4-Methylmethcathinone (mephedrone): Neuropharmacological Effects of a Designer Stimulant of Abuse

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2011 Aug 4

PMID 21810934

Citations 121

Authors

Gregory C Hadlock

Katy M Webb

Lisa M McFadden

Pei Wen Chu

Jonathan D Ellis

Scott C Allen

David M Andrenyak

Paula L Vieira-Brock

Christopher L German

Kevin M Conrad

Amanda J Hoonakker

James W Gibb

Diana G Wilkins

Glen R Hanson

Annette E Fleckenstein

Affiliations

Soon will be listed here.

Abstract

The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant "binge" treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.

Citing Articles

Neurotoxicity mechanisms and clinical implications of six common recreational drugs.

Wang J, Hao Y, Ma D, Feng L, Yang F, An P Front Pharmacol. 2025; 16:1526270.

PMID: 40034818 PMC: 11873747. DOI: 10.3389/fphar.2025.1526270.

Structure-Activity Relationship of Synthetic Cathinones: An Updated Review.

Nadal-Gratacos N, Pazos M, Pubill D, Camarasa J, Escubedo E, Berzosa X ACS Pharmacol Transl Sci. 2024; 7(9):2588-2603.

PMID: 39296271 PMC: 11406692. DOI: 10.1021/acsptsci.4c00299.

Opposite Contractile Effects of Amphetamine-Related Hallucinogenic Drugs in the Isolated Human Atrium.

Neumann J, Hofmann B, Gergs U Int J Mol Sci. 2024; 25(16).

PMID: 39201573 PMC: 11354304. DOI: 10.3390/ijms25168887.

Synthetic Cathinones: Epidemiology, Toxicity, Potential for Abuse, and Current Public Health Perspective.

Chen S, Zhou W, Lai M Brain Sci. 2024; 14(4).

PMID: 38671986 PMC: 11048581. DOI: 10.3390/brainsci14040334.

Dopamine Concentration Changes Associated with the Retrodialysis of Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) into the Caudate Putamen.

Goldsmith R, Aburahma A, Sprague J Brain Sci. 2024; 14(3).

PMID: 38539653 PMC: 10968967. DOI: 10.3390/brainsci14030265.

References

Clausing P, Gough B, Holson R, Slikker Jr W, Bowyer J . Amphetamine levels in brain microdialysate, caudate/putamen, substantia nigra and plasma after dosage that produces either behavioral or neurotoxic effects. J Pharmacol Exp Ther. 1995; 274(2):614-21. View

Truong J, Wilkins D, Baudys J, Crouch D, Johnson-Davis K, Gibb J . Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity. J Pharmacol Exp Ther. 2005; 314(3):1087-92. DOI: 10.1124/jpet.105.085951. View

Schifano F, Albanese A, Fergus S, Stair J, Deluca P, Corazza O . Mephedrone (4-methylmethcathinone; 'meow meow'): chemical, pharmacological and clinical issues. Psychopharmacology (Berl). 2010; 214(3):593-602. DOI: 10.1007/s00213-010-2070-x. View

Volkow N, Wang G, Fowler J, Logan J, Gatley S, Wong C . Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther. 1999; 291(1):409-15. View

Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H . Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry. 2001; 158(8):1206-14. DOI: 10.1176/appi.ajp.158.8.1206. View

Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F . Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. Br J Pharmacol. 2011; 164(8):1949-58. PMC: 3246659. DOI: 10.1111/j.1476-5381.2011.01499.x. View

McCann U, Ridenour A, Shaham Y, Ricaurte G . Serotonin neurotoxicity after (+/-)3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy"): a controlled study in humans. Neuropsychopharmacology. 1994; 10(2):129-38. DOI: 10.1038/npp.1994.15. View

Gygi M, Fleckenstein A, GIBB J, Hanson G . Role of endogenous dopamine in the neurochemical deficits induced by methcathinone. J Pharmacol Exp Ther. 1998; 283(3):1350-5. View

Tata D, Yamamoto B . Interactions between methamphetamine and environmental stress: role of oxidative stress, glutamate and mitochondrial dysfunction. Addiction. 2007; 102 Suppl 1:49-60. DOI: 10.1111/j.1360-0443.2007.01770.x. View

10.

Kokoshka J, Vaughan R, Hanson G, Fleckenstein A . Nature of methamphetamine-induced rapid and reversible changes in dopamine transporters. Eur J Pharmacol. 1998; 361(2-3):269-75. DOI: 10.1016/s0014-2999(98)00741-9. View

11.

Hansen J, Riddle E, Sandoval V, Brown J, Gibb J, Hanson G . Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther. 2002; 300(3):1093-100. DOI: 10.1124/jpet.300.3.1093. View

12.

Mereu G, Pacitti C, Argiolas A . Effect of (-)-cathinone, a khat leaf constituent, on dopaminergic firing and dopamine metabolism in the rat brain. Life Sci. 1983; 32(12):1383-9. DOI: 10.1016/0024-3205(83)90814-7. View

13.

McCann U, Wong D, Yokoi F, Villemagne V, Dannals R, Ricaurte G . Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci. 1998; 18(20):8417-22. PMC: 6792853. View

14.

Reneman L, Lavalaye J, Schmand B, de Wolff F, van den Brink W, den Heeten G . Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings. Arch Gen Psychiatry. 2001; 58(10):901-6. DOI: 10.1001/archpsyc.58.10.901. View

15.

Guilarte T, Nihei M, McGlothan J, Howard A . Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity. Neuroscience. 2003; 122(2):499-513. DOI: 10.1016/s0306-4522(03)00476-7. View

16.

Morris K . UK places generic ban on mephedrone drug family. Lancet. 2010; 375(9723):1333-4. DOI: 10.1016/s0140-6736(10)60559-4. View

17.

Fleckenstein A, Haughey H, Metzger R, Kokoshka J, Riddle E, Hanson J . Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function. Eur J Pharmacol. 1999; 382(1):45-9. DOI: 10.1016/s0014-2999(99)00588-9. View

18.

Stone D, Stahl D, Hanson G, GIBB J . The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol. 1986; 128(1-2):41-8. DOI: 10.1016/0014-2999(86)90555-8. View

19.

Wagner G, Ricaurte G, Seiden L, Schuster C, Miller R, Westley J . Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res. 1980; 181(1):151-60. DOI: 10.1016/0006-8993(80)91265-2. View

20.

Kuczenski R, Segal D, Cho A, Melega W . Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci. 1995; 15(2):1308-17. PMC: 6577819. View