**5. Pharmacology**

Given the affiliation of cathinone derivatives to beta-keto amphetamines, mephedrone would be expected to act as a Central Nervous System stimulant. In vitro studies on the effects of the cathinone derivatives methcathinone and methylone confirm that the main mechanism of action is very similar to that of amphetamine, being characterised by a predominant action on plasma membrane catecholamine transporters (Cozzi et al., 1999). The presence of the ring substituent on the phenethylamine core modifies the

Mephedrone-Related Fatalities in the United Kingdom: Contextual, Clinical and Practical Issues 359

The effects of mephedrone have been compared by users variously to those of cocaine, amphetamine and MDMA. Self-reported subjective effects may include (Winstock et al., 2011; Deluca et al., 2009): intense stimulation and alertness, euphoria; empathy/feelings of closeness, sociability and talkativeness; intensification of sensory experiences; moderate

Dargan et al. (2010) report that some 56% of those who had used mephedrone may complain of at least one unwanted effect associated with mephedrone use. These may include (ACMD, 2010; Deluca et al., 2009; James et al., 2010; Wood et al., 2009, 2010b): loss of appetite, nausea, vomiting and stomach discomfort; tremors, headache (very common), dizziness/light-headedness, seizures, nystagmus, pupil dilation, blurred vision, numbness of tactile sensitivity (reported at higher dosages); anxiety, confusion, dysphoria, aggression, depression, long-lasting hallucinations, paranoid delusions, short-term psychosis, shortterm mania, insomnia and nightmares, impaired short-term memory, poor concentration, tachycardia, elevated blood pressure, respiratory difficulties, chest pain. Possibly due to vasoconstriction, users have anecdotally described cold/blue fingers. Of particular interest are recent reports of clinical significance: severe refractory left ventricular failure (Chhabra et al., 2010); and acute myocarditis (Nicholson et al., 2010). Further unwanted effects may include: difficulties in urination, possible nephrotoxicity, anorgasmia; changes in body temperature regulation, with hot flushes and sweating; immunological toxicity (vasculitis, infections and ulcerations); posterior reversible encephalopathy syndrome (Omer &

Most of the above untoward effects seem to be similar to those already documented for amphetamine, methylamphetamine and MDMA (Schifano et al., 2010), implicitly supporting a sympathomimetic activity of mephedrone. Conversely, symptoms of depression and anhedonia could be tentatively associated to a putative depletion of serotonin and dopamine as a consequence of drug use (ACMD, 2010), similarly to what may occur with other stimulants (Schifano, 1996). It is impossible to determine a 'safe' dose for mephedrone since negative side-effects may present in association with any dosage taken. Furthermore, similar dosages may have dramatically different consequences in different

During the last few months of 2009 and the first few months of 2010, the UK media were constantly reporting fatalities allegedly related to mephedrone consumption, but only a proportion of them had by that time been formally confirmed. A report on a mephedronerelated fatality first appeared in Sweden, referring to an 18-year-old female death which occurred in December 2008. No other drugs, apart from mephedrone, were identified by the toxicological screenings (Gustaffson & Escher, 2009). Previously, a Danish teenager found in possession of mephedrone died in May 2008, although toxicology reports were inconclusive (Campbell, 2009). The first mephedrone-related death in the USA involved the combined use of mephedrone and heroin (Dickson et al., 2010). More recently, the first cases from the Netherlands (Lusthof et al., 2011) and the Republic of Ireland (EMCDDA, 2011:85) have

sexual arousal; and perceptual distortions (reported with higher dosages only).

Doherty, 2010); and finally serotonin syndrome (Garrett & Sweeney, 2011).

**7. Adverse effects** 

individuals (Dickson et al., 2010).

**8. Fatalities** 

been reported.

pharmacological properties by giving the compound some MDMA-like effects (Europol-EMCDDA, 2010). Cathinones' potencies are mostly lower than those of amphetamines as beta-keto amphetamines show a reduced ability to cross the blood–brain barrier due to the presence of the beta group (Nagai et al., 2007; Gygi et al., 1996).

N-demethylation to the primary amine, reduction of the keto moiety to the respective alcohol, and oxidation of the tolyl moiety to the corresponding alcohols and carboxylic acid is the major metabolic pathway for mephedrone, followed by N-dealkylation.

#### **6. Routes of administration, dosage, use in combination with other drugs, effects**

The most common routes for recreational use include insufflation (snorting) and oral ingestion. Because of its solubility in water, mephedrone is reportedly used by rectal administration or injected intravenously. Other typical methods of intake include oral ingestion as capsules or tablets; swallowing mephedrone powder wrapped up in cigarette paper (bombing); or mixed with water. Insufflation is likely to be the most common modality as, when snorted, mephedrone elicits its effects within a few minutes, with the peak being reached in less than 30 min followed by a rapid comedown. According to online users, the mephedrone dosage for snorting may range between 25 and 75 mg, with a lower threshold at 5–15 mg and levels in excess of 90 mg considered a high dosage (Sumnall and Wooding, 2009). Dosing is more frequent when taken intranasally; this route is allegedly associated with greater abuse liability than the oral route (Winstock et al., 2010, 2011). On average, the most common oral dosages are higher than the snorting ones (Sumnall & Wooding, 2009), in the range 150 to 250 mg.

Time of onset may be from 45 min to 2 h and may vary in association with the amount of food in the stomach. Because of this, users suggest taking mephedrone on an empty stomach. Psychoactive effects may last longer (up to 2–4 h) with oral ingestion; side-effects might be milder and the need to re-dose less urgent. Some users employ both insufflation and oral ingestion in combination to obtain faster onset and long-lasting effects (Deluca et al., 2009). Users report that rectal administration is characterised by faster onset of the effects and requires lower doses, e.g. 100 mg on average than oral ingestion (Deluca et al., 2009). Although not typically advised, because this may increase the drug's addictive liability levels (Deluca et al., 2009), mephedrone may also be injected either intramuscularly (Wood et al., 2010a) or intravenously, at one half or two-thirds of the oral dose (Deluca et al., 2009). According to online user fora, mephedrone may be taken in combination with a number of stimulants, sedatives and psychedelics (Deluca et al., 2009; Schifano et al., 2011).

As mephedrone has the capacity to induce tolerance on repeated dosing, an increasing number of user reports have stated a quick progression to either regular drug use and/or uncontrolled bingeing behaviour (known as 'fiending'), with 1–4 g of mephedrone consumed in a session to prolong the duration of its effects (Deluca et al., 2009; Europol-EMCDDA, 2010; Dargan et al., 2010). A recent survey carried out by a drug-related web site has unveiled an average monthly use of 11.16 g for each mephedrone consumer (Drugsforum, 2010). Although withdrawal symptoms are not commonly reported, users often display strong cravings for mephedrone (Newcombe, 2009).

The effects of mephedrone have been compared by users variously to those of cocaine, amphetamine and MDMA. Self-reported subjective effects may include (Winstock et al., 2011; Deluca et al., 2009): intense stimulation and alertness, euphoria; empathy/feelings of closeness, sociability and talkativeness; intensification of sensory experiences; moderate sexual arousal; and perceptual distortions (reported with higher dosages only).
