Bath Salts, Mephedrone, and Methylenedioxypyrovalerone as Emerging Illicit Drugs That Will Need Targeted Therapeutic Intervention

Abstract

The term “synthetic cathinones” is fairly new, but, although the abuse of synthetic cathinones is a recent problem, research on cathinone analogs dates back > 100 years. One structural element cathinone analogs have in common is an α-aminophenone moiety. Introduction of amine and/or aryl substituents affords a large number of agents. Today, > 40 synthetic cathinones have been identified on the clandestine market and many have multiple “street names.” Many cathinone analogs, although not referred to as such until the late 1970s, were initially prepared as intermediates in the synthesis of ephedrine analogs. The cathinones do not represent a pharmacologically or mechanistically homogeneous class of agents. Currently abused synthetic cathinones are derived from earlier agents and seem to produce their actions primarily via the dopamine, norepinephrine, and/or serotonin transporter; that is, they either release and/or inhibit the reuptake of one or more of these neurotransmitters. The actions of these agents can resemble those of central stimulants such as methamphetamine, cocaine, and/or empathogens such as 1-(3,4-methylenedioxyphenyl)-2-aminopropane (Ecstasy) and/or produce other effects. Side effects are primarily of a neurological and/or cardiovascular nature. The use of the “and/or” term is emphasized because synthetic cathinones represent a broad class of agents that produce a variety of actions; the agents cannot be viewed as being pharmacologically equivalent. Until valid structure–activity relationships are formulated for each behavioral/mechanistic action, individual synthetic cathinones remain to be evaluated on a case-by-case basis. Treatment of synthetic cathinone intoxication requires more “basic science” research. At this time, treatment is mostly palliative.

Introduction

“Synthetic cathinones” represent an emerging drug-abuse problem. Relatively little seems to be known about these “mysterious” new agents and their pharmacology. But, more might be known than (or might be inferred from) what is commonly recognized or acknowledged. What are synthetic cathinones? Where did they come from? Do they really represent something new? Synthetic cathinones constitute a broad category of agents whose individual members produce similar, somewhat similar, dissimilar, and, occasionally, unique effects; hence, their mechanisms of action cannot be identical. What should emerge from this review are the following: (i) synthetic cathinones are structurally (i.e., chemically and stereochemically) derived from amphetamine (i.e., phenylisopropylamine) analogs, (ii) the actions and mechanisms of action of synthetic cathinones are no more homogeneous than those of other “amphetamine-related” phenylisopropylamines (PIAs), and (iii) an understanding of amphetamine-related PIAs and their structure–activity relationships (SARs) will provide a sound backdrop for understanding the synthetic cathinones.

Synthetic cathinones should not be viewed as an entirely novel class of drugs of abuse for which no previous literature or prior understanding is available. Actually, synthetic cathinones are derivatives of an agent (i.e., cathinone) that is the active stimulant component of a natural product (i.e., the khat plant). The use/abuse of khat is many centuries old; however, cathinone was not specifically identified as its active stimulant constituent until 1975 (UN Document, 1975). Much can be learned from an examination of earlier literature. In fact, many synthetic cathinones, although it should be recognized that they were not termed as such at the time of their initial discovery, have been around for decades; some have been known for 100 years. Unfortunately, complex and inconsistent chemical nomenclature has often obscured, or at least complicated, a proper understanding or appreciation of these agents.

Prior to just a few years ago, the scientific literature on cathinone, and cathinone-related analogs (α-aminopropiophenones and chain-extended derivatives thereof, now termed “synthetic cathinones”), was relatively meager, quite manageable, and presented an interesting (if somewhat incomplete) story. In the past, except for a brief period in the early 1980s—coincident with the identification of cathinone as a natural plant-derived product with abuse potential—there was relatively little scientific interest in cathinone or cathinone analogs. There was a second wave of interest in the early 1990s when methcathinone (N-methylcathinone or MCAT) was identified as a potential drug-abuse problem and scheduled by the US government as a schedule I substance. Since then, the field has burgeoned tremendously. “Synthetic cathinones” and new “synthetic cannabinoids” are two of the latest global drug-abuse problems, and both seem to have had a nearly exponential growth rate. The two “problems” are not related from a structural or mechanistic perspective. Only the former will be discussed here.

Synthetic cathinones, synthetic cannabinoids, and other novel agents—including some recently introduced LSD-like (i.e., lysergic acid diethylamide-like) hallucinogenic agents—have been termed “new psychoactive substances” or “NPSs” (UNODC, 2013). This is a “bucket” appellation that is appropriate and well suited for legal purposes (perhaps the goal for which it was intended) and is a term suitable for the lay press, but it lends no understanding of the actions and mechanisms of action of the individual agents (or classes of agents) involved. Indeed, several NPSs already have been investigated and they are structurally diverse, produce different effects, and act by different mechanisms. Structurally, synthetic cathinones might be described as “nuevo amphetamines” or, better yet, as “nuevo phenylisopropylamine analogs” because their actions and, particularly, mechanisms of action, are not necessarily identical to that of amphetamine itself.

The roots of the “cathinone story” are > 1000 years old, but the bulk of what has been published on synthetic cathinones has occurred only in the past few years. By means of analogy, some parallels can be drawn from the current cocaine-abuse problem. Coca leaf (primarily Erythroxylum coca) was (and continues to be) chewed in certain parts of South America as an antifatigue agent. It was not until cocaine was identified as the major active stimulant constituent of coca leaf, and made widely available in pure form (i.e., in the form of cocaine and “crack”), that it became a major, worldwide drug-abuse problem. The same might be said about the khat plant—with cathinone now being considered its most potent central stimulant constituent—but with a twist. Cocaine analogs never became widely available. Why? Difficulty of synthesis of cocaine analogs? Indeed, there are some complex synthetic and stereochemistry problems here. The ready availability of cocaine? In contrast, many novel synthetic cathinone analogs are now flooding clandestine markets. The khat plant is not readily available outside its indigenous area, and it is the fresh plant that is desired (i.e., cathinone degrades as the harvested khat plant ages). Pure cathinone, unlike cocaine, has never been heavily trafficked. However, cathinone analogs are relatively easier to synthesize than cocaine analogs, they are generally more stable than cathinone (particularly in solution), and their synthetic precursors are readily available. Some synthetic cathinones are more potent than cathinone itself, can produce a different effect than cathinone, and possess different mechanisms of action (see the succeeding text). Hence, they are fairly simple to synthesize, and a wide variety of analogs is possible. This might explain the rapid shift in market-available synthetic cathinone products, as time goes on, to circumvent legal restrictions.

Structurally, synthetic cathinones are, simply put, β-keto analogs of amphetamine-related structures. Cathinone, for example, is the β-keto analog of amphetamine (AMPH). In theory, each “AMPH analog” can have a synthetic cathinone counterpart. However, some synthetic cathinones represent novel entities whose parent AMPH has never been extensively (or at all) investigated (at least not in a systematic, scientific manner or in human subjects). So, it is not surprising that little is known about many of the new synthetic cathinones. It might appear that the synthetic cathinones are wholly novel and unexpected drug-abuse entities, but a retrospective analysis suggests that there is/was some forethought behind the market introduction of the abused agents we now term synthetic cathinones.

Synthetic cathinones can be viewed from several perspectives. As mentioned earlier, they are β-keto analogs of AMPH (i.e., they are PIA analogs). They can also be viewed as oxidation products of phenylpropanolamines (i.e., β-hydroxyphenylisopropylamines) such as ephedrine and norephedrine. Cathinone is the oxidized version of norephedrine where the β-hydroxyl group of norephedrine has been oxidized to a carbonyl group.

PIAs do not represent a pharmacologically or mechanistically homogeneous class of agents (Glennon & Young, 2011). Hence, there is no reason to assume that synthetic cathinones (or phenylpropanonamines) will be any more pharmacologically or mechanistically homogeneous than their PIA parents. These agents need to be investigated on a case-by-case basis (Dal Cason, Young, & Glennon, 1997) until some general SARs can be identified. The pharmacology, SARs, and mechanism(s) of action of PIAs and/or phenylpropanolamines have been the subject of scientific investigation for > 100 years now. The alarming increase in the number of new phenylpropanonamines (i.e., synthetic cathinones) appearing on the clandestine market in the past few years will require a considerable catch-up effort by scientists, the medical community, and drug enforcement agencies so that intelligent treatment and legal decisions can be made.