Archives of Toxicology

, Volume 86, Issue 8, pp 1167–1231 | Cite as

Toxicity of amphetamines: an update

  • Márcia Carvalho
  • Helena Carmo
  • Vera Marisa Costa
  • João Paulo Capela
  • Helena Pontes
  • Fernando Remião
  • Félix Carvalho
  • Maria de Lourdes Bastos
Review Article

Abstract

Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood–brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines—amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.

Keywords

Amphetamines Amphetamine Methamphetamine 3,4-Methylenedioxymethamphetamine Pharmacokinetics Hyperthermia Oxidative stress Neurotoxicity Cardiovascular toxicity Hepatotoxicity Rhabdomyolysis Nephrotoxicity 

Abbreviations

AMPH

Amphetamine

AUC

Area under the curve

Cmax

Maximum concentration

CNS

Central nervous system

COMT

Catechol-o-methyltransferase

CSF

Cerebrospinal fluid

CYP

Cytochrome P450

DA

Dopamine

DAT

Dopamine transporter

2,3-DHBA

2,3-Dihydroxybenzoic acid

DIC

Disseminated intravascular coagulation

DMA

2,5-Dimethoxyphenylisopropylamine

DOM

2,5-Dimethoxy-4-methylphenylisopropylamine

DOPAC

3,4-Dihydroxyphenylacetic acid

EC50

Effective concentration 50%

ETC

Electron respiratory chain

EU

European Union

fMRI

Functional magnetic resonance imaging

GABA

Gamma-aminobutyric acid

GFAP

Glial fibrillary acidic protein

GPX

Glutathione peroxidase

GR

Glutathione redutase

GSH

Glutathione (reduced form)

GST

Glutathione S-transferase

γ-GT

γ-Glutamyl transpeptidase or γ-glutamyltransferase

h

Hours

5-HIAA

5-Hydroxyindoleacetic acid

HMA

4-Hydroxy-3-methoxyamphetamine, 3-O-Me-α-MeDA

HMMA

4-Hydroxy-3-methoxymethamphetamine; 3-O-Me-N-Me-α-MeDA

HO

Hydroxyl radical

5-HT

5-Hydroxytryptamine, Serotonin

5-HTT

Serotonin transporter; SERT

HVA

4-Hydroxy-3-methoxyphenylacetic acid, Homovanillic acid

i.p.

Intraperitoneal

ICV

Intracerebroventricular

i.v.

Intravenous

Ke

Elimination constant

KO

Knockout

LSD

Lysergic acid diethylamide

MAO

Monoamine oxidase

MAOi

Monoamine oxidase inhibitor

MDA

(±)-3,4-Methylenedioxyamphetamine

MDEA

Methylenedioxyethylamphetamine

MDMA

(±)-3,4-Methylenedioxymethamphetamine, “Ecstasy”

α-MeDA

α-Methyldopamine, 3,4-Dihydroxyamphetamine, HHA

METH

Methamphetamine

4-MTA

4-Methylthioampethamine

mtDNA

Mitochondrial DNA

MPT

Mitochondrial permeability transition

NA

Noradrenaline

NAC

N-Acetylcysteine

NAT

Noradrenaline transporter

NMDA

N-methyl-d-aspartic acid

N-Me-α-MeDA

N-methyl-α-methyldopamine, 3,4-Dihydroxymethamphetamine, HHMA

NO

Nitric oxide radical

O2

Superoxide anion

ONOO

Peroxynitrite

PET

Positron emission tomography

PD

Pharmacodynamic

PK

Pharmacokinetic

PKC

Protein kinase C

p.o.

Per os

PMA

p-Methoxyamphetamine

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

s.c.

Subcutaneous

-SH

Sulfhydryl

SPECT

Single-photon emission computed tomography

SOD

Superoxide dismutase

SULT

Sulfotransferase

t1/2

Elimination half-life

TH

Tyrosine hydroxylase

THC

Δ9-Tetrahydrocannabinol

Tmax

Median time to maximum concentration

TPH

Tryptophan hydroxylase

UGT

UDP-glucuronosyltransferase

UK

United Kingdom

USA

United States of America

VMAT

Vesicular monoamine transporter

WT

Wild type

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Márcia Carvalho
    • 1
    • 2
  • Helena Carmo
    • 1
  • Vera Marisa Costa
    • 1
  • João Paulo Capela
    • 1
    • 2
  • Helena Pontes
    • 1
  • Fernando Remião
    • 1
  • Félix Carvalho
    • 1
  • Maria de Lourdes Bastos
    • 1
  1. 1. REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
  2. 2.Faculty of Health SciencesUniversity Fernando PessoaPortoPortugal

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