evaluated for pharmacologic effects in mice. These can be viewed as analogues of the known psychotomimetic agent 3,4-(methylenedioxy)amphetamine (MDA). Their hydrochloride salts were compared with MDA for their ability to increase spontaneous motor activity and to elicit behavioral effects. The former compounds was MDA-like in action, while the latter was not. The results suggest that one face of the molecule must be free of steric bulk to possess activity.

Conformationally rigid amphetamine analogs as inhibitors of monoamine uptake by brain synaptosomes.

Four 3-phenyl-2-amino-trans-decalin isomers were synthesized in order to obtain derivatives of phenylethylamine with a rigid conformation between the phenyl ring and the amino function. The stereoisomers were tested as inhibitors of catecholamine uptake by rat brain synaptosomes, and their potency was compared with that of amphetamine. The most potent inhibitor of catecholamine uptake was the diaxial 2(a)-amino-3(a)-phenyl-trans-decalin, which was one-fourth to one-third as potent as (+/)-amphetamine. As a dopamine uptake inhibitor in the stiatum, this compound was competitive. The results differ from those obtained earlier with similar analogs with a norepinephrine moiety incorporated into the decalin structure, since a gauche derivative [2(a)-amino-3(e)-3,4-dihydroxyphenyl-3-trans-decalol] was then the most potent and over 20 times as potent as the diaxial anti derivative. It remains to be seen whether this indicates that the mode of binding of phenylethylamines is different from that of catecholamines.

Behavioral and serotonin receptor properties of 4-substituted derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane.

The serotonin (5-HT) receptor affinities and behavioral (discriminative stimulus) properties of a series of 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropanes (2,5-DMA) were investigated. The substituents at the 4-position included H, OMe, OEt, Me, Et, F, Br, I, and NO2. Substituent lipophilicities (pi values) of these functionalities appear to have a minimal effect on either 5-HT receptor affinity or behavioral activity. Those derivatives previously found to be most potent in human studies possess significant affinity for 5-HT receptors. Furthermore, when rats trained to discriminate (+/-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline were used, generalization was found to occur upon administration of the 4-substituted 2,5-DMA derivatives. Because a direct relationship exists between the ED50 values obtained from these discrimination studies and human hallucinogenic potencies, the discriminative stimulus paradigm, with DOM as a training drug, appears to be a useful tool for comparing the quantitative and qualitative (DOM-like) effects produced by certain hallucinogenic agents.

Effects of certain hallucinogenic amphetamine analogues on the release of [3H]serotonin from rat brain synaptosomes.

The enantiomers of 3,4-(methylenedioxy)amphetamine (MDA), p-methoxyamphetamine (PMA), and N-Me-MDA (MDMA), along with their alpha, alpha-dimethylated derivatives, were evaluated for an effect on the release of [3H]serotonin from rat whole brain synaptosomes. The amphetamine isomers were all potent in inducing the release of [3H]serotonin at bath concentrations of 1 and 10 micrometers but were inactive at 0.1 micrometers. No significant difference in isomer potency was observed at the 10 micrometers concentration. However, at 1 micrometer the (+) isomer of MDMA was more effective in inducing release than was the (-) isomer. Since it is the (+) isomer which is clinically active, this result suggests that transmitter release may play a role in the biological activity of MDMA. By contrast, the alpha, alpha-dimethyl compounds were not effective in releasing serotonin, even at the highest bath concentration.

Resolution and absolute configuration of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, a potent hallucinogen analogue.

An hallucinogen analogue, trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), was resolved into ints two enantiomers by fractional crystallization of salts with d- or l-O,O-dibenzoyltartaric acid. A comparison of the ORD and CD curves of the N-5-bromosalicylidene derivatives of trans-2-phenylcyclopropylamine of known absolute configuration and of the title compound established the stereochemistry of the latter to be (1R,2S)-(-) and (1s,2r)-(+). We have earlier shown that the (-) isomer shows selective behavioral effects in cats and mice. In present study it was found that the (-) isomer selectively elicits rabbit hyperthermia when compared with the (+) isomer. In view of the stereoselective ability of the (-) isomer to elicit hallucinogen-like behavioral profiles in these animal models, the proof of absolute configuration lends further support to a new model which interrelates the active binding, conformation of phenethylamine hallucinogens to that of serotonin and tryptamines.

Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA).

Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.

Isomeric cyclopropyl ring-methylated homologues of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, an hallucinogen analogue.

The hallucinogen analogue trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine was modified by adding a 3-methyl group, either cis or trans with respect to the amino group. These two isomeric cyclopropyl ring-methylated compounds were then tested for activity in the mouse ear-scratch assay and for a contractile effect in the rat fundus preparation. Neither compound was found to possess appreciable activity when compared to the nonmethylated parent, in either assay.

Effects of thiophene analogues of chloroamphetamines on central serotonergic mechanisms.

Ring-chlorinated thienylisopropylamines, thiophene analogues of chloroamphetamines, have been synthesized and their effects on serotonergic mechanisms in the rat brain have been evaluated. With 4,5-dichlorothienylisopropylamine (3e), a pharmacological profile similar to that of p-chloroamphetamine, consisting in a marked and long-lasting serotonin depletion and a rather strong and prolonged inhibition of synaptosomal uptake of serotonin, was found. Chloro substitution in position C3 of the thiophene ring did not determine brain serotonin depletion nor serotonin uptake inhibition but enhanced brain MAO inhibitory activity present in all these compounds. 3,5-Dichlorothienylisopropylamine (3g) was the only compound of the series in which the inhibition of serotonin uptake was more marked than the serotonin depleting property.

Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists.

The affinity of ligands for either the 5-HT(2A) or 5-HT(2C) agonist binding site was enhanced by modification of the 2,5-oxygen substituents that are found in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of the conformationally flexible 2,5-dimethoxy substituents into fused dihydrofuran rings generally resulted in increased potency relative to the parent 2,5-dimethoxy compounds. The pure enantiomers of these arylalkylamines were obtained by enantiospecific synthesis that involved acylation of the heterocyclic nucleus 7 with N-trifluoroacetyl-protected D- or L-alanyl chloride, followed by ketone reduction and N-deprotection. The enantiomers demonstrated modest stereoselectivity at the two receptors. Several general trends within these classes of new compounds were observed during their pharmacological investigation. For most pairs of optical isomers tested, the R-enantiomers of the compounds containing heterocycle 7 bound with only slightly higher affinity than their S-antipodes at the 5-HT(2A) and 5-HT(2C) receptors. Likewise, functional studies indicated that the R-enantiomers generally displayed increased potency compared to the S-enantiomers. Aromatization of the dihydrofuran rings of these arylalkylamines further increased affinity and potency. Only a few compounds were full agonists with most of them possessing intrinsic activities in the range of 60-80%. These compounds with a fully aromatic linear tricyclic nucleus are some of the highest-affinity ligands for the 5-HT(2A) receptor reported to date.

4-MTA: a new synthetic drug on the dance scene.

4-MTA (p-methylthioamphetamine) is a new synthetic sulphur derivative of amphetamine that has been associated with six deaths since it was first identified in Europe in 1997. Sold as 'ecstasy' or 'Flatliners', the drug like MDMA is a potent serotonin releaser. Using a self-nominated sampling methodology we accessed over 1000 dance drug users through a magazine survey. Ten percent of respondents thought that they had used 4-MTA. Those with experience of 4-MTA tended to come from a sub-population of heavy 'ecstasy'-users. Responses to the effects of the drug were mixed, although about a quarter of those who believed that they had tried 4-MTA thought that they would use it again.