drug neurotoxicity chart

It’s quite understandable that people are afraid of brain damage when they experience this sort of mental disruption; the average person has never been told that there were any other possible explanations, in spite of virtually all of us being familiar with the basic phenomenon in the form of ‘needing that first cup of coffee in the morning to get going’ and the like. Here is another, more recent look at MDMA supplements. Here’s a graph from the research that inspired this idea [32]: The height of the bars indicates how much serotonin each test group’s brains had one week after the experiment. work partly by getting your brain to change its sensitivity to serotonin (for those drugs the process is somewhat slow, which is why it takes several weeks for an SSRI to become fully effective against depression.). Morphine, buprenorphine, fentanyl (opioid analgesics or pain medications)- We suspect that these drugs are pumped by P-glycoprotein (the protein encoded by the MDR1 gene) in dogs because they have been reported to be … Cardiovascular effects of METH can lead to ischemic and hypoxic tissue damage. Neurotoxicity from METH use is traditionally thought to initiate within the brain, but other toxicities of METH should also be considered. Knowing this, the researchers took another group of dopamine depleted animals, gave them another overdose of MDMA, and warmed them with heating pads so that their temperature reached the same levels as normal (control) animals did when given the same amount of MDMA. METH effects on peripheral organs: contributions to brain injury. Abstract. Moreover, we introduce some of the potential pharmacological antineurotoxic interventions deduced from experimental animal studies. Where Ricaurte had 14 ecstasy users with an average use of 880 tablets, the German group had 29 current users with an average of 827 tablets and 29 former users with an average use of 793 tablets. That it wasn’t suggests that these users had not suffered any significant lasting harm from their ‘ecstasy’ use. How can you control for this sort of bias? Blood flow is significant, because it’s partly dependent on serotonin. New research like this is brought to the attention of the press (and through them, the public) by press releases, which gives the people writing the press releases a great deal of influence over what the public thinks it meant. As mentioned above, the moderate users were normal, the heavy male users were normal, the heavy current female users were below average, but former female users were again normal. (Antioxidant use is actually good advice for any drug user, including smokers and drinkers.) The researchers concluded that it was “extremely unlikely that a moderate dose of MDMA leads to neurotoxic damage…” [11]. A list of chemicals to be used in the development of an in vitro DNT testing method has been developed (Table 14.4), although never utilized, and strategies to improve such endeavor have been proposed (Kadereit et al., 2012). Another view of the data, this time including the men: As you can see, the monkeys who’s serotonin systems had been damaged by MDMA had a much larger stress reaction to the drug. Abstract. In addition, new medications, both within existing categories of anti-infectives and with new mechanisms of action, are continually being developed. Drugs that are known to be transported by the human or rodent forms of the protein encoded by the MDR1 gene but appear to be tolerated by dogs with the MDR1 mutation:. [10] Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M “Long-term effects of “Ecstasy” use on serotonin transporters of the brain investigated by PET.” J Nucl Med 44: 375-84 (2003). Independent of the chosen approach, the key issue is that it needs to undergo a rigorous validation process. These monkeys were injected with 10 mg/kg of MDMA a day for four days straight by Ricaurte.[16]. Behavioral signs include acute psychosis, restlessness, wide mood swings with inappropriate crying and laughing, cortical blindness, visual hallucinations, stupor, and akinetic mutism (Video 22, Delusional Thinking). Without concerted efforts by regulatory agencies, institutions, foundations, and private entities worldwide, it is doubtful that such validation process will take place. Abstract. [12] de la Torre R, Farre M, Roset PN, Hernandez Lopez C, Mas M, Ortuno J, Menoyo E, Pizarro N, Segura J, Cami J “Pharmacology of MDMA in humans” Ann N Y Acad Sci, 2000; 914:225-37. The scan on the left side was selected from the ‘non-user’ group because it had a high number of SERTs. The patient developed memory failure, gait ataxia, and incontinence in the postradiation setting. Rats show complete re-setting of serotonin receptor densities within 3-4 weeks of their last dose of MDMA. So far, only 10–20 chemicals have been used in limited validation experiments. The government of course hailed this as proof that the demon-drug ecstasy was destroying poor young minds. [2]Other researchers disagreed with Ricaurte, condemning his techniques and claims as something other than science…but controversy within academic circles hardly mattered to the government. For a copy of the paper, go to — "Neuroscience of Addiction: Relevance to Prevention and Treatment. In the mid 1980s in the United States, MDMA was starting to be sold very openly and widely. Neurotoxicity is a dose-limiting side effect of many different agents used in chemotherapy treatments; in particular, platinum drugs, including oxaliplatin, are associated with neurotoxicity. A chemical may cause a neuronopathy, an axonopathy or affect synaptic transmission; it may alter astrocyte or oligodendrocyte/Schwann cell functions, or act by other mechanisms that may lead to neuro-inflammation. Regardless of the mechanism, SERTs come back as long as the axon is still there…and there is good reason to believe the axons are still there in these people. [33]) It’s also possible that the axons make fewer SERTs available on their surface as a response to over-activation during MDMA exposure. This phenomenon appears to be the result of adaptive changes to the brain, not neurotoxicity.). Abstract. In addition, the known factors that trigger and/or predispose to drug-induced neurotoxicity are discussed. [38] Reneman L,, Endert E, de Bruin K, Lavalaye J, Feenstra MG, de Wolff F, Booij J “The acute and chronic effects of MDMA (“Ecstasy”) on cortical 5-HT 2A receptors in rat and human brain” Neuropsychopharmacology, 2002; 26:387–396. So, how do you suppose the press reported this research? If they decide to render blood flow from 99%-101% of normal, then an area with 98% of normal blood flow will show up as a gaping hole. [17] Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M “Long-Term Effects of “Ecstasy” Use on Serotonin Transporters of the Brain Investigated by PET”, J Nucl Med 2003; 44: 375-84. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. Lower levels of serotonin indicate neurotoxicity has occurred (since serotonin is made by and stored in the serotonin axons. Abstract. Similarly, chemicals to be used as positive controls in validation studies should cover most, if not all, of these processes, and would thus need to be several dozens. [12] Semple DM, Ebmeier KP, Glabus MF, O’Carroll RE, Johnstone EC “Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (“ecstasy”) users” Br J Psychiatry, 1999; 175:63-9. In one of the earlier experiments with MDMA neurotoxicity, MDMA was directly injected into a small part of some rat’s brains. Although many researchers have investigated the medical and cognitive consequences of drug abuse, the neurotoxicity induced by these drugs still requires comprehensive attention. More typically, experimental animals that develop MDMA neurotoxicity reach body temperatures of about 39C (103F). In spite of appearances, those aren’t holes. [23] O’Shea E, Easton N, Fry JR, Green AR, Marsden CA “Protection against 3,4-methylenedioxymethamphetamine-induced neurodegeneration produced by glutathione depletion in rats is mediated by attenuation of hyperthermia” Journal of Neurochemistry, 2002; 81(4):686-695. They got what they paid for: A scientist suggesting that human MDMA users were damaging their brains. Finally, a battery of alternative testing models for neurotoxicity is not expected to fully replace current in vivo animal testing, but would limit such testing only to those compounds for which, for different reasons, additional information on neurotoxicity is deemed important. Abstract. In their first study, they found that recent ‘ecstasy’ users had slightly lower SERT density when compared to non-users, but former users had normal SERT density. METH causes liver damage and may result in damage to other peripheral organs such as the lungs, kidneys, muscles, heart, and GI tract. However, the new axons that had grown didn’t get far from the center of the brain. Equally intriguing is the author’s claim that “oral administration offers little or no significant neuroprotection” relative to the injected route used in the experiment. As indicated earlier, neurons and various types of glial cells can be affected by neurotoxicants. Most people would agree that this looks pretty bad. Download as PDF. Alternative models for neurotoxicity should thus attempt to mimic several processes that may occur in vivo. [7], (It should be noted that minor memory problems in the days after use are common, due to disruption of the serotonin system and fatigue. Abstract. Which drugs cause the most and least long lasting structural changes to the brain. [6][7] While the latter study may not have yet been available to the authors at the time of publication, surely they should have mentioned that there was existing evidence of the absence of harm to user’s dopamine systems before publishing a paper that so shamelessly encourages public panic. Abstract. Drugs with least and most neurotoxicity/long term changes to the brain. One patient developed decreasing visual sensitivity in one eye after the 5th dose of liposomal cytarabine 50 mg; the condition improved upon discontinuation of liposomal cytarabine [27c]. This is untrue. Abstract. It found that, compared to non-users, the ‘ecstasy’ users had slightly worse memory in some areas (mainly word recall.)[6]. as more of an act of propaganda than a sincere attempt to advance public understanding. Assumption 1 has been disproven; pre drug-use rates of mental illness in ecstasy users are higher than those of non-drug users as well as users of other categories of drugs. Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. The quality of retrospective human research has, however, been increasing over the years; with luck, the future may bring more substantive work. Another theory implicates endothelin, a potent vasoconstrictive neuropeptide, in combination with breakdown of the blood‐brain barrier, resulting in local ischemia. It’s a very widely used approach, and in many cases works well. In 1998, a piece of research was published that claimed to have found massive neurotoxicity in human ‘ecstasy’ users. (Read MDMA History for more info. Some act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. In one study, 100% of patients older than 60 years who were treated with WBRT-containing regimens for PCNSL experienced clinical neurotoxicity manifesting as dementia, ataxia, and incontinence, with a median time to onset of 13.2 months [80]. However, such in vivo tests are time consuming, expensive, and require the use of a substantial number of animals. Abstract. This document expresses and makes the case for the final opinion that my research brought me to: That moderate recreational use of MDMA does not present a credible risk for neurotoxicity. Neurotoxicity, Immunotoxicity and Drug Toxicity – A Review. The results were striking: The animals with essentially no dopamine in their brains suffered the same level of neurotoxic damage as the control animals did when their body temperatures were kept as high. Lucio G. Costa, ... Marina Guizzetti, in Reproductive and Developmental Toxicology, 2011. In patients with neurological signs, cyclosporine levels are usually outside the normal range, and after lowering the dose or withholding administration, neurotoxicity clears in most cases. And finally, the axon’s supply of antioxidants must be largely exhausted. Hence, there is a great need to develop alternative models, utilizing mammalian cell preparations of different complexity and/or nonmammalian animal system, as indicated earlier. This sort of problem is especially great when testing drug users for cognitive effects, because not only do they know if they’re in the control group or not, they probably have some idea of what the researchers expect the result to be. Or has he? How MDMA exposure can cause reduced SERT density isn’t clear. This study is one of the largest, most sophisticated pieces of research of its type to date. In extreme cases, this can apparently lead to users becoming seriously depressed, anxious, unmotivated, poor memories, etc. The neuron itself (cell body) is not destroyed; only the axon is. The entire legal record is available at MAPS. (Indeed, it’s about the only sort of research Ricaurte seems to have ever done.) The toxic effects of METH on the liver, heart, GI tract, and muscle can further contribute to METH-induced neurotoxicity. And happily, science does indeed have the answer to whether ‘ecstasy’/MDMA use reduces or alters levels of activity/blood flow within the brain. The toxic effects of METH on the liver, heart, GI tract, and muscle can further contribute to METH-induced neurotoxicity. It may not be possible to avoid all the sources, but at least if known, a person can try to reduce its exposure as much as possible. A month after they had taken the MDMA, new brain scans were taken. They needed a ‘scientist’ to do the research, and they knew just who to call: George Ricaurte. Absolutely no change. Drugs with least and most neurotoxicity/long term changes to the brain. In their final report, the researchers concluded that “Low-dose recreational MDMA use does not cause detectable persistent rCBF (regional cerebral blood flow) changes in humans.”. If only on the grounds of the sheer novelty of the results from this particular dosage regimen it seems presumptuous to declare equivalency to human users until some explanation can be offered for the sharp divergence of results between these two experiments. An argument could be made that the ‘ecstasy’ users brains might have suffered neurotoxicity but were not sensitized because they had downregulated serotonin receptors in response to recent drug exposure. What that means is that the data is actually spread out over a lot more space than it appears. • Visit the Mental Health page for more information. Crit Care. If so, ten years from now, we will still be discussing perhaps new, sophisticated models that have the potential to serve as screening tools for neurotoxicity, but that would leave this potential still unfulfilled. First, the ‘height’ of the graph has been done on a log (ln) scale. No topic related to MDMA has caused as much controversy as the claim that it damages user’s brains. (Visit Heatstroke for more information; too much water can be dangerous as well.). While dosages of such scale do (infrequently) occur in human users, it is likely that these users have reached such dosages in response to growing drug tolerance; with such progressive elevations of dosage over time, neurotoxic potential is reduced. [22] Bleh, ref has gone missing…try again in a month or two if you’re comitted. These interventions involve various targets such as dopaminergic system, mitochondria, cell death signaling, and NMDA receptors, among others. Neurotoxicity and developmental neurotoxicity are important adverse health effects of hundreds of environmental contaminants and occupational chemicals, natural toxins and pharmaceutical drugs. [30] de la Torre R, Farre M, Roset PN, Hernandez Lopez C, Mas M, Ortuno J, Menoyo E, Pizarro N, Segura J, Cami J “Pharmacology of MDMA in humans”, Annals of New York Academy of Sciences 2000; 914:225-37. No other drugs that the volunteers use will affect results. Managing oxaliplatin-induced neurotoxicity A fairly simple protocol of calcium and magnesium supplementation has been proposed to reduce the … They declared that MDMA had to be placed in Schedule 1 (even after the judge reviewing the case had told them that it legally couldn’t be) and did just that. Given the complexity of the nervous system and the multiple facets of possible neurotoxic effects, it is highly unlikely that a single test (as the Ames test for mutagenicity) will cover the spectrum of neurotoxicity or developmental neurotoxicity. The Drug Enforcement Agency responded the way it always does when a drug becomes popular: It declared that MDMA was a terrible menace and had to be outlawed. If serotonin axons have been lost, then the number of SERTs will be lower as well, since they are part of the axons. Hence, there is a great need to develop alternative models, utilizing mammalian cell preparations of different complexity and/or non-mammalian animal system, as indicated earlier. [3] At first, it seemed as though the ‘dopamine’ camp had been right. It clears out alcohol, drugs, and chemicals from your blood. A less obvious problem in such human research is subject bias. It was also reported that patients aged 60 years or above were more susceptible to neurotoxic side effects of high dose cytarabine. This question has also been answered: When baboons were given a neurotoxic dose of MDMA (destroying many of their serotonin axons), then given brain scans for SERT density a year later, axon regrowth was seen. • Antioxidants are chemicals that, when they run into an oxidizer like hydrogen peroxide or superoxide, will easily react with it, neutralizing it. Neurotoxicity is defined as any adverse effect on the structure or function of the central and peripheral nervous systems at the result of a diversity of biological, chemical, or physical agents. In the latter case, users are given tests to check their memory, etc. Any differences that are found must be due to permanent damage. [15] Scheffel U, Szabo Z, Mathews WB, Finley PA, Dannals RF, Ravert HT, Szabo K, Yuan J, Ricaurte GA “In Vivo Detection of Short- and Long-Term MDMA Neurotoxicity–A Positron Emission Tomography Study in the Living Baboon Brain”, Synapse 1998; 29(2):183-92. Lein, in Encyclopedia of Toxicology (Third Edition), 2014. [20] Bai F, Lau SS, Monks TJ “Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity.” Chem Res Toxicol, 1999; 12(12):1150-7. [13] Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ, Booij J “Cortical serotonin transporter density and verbal memory in individuals who stopped taking MDMA: Preliminary findings”, Archives of General Psychiatry, 2001; 58(10):901-906. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. 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