CNR - Institute of Neuroscience CNR
Institute of Neuroscience


Caffeine and psychostimulant drugs: effects of their interaction


Caffeine is the most common psychoactive substance being consumed worldwide by adult as well as young population. Due to its widespread use and low abuse potential, caffeine is considered an atypical drug of abuse. However, beverages with high quantity of caffeine are often consumed with psychostimulant drugs (such as amphetamine, MDMA etc) in order to amplify their stimulant properties and reduce fatigue.

3,4-Methylenedioxymethamphetamine (MDMA), known as ecstasy, is one of the most popular psychostimulant whose neurotoxic effects on the central nervous system are often debated. These neurotoxic effects appear to result from free radical formation which in turn induces oxidative stress process and from hyperthermia. MDMA is often associated with other substances concomitantly, either intentionally or due to impurities in ecstasy tablets. The most popular of these associated substances is caffeine. Several findings have suggested that neuroinflammation may play an active role in the pathogenesis of neurodegenerative diseases. Microglial and astroglial activation appear to play an important role in neurotoxicity and MDMA induced toxicity is associated with microglial activation, which generates many reactive species (e.g., nitric oxide, superoxide, cytokines) favouring neurodegeneration. In this context it becomes of great importance to investigate whether caffeine interferes with neurotoxic effects and gliosis induced by MDMA.

Some results

Our group examined whether subchronic caffeine administration produces long-lasting modifications in caffeine- and amphetamine-mediated motor activity in neurologically intact and unilaterally 6-hydroxydopamine-(6-OHDA)-lesioned rats. Subchronic caffeine resulted in an increase in caffeine-induced motor activity in intact rats and in turning behaviour in 6-OHDA-lesioned rats. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-OHDA-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects and induces neuroadaptive facilitatory changes in dopamine transmission. Moreover, potentiation of amphetamine effects was not associated with modifications of amphetamine-induced dopamine release in nucleus accumbens and in striatum of caffeine-pretreated rats compared with vehicle-pretreated rats in both intact and 6-OHDA-lesioned rats. Sensitization to caffeine and cross-sensitization to amphetamine are associated with post-synaptic neuroadaptive changes in selective neuronal populations of the striatum.

Furthermore to evaluate the influence of caffeine in MDMA-induced neurotoxicity, MDMA was acutely administered to mice, alone or in combination with caffeine. CD11b and GFAP immunoreactivity were evaluated as markers of microglia and astroglia activation in the substantia nigra pars-compacta (SNc) and striatum. MDMA was associated with significantly higher GFAP immunoreactivity in striatum and CD11b immunoreactivity in both areas. Caffeine potentiated the increase in CD11b and GFAP in the striatum but not in the SNc of MDMA-treated mice. The abuse of MDMA is a growing worldwide problem. The results of this study suggest that combination of MDMA plus caffeine by increasing glial activation might have harmful health consequences.


  • Khairnar A, Plumitallo A, Frau L, Schintu N, Morelli M (2010) Caffeine enhances astroglia and microglia reactivity induced by 3,4-methylenedioxymethamphetamine ('ecstasy') in mouse brain. Neurotox Res 17:435-9.
  • Simola N, Morelli M, Seeman P (2008) Increase of dopamine D2(High) receptors in the striatum of rats sensitized to caffeine motor effects. Synapse 62:394-7.
  • Simola N, Tronci E, Pinna A, Morelli M (2006) Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats. Amino Acids 31:359-63.
  • Tronci E, Simola N, Carta AR, De Luca MA, Morelli M (2006) Potentiation of amphetamine-mediated responses in caffeine-sensitized rats involves modifications in A2A receptors and zif-268 mRNAs in striatal neurons. J. Neurochem. 98:1078-89.
  • Simola N, Cauli O, Morelli M (2006) Sensitization to caffeine and cross-sensitization to amphetamine: influence of individual response to caffeine. Behav. Brain Res. 172:72-9.
  • Cauli O, Pinna A, Morelli M (2005) Subchronic intermittent caffeine administration to unilaterally 6-hydroxydopamine-lesioned rats sensitizes turning behaviour in response to dopamine D(1) but not D(2) receptor agonists. Behav Pharmacol 16:621-6.
  • Cauli O, Pinna A, Valentini V, Morelli M (2003) Subchronic caffeine exposure induces sensitization to caffeine and cross-sensitization to amphetamine ipsilateral turning behavior independent from dopamine release. Neuropsychopharmacology 28:1752-9.


  • Prof. A. Plumitallo, Department of Pharmaceutical Chemistry and Technology, University of Cagliari, Italy.
  • Prof. Philip Seeman, Department of Pharmacology, University of Toronto, Canada.


PI photo

Micaela Morelli

Contact information

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Participating staff

Omar Cauli

Lucia Frau

Amit Khairnar

Annalisa Pinna

Nicoletta Schintu

Nicola Simola

Elisabetta Tronci