By Lysander Dusseljee
March 2016
Last modified: September 5, 2018
Posted on lysanderdusseljee.blogspot.com
This page as a published Google Doc.
Prelude
MDMA, known as “ecstasy” or “E”, is the perfect utopian drug. The MDMA high even has it’s own name; it’s called “rolling”. This “hug drug” offers euphoria, empathy, and can lead to the phenomenon of the “puppy pile”. However, the experience is fleeting and not without side effects. Can you imagine a world where people are always in a state of empathetic bliss? I can, and just might know how to make it happen. MDMA may have been suitable for this purpose all along, we’ve just been using it wrong.
Disclaimer:
I do not advocate taking MDMA. There are potential dangers in doing so. Additionally, I’m unable to cover all the research, so this should not be your only source with regards to the MDMA safety profile. Lastly, there is no guarantee that my interpretation of the MDMA literature applies to humans.
Jump to:
Defining Scientific Terms
Since I want this article to be generally readable for the layperson, here is the definition for some of the terms used.
Serotonergic:
This term denotes a relationship to the neurotransmitter serotonin. A serotonergic neuron, for example, releases serotonin when stimulated. This released serotonin then signals other neurons via serotonin receptors. Serotonergic depletion, therefore, means a reduction in serotonin, serotonin receptors, or serotonin releasing neurons.
Threshold dose:
The threshold dose is the lowest dose at which effects are noticed.
Toxic:
A toxic substance elicits damage to an organism or any component thereof. Sometimes this toxicity is target specific, such as the serotonergic toxicity induced by high dose MDMA.
Note: Serotonergic depletion does not necessarily equate to toxicity. However, I hold that the absence of serotonergic depletion indicates safety. I therefore use the two terms synonymously.
MDMA Neurotoxic Dose In Humans Based On Animal Studies
In female rhesus monkeys, MDMA was administered twice daily (oral route) for 4 consecutive days at three separate doses.[1] A dose of 1.25 mg/kg showed no toxicity, as measured by the lack of serotonergic depletion in any brain regions tested. In fact, serotonergic systems were enhanced to a non statistically significant extent, a topic I will come back to later. The next highest dose, 2.5 mg/kg, showed some serotonergic depletion in the hippocampus, but only in the hippocampus. The radically higher dose used, 20 mg/kg, showed severe serotonergic depletion in several brain regions. The study confirms that monkeys are more sensitive to MDMA toxicity than rats.
However, as another study noted, "humans are generally more sensitive than monkeys to the toxic effect of drugs".[2] The study found that a single dose of 5 mg/kg (oral route) caused long-lasting serotonin depletion in male squirrel monkeys’ brains.
Between these two studies, we can establish a rough minimum toxic dose in monkeys. Namely, 5 mg/kg/day is neurotoxic, whether administered in one or two doses. Further, while two 2.5 mg/kg doses per day is toxic, whether a single 2.5 mg/kg dose per day is toxic is not clear, but it seems plausible, if not likely. However, 1.25 mg/kg twice daily appears safe. How does this compare to human dosing? According to erowid, the usual MDMA doses ranges from 80-160 mg.[3] This corresponds to a dose of 1.14-2.29 mg/kg, based on a 70kg human. This is concerning, as the low-normal dose is roughly our maximum established safe dose in monkeys, and the high-normal dose exceeds that established safe dose. Adding to that, since humans may be more sensitive to the toxicity than monkeys, this is plausibly a toxic dose, or borderline toxic dose. Anecdotally, this is consistent with the “week-after effect”, as well as the “loss of magic”, seen in MDMA users.[4]
Between these two studies, we can establish a rough minimum toxic dose in monkeys. Namely, 5 mg/kg/day is neurotoxic, whether administered in one or two doses. Further, while two 2.5 mg/kg doses per day is toxic, whether a single 2.5 mg/kg dose per day is toxic is not clear, but it seems plausible, if not likely. However, 1.25 mg/kg twice daily appears safe. How does this compare to human dosing? According to erowid, the usual MDMA doses ranges from 80-160 mg.[3] This corresponds to a dose of 1.14-2.29 mg/kg, based on a 70kg human. This is concerning, as the low-normal dose is roughly our maximum established safe dose in monkeys, and the high-normal dose exceeds that established safe dose. Adding to that, since humans may be more sensitive to the toxicity than monkeys, this is plausibly a toxic dose, or borderline toxic dose. Anecdotally, this is consistent with the “week-after effect”, as well as the “loss of magic”, seen in MDMA users.[4]
MDMA Glutamate Excitotoxicity, Oxidative Stress, and inflammation: Preventable Toxicity Mechanisms
Excitotoxicity, inflammation, and oxidative stress are all implicated in neurodegenerative diseases.[5] These are interrelated stressors, whereby each of them can instigate the other two. For this reason, it appears that antioxidants lead to protection against MDMA induced serotonergic damage, as well as prevent MDMA tolerance.[6] MDMA serotonergic toxicity was also noted to be associated with reduced antioxidant stores, wherein oxidative stress is known to deplete antioxidant stores.[7] I recommend amla powder (up to 3g daily), as it is a cheap and extremely potent antioxidant.[8] Antioxidant content of one’s diet could potentially explain the the majority of the inter-individual differences in reported MDMA related side effects.
MDMA Upregulation / Reverse Tolerance / Sensitization.
Since data in monkeys is limited, especially since doses used in monkeys are usually neurotoxic, I must rely on data in rats. One study found that a single 4 mg/kg/day administration for four days was not neurotoxic to rats, while administering 4 mg/kg twice daily was neurotoxic to the serotonergic system.[9]
In doses that are not neurotoxic, MDMA appears to upregulate serotonergic systems. One study found that daily low doses of MDMA elevated, while high dose MDMA reduced, serotonin levels 13 days after administration.[10]
They had administered the drug at their respective doses 3 times spread 2 hours apart.
In doses that are not neurotoxic, MDMA appears to upregulate serotonergic systems. One study found that daily low doses of MDMA elevated, while high dose MDMA reduced, serotonin levels 13 days after administration.[10]
They had administered the drug at their respective doses 3 times spread 2 hours apart.
Figure 1: Forebrain serotonin, expressed as a percent of the control, in male pubescent rats that received MDMA 13 [consecutive] days previously. The S.E.M. (not shown for clarity) ranged from 10.1% to 13.4% for the control. … * p < .005 vs. 10 mg/kg.
As you can see, the 2 mg/kg dose was just as effective, if not more effective, than a 5 mg/kg dose at increasing serotonin levels. Unfortunately there is no data for lower doses, but one might extrapolate that somewhat lower doses should work. It’s important to note that the 2 mg/kg were administered 3 times, so the total dose on that day was 6 mg/kg. Additionally, while neurotoxic doses of MDMA can induce some neuroprotection against subsequent neurotoxic doses, this protective effect can be achieved with non-neurotoxic doses.[11] [12] This suggests that, provided MDMA doses are low enough, there is little cause for concern.
However, doses that are not neurotoxic in this timeframe may become neurotoxic over a longer timeframe. Namely, 2.5 mg/kg/day for 25 days, rather than just 13 days, induced neuronal degeneration in rats.[13] This could easily be explained by antioxidant depletion, as discussed earlier. Alternatively, since continual behavioral sensitization was seen over the 25 day period, it is plausible that hypersensitization to low dose MDMA resulted in low doses being equivalent to larger doses. Specifically, being equivalent to doses that are neurotoxic. Since it is not a free study, I’m not sure if I am allowed to show the graph of behavioral sensitization. Thus I have constructed my own graph.
As you can see, the 2 mg/kg dose was just as effective, if not more effective, than a 5 mg/kg dose at increasing serotonin levels. Unfortunately there is no data for lower doses, but one might extrapolate that somewhat lower doses should work. It’s important to note that the 2 mg/kg were administered 3 times, so the total dose on that day was 6 mg/kg. Additionally, while neurotoxic doses of MDMA can induce some neuroprotection against subsequent neurotoxic doses, this protective effect can be achieved with non-neurotoxic doses.[11] [12] This suggests that, provided MDMA doses are low enough, there is little cause for concern.
However, doses that are not neurotoxic in this timeframe may become neurotoxic over a longer timeframe. Namely, 2.5 mg/kg/day for 25 days, rather than just 13 days, induced neuronal degeneration in rats.[13] This could easily be explained by antioxidant depletion, as discussed earlier. Alternatively, since continual behavioral sensitization was seen over the 25 day period, it is plausible that hypersensitization to low dose MDMA resulted in low doses being equivalent to larger doses. Specifically, being equivalent to doses that are neurotoxic. Since it is not a free study, I’m not sure if I am allowed to show the graph of behavioral sensitization. Thus I have constructed my own graph.
Figure 2: Behavioral measures, relative to control, with daily injections of 2.5 mg/kg MDMA for 25 consecutive days. The figures are rough estimations based on two graphs from the study, (Fornai, et al., 2004). Since I don’t have permission to share the graphs, I intentionally left it ambiguous. Whether such precautions are necessary, I don’t know. However, the ambiguity should not cause any confusion, so it doesn’t matter much.
Interestingly, both neurotoxic and safer doses of MDMA appear to induce behavioral sensitization. However, safer doses appear more consistent and reliable. One study found behavioral sensitization during single 5 mg/kg and 10 mg/kg administration some days after a 6 day treatment period at their respective doses.[14] Another study tested behavioral sensitization to 5 mg/kg, on two separate occasions, after pre-treatment with either 5 mg/kg/day, or a neurotoxic 20 mg/kg/day.[15] Only the 5 mg/kg/day pre-treatment elicited statistically significant sensitization on both occasions, while the 20 mg/kg/day pre-treatment sensitization was only significant on one of the days. The later study is more relevant than the former because it tested for sensitization in both of the pre-treatment groups at the same dose afterwards, so the groups can be compared. Additionally, the former study tested a 2.5 mg/kg/day pre-treatment, but didn’t find reliable statistically significant sensitization, apparently due to the insufficient number of pre-treatment days (6 days). In contrast, the 25 day treatment, mentioned in the last paragraph, found their first statistically significant effects begin to kick in after ten days of 2.5 mg/kg/day, which is longer than the pre-treatment period used in either of these studies.
Human Anecdotes
I’m only aware of one report of people using sub-threshold doses of MDMA, which I found on a drug forum.[16] The report involves two cases of daily administration of 10 mg MDMA crystals. One individual took 10 mg MDMA for 14 days, and the other for 10 days. According to erowid, the threshold dose for MDMA is 30 mg.[17] Progressive effects from beginning to end of the treatment period were noted, as one might expect based on the data I’ve discussed. Also note that there were some side effects.
Another case I found took doses of up to “a maximum of 30 mg”.[18] They took it “every day, and more than once if needed. Typically, [they] would ingest up to 100 mg per day, sometimes less, and sometimes more”. Since it wasn’t administered all at once, I suspect that that is a relatively safe regimen. Additionally, MDMA has a nonlinear dose to exposure ratio in both rats and humans.[19] [20] Thusly, four 25 mg doses may result in less drug exposure than one 100 mg dose. Interestingly, they said they were taking it for pain, noting “I have now been taking continuous low doses of MDMA for more than six months, and I must admit that sofar [sic] the results are beyond my expectations”. They went on to say, “Incidentally, given the nature of MDMA and its potential effects on the human body and psyche, I have discovered that it helps me not only with the chronic pain, but also in several other areas of my life: psychologically and spiritually”.
Conclusions
The doses of MDMA taken recreationally are dangerously high, and not conducive to long term benefits. The risks can be mitigated by antioxidants. Conversely, low doses of MDMA are protective against future high doses of MDMA, and may yield long term psychophysiological benefits in general. However, precisely how low the dose should be is unknown, as virtually all animal studies use recreational doses or megadoses. Anecdotally, 10mg daily may be sufficient for antidepressant, euphoric, and pro-social effects. There is a need for more research, and even anecdotal reports, in the lower dose range.
Keywords and phrases not found in article: utopian pharmacology, real life soma, pharmacologically induced happiness, drug induced happiness, huxleyan utopia, permanent, permanently, indefinite, indefinitely, euphoria, euphoric empathy, “E”, ecstasy, love drug, hedonistic imperative, overcoming the hedonic treadmill, end suffering, ending all suffering, depression treatment.
[1] Ali, S. F., Newport, G. D., Scallet, A. C., Binienda, Z., Ferguson, S. A., Bailey, J. R., et al. (1993). Oral administration of 3, 4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate. Neurotoxicology and teratology, 15(2), 91-96.
[2] Ricaurte, GA, LE DeLanney, I Irwin, and JW Langston. 1988. Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration. Brain research 446, no. 1: 165-168.
[3] (2005). Erowid MDMA Vault : MDMA FAQ. Retrieved February 21, 2016, from https://www.erowid.org/chemicals/mdma/mdma_faq.shtml.
[4] (2005). MDMA Hangovers & Week-After Effects - Erowid. Retrieved February 21, 2016, from https://www.erowid.org/chemicals/mdma/mdma_effects_hangover1.shtml.
[5] Dong, X., Wang, Y., & Qin, Z. (2009). Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacologica Sinica, 30(4), 379-387.
[6] Shankaran, M., Yamamoto, B. K., & Gudelsky, G. A. (2001). Ascorbic acid prevents 3, 4‐methylenedioxymethamphetamine (MDMA)‐induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5‐HT. Synapse, 40(1), 55-64.
[7] Darvin, M. E., Patzelt, A., Knorr, F., Blume-Peytavi, U., Sterry, W., & Lademann, J. (2008). One-year study on the variation of carotenoid antioxidant substances in living human skin: influence of dietary supplementation and stress factors. Journal of Biomedical Optics, 13(4), 044028-044028-9.
[8] Carlsen, M. H., Halvorsen, B. L., Holte, K., Bøhn, S. K., Dragland, S., Sampson, L., et al. (2010). The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide. Nutrition journal, 9(1), 1.
[9] O'ʹshea, E et al. "The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (ecstasy')." Neuropharmacology 37.7 (1998): 919-926.
[10] Piper, B. J. (2007). A developmental comparison of the neurobehavioral effects of ecstasy (MDMA). Neurotoxicology and teratology, 29(2), 288-300.
[11] Bhide, N. S., Lipton, J. W., Cunningham, J. I., Yamamoto, B. K., & Gudelsky, G. A. (2009). Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain. Brain research, 1286, 32-41.
[12] Capela, J. P., Carmo, H., Remião, F., Bastos, M. L., Meisel, A., & Carvalho, F. (2009). Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview. Molecular neurobiology, 39(3), 210-271.
[13] Fornai, F., Gesi, M., Lenzi, P., Ferrucci, M., Lazzeri, G., Pizzanelli, C., et al. (2004). Effects of Repeated Low Doses of MDMA on EEG Activity and Fluoro‐Jade B Histochemistry. Annals of the New York Academy of Sciences, 1025(1), 181-188.
[14] Modi, G. M., Yang, P. B., Swann, A. C., & Dafny, N. (2006). Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants. Behavioral and Brain Functions, 2(1), 1.
[15] Kalivas, P. W., Duffy, P., & White, S. R. (1998). MDMA elicits behavioral and neurochemical sensitization in rats. Neuropsychopharmacology, 18(6), 469-479.
[16] (2014). Low Dose MDMA and Upregulation - Bluelight. Retrieved February 23, 2016, from http://www.bluelight.org/vb/threads/682252-Low-Dose-MDMA-and-Upregulation?p=12120662&viewfull=1#post12120662.
[17] "Erowid MDMA Vault : Dosage." 2005. 23 Feb. 2016 <https://www.erowid.org/chemicals/mdma/mdma_dose.shtml>
[18] "MDMA Accounts of Healing." 2004. 23 Feb. 2016 <http://www.maps.org/mdma/healing/cp-antwerp.html>
[19] Concheiro, Marta et al. "Nonlinear pharmacokinetics of (±) 3, 4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat." Drug Metabolism and Disposition 42.1 (2014): 119-125.
[20] De La Torre, Rafael et al. "Non‐linear pharmacokinetics of MDMA (‘ecstasy’) in humans." British journal of clinical pharmacology 49.2 (2000): 104-109.
A study examining the mechanism of MDMA neuroprotection.
ReplyDeleteIncreased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA
https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-8-165