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.
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Abbreviations
- AMPH:
-
Amphetamine
- AUC:
-
Area under the curve
- C max :
-
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
- O •−2 :
-
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
- T max :
-
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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Acknowledgements
The authors are grateful to Fundaçãopara a CiênciaeTecnologia (FCT) for grant Pest C/EQB/LA0006/2011 and to the project [PTDC/SAU-FCF/102958/2008]-QREN initiative with EU/FEDER financing through COMPETE. VMC and JPC acknowledge FCT for their Post-doc grants (SFRH/BPD/63746/2009 and SFRH/BPD/30776/2006).
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Carvalho, M., Carmo, H., Costa, V.M. et al. Toxicity of amphetamines: an update. Arch Toxicol 86, 1167–1231 (2012). https://doi.org/10.1007/s00204-012-0815-5
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DOI: https://doi.org/10.1007/s00204-012-0815-5