Annals of the New York Academy of Sciences
January 8, 2010
Bryan K. Yamamoto, Anna Moszczyńska, Gary A. Gudelsky
280 citations
Methamphetamine and MDMA cause long-lasting reductions in markers of biogenic amine neurotransmission, traditionally linked to nerve terminal damage, in rodents, nonhuman primates, and humans. Recent evidence shows damage may extend to cell bodies of various neurons and blood–brain barrier endothelial cells. The damage involves oxidative stress, excitotoxicity, neuroinflammation, ubiquitin proteasome dysfunction, and mitochondrial and neurotrophic factor impairment. These mechanisms overlap with those in chronic stress and HIV infection, both of which amplify methamphetamine toxicity. The frequent co-occurrence of substituted amphetamine abuse with HIV or chronic stress suggests increased vulnerability to neurotoxicity in these individuals.
Synapse
January 1, 2001
Mahalakshmi Shankaran, Bryan K. Yamamoto, Gary A. Gudelsky
97 citations
MDMA (ecstasy) causes long-term damage to serotonin (5-HT) neurons in the brain, likely through oxidative stress from free radicals. Giving rats the antioxidant ascorbic acid (vitamin C) blocked the formation of hydroxyl radicals and prevented MDMA-induced depletion of serotonin in the striatum. Rats that received a neurotoxic dose of MDMA later showed blunted serotonin release, behavioral responses, and hyperthermia when given another dose of MDMA; these functional deficits were also prevented by ascorbic acid. MDMA also reduced the brain's natural levels of vitamin E and ascorbic acid. The findings suggest that MDMA's neurotoxicity stems from oxidative stress and diminished antioxidant defenses.
Journal of Neuroimmune Pharmacology
November 17, 2012
John H. Anneken, Jacobi I. Cunningham, Stuart A. Collins et al.
52 citations
Repeated doses of MDMA (Ecstasy) cause a delayed and sustained increase in glutamate release in the rat hippocampus. Blocking cyclooxygenase (COX) enzymes, particularly COX-2, with drugs like ketoprofen or nimesulide reduces this glutamate rise, while a COX-1 inhibitor does not. Direct application of prostaglandin E2, a COX product, also raises glutamate levels. Repeated MDMA treatment reduces the number of parvalbumin-positive GABA interneurons in the dentate gyrus, an effect lessened by ketoprofen. However, COX inhibition does not prevent long-term serotonin depletion in the hippocampus. These findings suggest COX activity contributes to MDMA-induced glutamate release and GABA neuron loss but not to serotonin depletion.
BioMed Research International
January 1, 2014
Georg F. Weber, Bethann N. Johnson, Bryan K. Yamamoto et al.
19 citations
MDMA, a substituted amphetamine and recreational drug, can produce mood-enhancing short-term effects that may lead to its use under stress. Clinical studies suggest MDMA treatment might alleviate symptoms of stress disorders like PTSD, but repeated use causes lasting deficits in serotonergic nerve terminal markers, indicating possible neurotoxicity. Chronic stress worsens MDMA-induced serotonergic neurotoxicity. In rats, MDMA altered gene expression in the hippocampus related to protein folding and neuropeptide signaling. In stressed rats, MDMA changed genetic responses affecting sensory processing and tissue damage responses, and reversed stress-induced downregulation of circadian rhythm genes. These transcriptional changes accompany the drug's persistent effects on neuronal structure and function.
British Journal of Pharmacology
September 2, 2025
Lucas M Wittenkeller, Gary A. Gudelsky, Theresa Winhusen et al.
3 citations
Psychedelics are being studied as treatments for substance use disorders (SUDs), not just depression. A scoping review identified 34 clinical trials targeting alcohol, cannabis, cocaine, methamphetamine, nicotine, and opioid use disorders, mostly open-label without placebo controls. Alcohol use disorder was the most common target. From animal studies, four publications measured dopamine in the nucleus accumbens after psilocybin or MDMA. High-dose psilocybin caused a sustained mild increase in dopamine, suggesting it may help restore tonic dopamine levels, which could be relevant for treating addiction.
medRxiv
April 6, 2025
Lucas M Wittenkeller, Gary A. Gudelsky, John T. Winhusen et al.
3 citations
preprint
Psychedelics are being tested as treatments for substance use disorders, building on their promise for depression. A scoping review of clinical trials and publications identifies a potential new mechanism: restoring dopamine homeostasis. This process may reduce drug-seeking behavior and support abstinence, complementing previously known effects. The neurobiological basis of psychedelics' therapeutic action remains incompletely understood, but this dopamine-related pathway offers a novel target for treating addiction.