Alcohol may prevent amphetamine action by impairing central insulin signaling

Alcohol may prevent amphetamine action by impairing central insulin signaling.

These alterations produced by alcohol cause severe hepatic and central nervous system insulin resistance as the cells fail to adequately transmit signals downstream through Erk/mitogen-activated protein kinase (MAPK), which is needed for DNA synthesis and liver regeneration, and phosphatidylinositol 3-kinase (PI3K), which promotes growth, survival, cell motility, glucose utilization, plasticity, and energy metabolism

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550293/

Because insulin and PI3K signaling have been shown to fine-tune DAT cell surface expression (Garcia et al., 2005; Wei et al., 2007), it is possible that inhibition of PI3K signaling in vivo, by reducing DAT cell surface expression, inhibits AMPH-induced DA efflux. Selective inhibition of PI3K via LY294002 results in a dramatic reduction in AMPH's ability to elicit DAT-mediated DA efflux in heterologous cells, dopaminergic neurons, and in vivo within the striatum of rats as measured by both in vivo voltammetry and fMRI (Lute et al., 2008; Williams et al., 2007).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518862/

Caffeine competitively inhibits amphetamine action?

Caffeine-amphetamine interactions were studied to determine whether attenuation of amphetamine-induced activity by caffeine pretreatment (30 mg/kg) is the result of increased or decreased sensitivity to amphetamine. Caffeine pretreatment attenuated amphetamine activity in the rats without producing a horizontal shift in the dose-response curve. Results support a reduction in sensitivity to amphetamine. A cross-tolerance design revealed an asymmetrical interaction between caffeine and amphetamine. Multiple caffeine treatments (30 mg/kg) produced tolerance and attenuation of subsequent amphetamine activity (1.5 mg/kg). Amphetamine did not produce tolerance or affect subsequent caffeine-induced activity.

Caffeine + Amphetamine is more neurotoxic than Amphetamine alone, but not through adenosine receptor antagonism

To investigate mechanisms, additional animals were pretreated with the adenosine agonist, 2-chloroadenosine (2.5 and 10 mg/kg), before being challenged with NS, 90 mg/kg cocaine, or 42 mg/kg amphetamine. Pretreatment with 2-chloroadenosine had no affect in reducing cocaine or amphetamine toxicity. Combination pretreatment with caffeine and 2-chloroadenosine potentiated cocaine toxicity. The phosphodiesterase inhibitor, pentoxifylline, did not potentiate cocaine toxicity. The authors conclude that caffeine potentiates the acute toxicity of both cocaine and amphetamine, and that the failure of 2-chloroadenosine to alter this suggests that the toxicity of the stimulants cocaine and amphetamine may be modulated by nonspecific rather than specific adenosine- or phosphodiesterase-induced mechanisms.

Conclusion

It may be difficult for amphetamine to be significantly more neurotoxic in presence of other psychoactive substances or unfavorable states where the latters are not significantly adverse alone. Higher mental functioning is progressed to be efficient in the human state and additional efficiencies are expensive to achieve, and therefore adverse scenarios require exceptional conditions. Amphetamines may be illusionary in cognitive benefit that is not derived from increasing arousal.