Background and purpose: Designer beta-keto amphetamines (e.g., cathinones, "bath salts," and "research chemicals") have become popular recreational drugs, but their pharmacology is poorly characterized. Experimental approach: We determined the potencies of cathinones to inhibit dopamine (DA), noradrenaline (NA), and serotonin (5-hydroxytryptamine [5-HT]) transport into transporter-transfected human embryonic kidney 293 cells, DA and 5-HT efflux from monoamine-preloaded cells, and monoamine receptor binding affinity. Key results: Mephedrone, methylone, ethylone, butylone, and naphyrone act as nonselective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone, and butylone also release 5-HT, similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone, and flephedrone act as preferential DA and NA uptake inhibitors and DA releasers, similar to amphetamine and methamphetamine. Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) are highly potent and selective DA and NA transporter inhibitors but unlike amphetamines do not release monoamines. The non-beta-keto amphetamines are trace amine-associated receptor 1 ligands, whereas cathinones are not. All cathinones showed high blood-brain barrier permeability in an in vitro model. Mephedrone and MDPV exhibited particularly high permeability. Conclusions and implications: Cathinones have considerable pharmacological differences that form the basis for their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is likely associated with a considerable risk of addiction. (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British Pharmacological Society.

/pdf/pharmacological-characterization-of-designer-cathinones-in-1czmv3hjbv.pdf

Pharmacological characterization of designer cathinones in vitro

Assessing African medicinal plants for efficacy and safety: pharmacological screening and toxicology.

The definitive version can be found at: http://onlinelibrary.wiley.com/ Copyright Society for the Study of Addiction [Full text of this article is not available in the UHRA]

Mephedrone, new kid for the chop?

Despite their widespread Internet availability and use, many of the new drugs of abuse remain unfamiliar to health care providers. The herbal marijuana alternatives, like K2 or Spice, are a group of herbal blends that contain a mixture of plant matter in addition to chemical grade synthetic cannabinoids. The synthetic cathinones, commonly called “bath salts,” have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. Kratom, a plant product derived from Mitragyna speciosa Korth, has opioid-like effects, and has been used for the treatment of chronic pain and amelioration of opioid-withdrawal symptoms. Salvia divinorum is a hallucinogen with unique pharmacology that has therapeutic potential but has been banned in many states due to concerns regarding its psychiatric effects. Methoxetamine has recently become available via the Internet and is marked as “legal ketamine.” Moreover, the piperazine derivatives, a class of amphetamine-like compounds that includes BZP and TMFPP, are making a resurgence as “legal Ecstasy.” These psychoactives are available via the Internet, frequently legal, and often perceived as safe by the public. Unfortunately, these drugs often have adverse effects, which range from minimal to life-threatening. Health care providers must be familiar with these important new classes of drugs. This paper discusses the background, pharmacology, clinical effects, detection, and management of synthetic cannabinoid, synthetic cathinone, methoxetamine, and piperazine exposures.

/pdf/here-today-gone-tomorrow-and-back-again-a-review-of-herbal-24f0917m15.pdf

Here Today, Gone Tomorrow…and Back Again? A Review of Herbal Marijuana Alternatives (K2, Spice), Synthetic Cathinones (Bath Salts), Kratom, Salvia divinorum, Methoxetamine, and Piperazines

Fresh leaves of the khat tree (Catha edulis Forsk.) are chewed for their euphoric properties in East Africa and parts of the Middle East, such as The Yemen. This review describes the history, cultivation and constituents of khat, and the social aspects of khat chewing in Yemen. The major pharmacologically active constituent of the fresh leaves is (--)-S-cathinone. The pharmacology of (--)-S-cathinone in the central nervous system and the peripheral effects are described. (--)-S-Cathinone is regarded as an amphetamine-like sympathomimetic amine and this mechanism of action is discussed in relation to the central stimulant actions and the cardiovascular effects of increasing blood pressure and heart rate. The risk factors associated with khat chewing are described, with emphasis on the reported increased incidence of acute myocardial infarction.

/pdf/khat-pharmacological-and-medical-aspects-and-its-social-use-xoqpm0azl7.pdf

Khat: pharmacological and medical aspects and its social use in Yemen.

Pharmacological aspects of the chewing of khat leaves.

Cathinone is an alkaloid that has been discovered some fifteen years ago in the leaves of the khat bush. This plant grows in East Africa and in southern Arabia, and the inhabitants of these regions frequently chew khat because of its stimulating properties. Cathinone, which is S(–)-α-aminopropiophenone, was soon found to have a pharmacological profile closely resembling that of amphetamine; indeed, in a wide variety of in vitro and in vivo experiments it was demonstrated that cathinone shares the action of amphetamine on CNS as well as its sympathomimetic effects; thus, for example, drug-conditioned animals will not distinguish between cathinone and amphetamine. These various observations were confirmed by a clinical experiment showing that cathinone also in humans produces amphetamine-like objective and subjective effects. Finally, it was demonstrated that cathinone operates through the same mechanism as amphetamine, i.e. it acts by releasing catecholamines from presynaptic storage sites. Thus, much experimental evidence indicates that cathinone is the main psychoactive constituent of the khat leaf and that, in fact, this alkaloid is a natural amphetamine.

Cathinone, a Natural Amphetamine

1. The chewing of khat leaves as a stimulant is common in certain countries, and the effects of this material are supposed to be due to the phenylalkylamine alkaloid cathinone. In order to determine the effects of this substance in humans, a single oral dose of cathinone or placebo was administered to six healthy male volunteers in a double-blind, random order crossover study. 2. Cathinone produced increases in blood pressure and in heart rate, and these changes were concomitant with the presence of cathinone in blood plasma. 3. The physical and mental changes that the subjects reported during the experiment indicated that cathinone has in humans euphorigenic and psychostimulant effects. 4. These observations support the assumption that cathinone is the constituent mainly responsible for the effects of khat, and they show that this alkaloid has also in humans amphetamine-like effects.

Amphetamine-like effects in humans of the khat alkaloid cathinone.

Objectives

To show the subjective and cardiovascular effects of khat leaves having a standardized content of cathinone.



Background

The main effect of khat is an increase of energy and alertness. This effect is thought to be attributable to the phenylalkylamine cathinone, but no controlled clinical trials have been published.



Design

The design was balanced and double blind. Six drug-naive volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight, as well as alkaloid-free khat as a placebo. Psychologic effects were evaluated by the Addiction Research Center Inventory (ARCI) and visual analog scales. Physiologic measures were systolic blood pressure, diastolic blood pressure, and heart rate. Plasma concentrations of cathinone and its metabolites norephedrine and R,R-(—) norpseudoephedrine were determined by HPLC.



Results

Maximal plasma concentrations of cathinone (127 ± 53 [SD] ng/ml) were attained after 127 ± 30 minutes. The area under the plasma concentration—time curve from 0 to 9 hours was 415 ± 207 ng/ml · hr, and the terminal elimination half-life was 260 ± 102 minutes. An effect of khat was observed in the ARCI scales Abuse Potential (p < 0.01), Motor Stimulation (p < 0.02), Amphetamine-Like Effect (p < 0.005), and Stimulation-Euphoria (p < 0.005), as well as in the visual analog scales Excited-Calm (p < 0.001) and Energetic-Lethargic (p < 0.001).



Conclusions

Our results provide objective evidence for the amphetamine-like stimulatory effects of khat leaves. These effects were closely similar to those observed after cathinone, 0.5 mg/kg body weight, although peak plasma concentrations of cathinone after khat were delayed.



Clinical Pharmacology and Therapeutics (1994) 55, 556–562; doi:10.1038/clpt.1994.69

Peter Kalix

Papers

Pharmacological aspects of the chewing of khat leaves.

Cathinone, a Natural Amphetamine

Amphetamine-like effects in humans of the khat alkaloid cathinone.

Pharmacodynamics and pharmacokinetics of khat: a controlled study.

Pharmacological properties of the stimulant khat