The Origins of Methamphetamine
Japan 1893, just six years after the discovery of amphetamines, a Japanese scientist Nagai Nagayoshi was working on the identification of the active component ephedrine from the ephedra plant. He discovered and produced for the first time desoxyephedrine or Methamphetamine (METH), primarily used against obesity, asthma, and major depressive disorder until World War II when Germany, the USA, and Japan forced the use of METH to keep their troops awake without taking into consideration its highly addictive properties. Today, METH is a schedule II drug that can only be prescribed for attention deficit hyperactivity disorder (ADHD)1,4 but according to the UN World Drug Report 2019, METH is being abused by more than 35 million people, becoming a worldwide epidemic, with 1.3 million users in Australia alone2.
Properties of Methamphetamine
METH is a cationic molecule and chiral compound based around a phenylethylamine core3, which has been shown to be more potent than amphetamine due to the added methyl group to its amphetamine structure, which makes it highly lipophilic with the ability to cross the blood-brain barrier into the central nervous system (CNS) inhibiting and reversing neurotransmitter transporters of dopamine, norepinephrine, and serotonin4. Its half-life is between 9-12 hours, with the shortest half-life if taken orally compared to intravenous administration which lasts longer, with a peak concentration of 2.5-3.5 hours5. Its effects depend on the dose of administration but its stages are commonly described with an initial rush of the heart rate and increase in blood pressure followed by hyperactive mental and physical behaviors which with time lead to tolerance and the cravings are no longer satisfied, consequently, entering a delusional state with hallucinations and insomnia6.
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Effect of METH in the Brain and possible treatments
METH increases activation of the dopamine, norepinephrine, and serotonin systems. METH mostly affects the reward system of the brain or limbic system, which includes the striatum that encompasses the nucleus accumbens. The use of METH causes the release of dopamine into the synaptic cleft in the striatum by disrupting the proton gradient through the dopamine vesicles due to its high pKa, making the acidic compartment more basic7,8,9. Additionally, METH blocks the dopamine transporters of the presynaptic neuron hence inhibiting the transport of dopamine back into the vesicles, thus increasing the synaptic dopamine concentration even more. This ultimately leads to neuron degeneration9. It has also been shown that METH causes mitochondrial dysfunction through the activation of Tol-like receptor 4 (TOL4) and NF-KB signaling pathway leading to death of neurons10. On the other hand, Hajheidari and colleagues showed that METH-sensitized rats had a decreased number of neurons in the Dentate Gyrus (DG) and Hippocampus which in turn is associated with the reduction of brain-derived neurotrophic factor (BDNF)11. A recent study investigated the use of a medicinal herb, Crocin, which proved to have neuroprotective properties on the Hippocampus through the CREB-BDNF signaling pathway by increasing BDNF12. In addition, another study demonstrated that by inhibiting METH-induced autophagy which is mediated by activation of Kappa opioid receptor (KOR), apoptosis of endothelial cells was accelerated. Therefore, KOR can be pharmaceutically developed to reduce the effect of METH on the blood-brain barrier13.
Relationship between METH and the body
Recent literature report that METH activates and accelerates the transcription of genes that would normally control the cell cycle, leading to early cellular aging. The mechanism involves the stimulation of sphingolipid messenger ceramide which is activated by reactive oxygen species through methamphetamine metabolism via P450, leading to oxidative stress14. In addition to this, METH has been shown to cause increased heart rate and blood pressure leading to cardiovascular toxicity such as myocardial ischemia, infarction, and cardiomyopathy. Literature shows that tachycardia caused by METH abuse is most likely mediated via β1 adrenoreceptors via direct action of METH on the heart15. A retrospective cohort study showed that patients using METH developed idiopathic pulmonary arterial hypertension16. Other studies have found that METH is more widely distributed in lungs and kidneys with a peak concentration of 55 seconds and increases the risk of pulmonary tissues becoming more vulnerable to infections. This can lead to developing tuberculosis and HIV17. Furthermore, it is believed that diabetes can occur as a result of METH abuse due to its harmful effects on glucose uptake in the cells and glucose transporter proteins18.
The role of microbiota
Recent investigations have uncovered the major role that the gut microbiota plays in the connection to the brain. Ning and colleagues reported that the genera, Ruminococcaceae, a family of bacteria in the class of Clostridia which is associated with anxiety and a decrease in cognitive function, were increased in METH-induced Sprague-Dawley rats19. In vivo, the fecal microbiota is higher in methamphetamine-treated rats, however, the genus Phascolarctobacterium which is positively correlated to the positive mood of the humans, is reduced, which in turn increases the susceptibility to depression20-21. More study is needed to assess the functional role of microbial changes. It has also been shown that METH disrupts the integrity of the gut allowing bacteria to escape into circulation, which can also cause an increase in the mucosal inflammatory cytokine IL-6 & TNF-α22.
References
- M. Douglas Anglin, Cynthia Burke, Brian Perrochet, Ewa Stamper & Samia Dawud-Noursi, History of the Methamphetamine Problem, Sep 2011.
- United Nations World Drug Report 2019
- Christopher G. Kevil, Nicholas E. Goeders, Matthew D. Woolard, Md. Shenuarin Bhuiyan, Paari Dominic, Gopi K. Kolluru, Connie L. Arnold, James G. Traylor, A. Wayne Orr, Methamphetamine Use and Cardiovascular Disease, 2019;39:1739–1746
- David J. Wagner, Jennifer E. Sager, Haichuan Duan, Nina Isoherranen and Joanne Wang, Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters, July 2017, 45 (7) 770-778
- Anna Moszczynska and Sean Patrick Callan, Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment, 2017, 362 (3) 474-488
- Lisa Proebstl, Felicia Kamp, Gabi Koller, Michael Soyka, Cognitive Deficits in Methamphetamine Users: How Strong is The Evidence? 2018 Nov;51(6):243-250
- Fiona Limanaqi, Stefano Gambardella, Francesca Biagioni, Carla L. Busceti, and Francesco Fornai, “Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress,” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 4982453, 28 pages, 2018
- Abhishek H. Ashok, Yuya Mizuno, Nora D. Volkow, Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine, 2017;74(5):511-519.
- Michela Ferrucci, Fiona Limanaqi, Larisa Ryskalin, Francesca Biagioni, Carla L. Busceti and Francesco Fornai, The Effects of Amphetamine and Methamphetamine on the Release of Norepinephrine, Dopamine and Acetylcholine From the Brainstem Reticular Formation, 13:48. doi: 10.3389/fnana.2019.00048.
- Majdi, Taheri, Salehi, Motaghinejad, Safari. Cannabinoids Δ9-tetrahydrocannabinol and cannabidiol may be effective against methamphetamine-induced mitochondrial dysfunction and inflammation by modulation of Toll-like type-4(Toll-like 4) receptors and NF-κB signaling. 2019 Aug 19;133:109371. doi: 10.1016/j.mehy.2019.109371.
- SamiraHajheidaria Hamid Reza Samenib Ahmad Reza Bandegic HosseinMiladi-gorged, Effects of prolonged abstinence from METH on the hippocampal BDNF levels, neuronal numbers and apoptosis in methamphetamine-sensitized rats, Volume 645, 3 April 2017
- Mozaffari, Ramezany Yasuj, Motaghinejad, Motevalian, Kheiri Crocin Acting as a Neuroprotective Agent against Methamphetamine-induced Neurodegeneration via CREB-BDNF Signaling Pathway. 18(2):745-758, 2019.
- J Ma, J Wan, J Meng, S Banerjee, S Ramakrishnan & S Roy, Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor, e (2014) 5, e1099; doi:10.1038/cddis.2014.64
- Giuseppe Astarita, Agnesa Avanesian, Benedetto Grimaldi, Natalia Realini, Zuzana Justinova, Leight V. Panlilio, Abdul Basit, Steven R. Goldberg, and Daniele Piomelli, Methamphetamine Accelerates Cellular Senescence through Stimulation of De Novo Ceramide Biosynthesis, 2015; 10(2): e0116961.
- Sarah F. Hassan Travis A. Wearne Jennifer L. Cornish Ann K. Goodchild, Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes, Volume 594, Issue 3, 20 November 2015
- Roham T. Zamanian, Haley Hedlin, Paul Greenwald, David M. Wilson, Joshua I. Segal, Michelle Jorden, Kristina Kudelko, Juliana Liu, Andrew His, Allyson Rupp, Andrew J. Sweatt, Rubin Tuder, Gerald J. Berry, Marlene Rabinovitch, Ramona L. Doyle, Vinicio de Jesus Perez, and Steven M. Kawut. Features and Outcomes of Methamphetamine-associated Pulmonary Arterial Hypertension, Vol. 197, No. 6 | Mar 15, 2018
- Nora D. Volkow, Joanna S. Fowler, Gene-Jack Wang, Elena Shumay, Frank Telang, Peter K. Thanos, and David Alexoff. Distribution and Pharmacokinetics of Methamphetamine in the Human Body: Clinical Implications. 2010; 5(12): e15269.
- P. M. Abdul Muneer, Saleena Alikunju, Adam M. Szlachetka, James Haorah, Methamphetamine Inhibits the Glucose Uptake by Human Neurons and Astrocytes: Stabilization by Acetyl-L-Carnitine, 6(4): e19258, 2011
- Tingting Ning, Xiaokang Gong, Lingling Xie and Baomiao Ma, Gut Microbiota Analysis in Rats with Methamphetamine-Induced Conditioned Place Preference, 8 (AUG), art. no. 1620, 2017
- Cussotto, S., Clarke, G., Dinan, T.G. et al. Psychotropics and the Microbiome: a Chamber of Secrets… (2019) 236: 1411.
- Feifan Wu,1 Xianfeng Guo,1,2 Jiachun Zhang,1,3 Min Zhang,1 Zihao Ou,1 and Yongzheng Peng1, Phascolarctobacterium faecium abundant colonization in human gastrointestinal tract, 2017 Oct; 14(4): 3122–3126.
- Jennifer A. Fulcher, Steven Shoptaw, Solomon B. Makgoeng, Julie Elliott, F. Javier Ibarrondo, Amy Ragsdale, Ron Brookmeyer, Peter A. Anton, and Pamina M. Gorbach, Recent Methamphetamine Use is Associated with Increased Rectal Mucosal Inflammatory Cytokines Regardless of HIV-1 Serostatus, 2018 May 1; 78(1): 119–123.
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