Wait…Cannabis potentiates the effects of Ecstasy?

May 15, 2009

Along with alcohol, caffeine and nicotine, the most-active ingredient in cannabis (Δ9-THC; “THC”) is frequently co-ingested with MDMA by the Ecstasy user. There are, in fact, some suggestions that cannabis may be consumed in some cases specifically to assist with modulating the MDMA high.
Now, those that are aware of the tetrad test for cannabinoid action (necessary back before the first cannabinoid receptor was cloned in the early 90s) might think to themselves of a specific protective effect. One of the hallmarks of THC is that it reduces body temperature in rats. So if one of the problems with MDMA is that it results in high body temperature, it might be convenient if smoking a little dope had an action that reversed this physiological outcome.
This was supported by a paper by Morley et al (2004) which reported that yes indeed, if you inject a rat with 2.5 mg/kg THC i.p. it completely blocks the tympanic temperature elevation produced by 5 mg/kg MDMA i.p.
A recent study in humans suggests that caution is warranted.

Cannabis Coadministration Potentiates the Effects of “Ecstasy” on Heart Rate and Temperature in Humans.
Dumont G, Kramers C, Sweep F, Touw D, van Hasselt J, de Kam M, van Gerven J, Buitelaar J, Verkes R. Clin Pharmacol Ther. 2009 May 13.

This study reports on the effects of 100 mg oral MDMA, three inhalations of about 6 mg THC (spaced at 90 min) and the combination in 13 human subjects. Plasma kinetics for the exogenous drugs, for norepinephrine and epinephrine and heart rate are reported. One of the more interesting bits, however, is reported in the following figure.
Dumont09-fig3.pngTympanic temperature was increased by oral consumption of MDMA, reaching a peak about 90 minutes after ingestion (consistent with the plasma peak), as one might expect*. inhaling vaporized THC did not block this effect. The first inhalation of THC (timed to pill ingestion) looks to have delayed the onset of the temperature increase. However the second inhalation did not induce further delay and temperature ultimately reached a peak change approximately equal to the one after MDMA alone. The elevated temperature was sustained up to the end of the 300 min observation interval in the THC-MDMA combined condition compared with MDMA alone.
Hmm. Looking for differences here. The biggest thing would seem to be that this level of THC inhalation did not produce a reduction in body temperature by itself in humans. The doses that decrease body temperature in rodents are fairly high ones so what were these humans receiving? Well, the inhalation procedure in this study resulted in plasma levels of 60-80 ng/ml. This NHTSA site claims that 100-200 ng/ml of THC are “routinely” observed in cannabis smokers. See this, this, this for confirmation. So the present study was perhaps on the low side of things, but then speculating exactly how much cannabis an Ecstasy user might smoke is…..well, speculative. And the study did report about a 20-30 bpm elevation in heart rate after THC inhalation that appeared to be independent of MDMA (which itself elevated heart rate by about 20-30 bpm). So it was certainly in the range of physiological relevance.
Give that this study is in humans, given the doses seem more in line with what would be expected in the user population, I’d have to put more confidence in this study than in the Morley et al (2004) rat paper. Thus it appears unlikely that cannabis smoking in the recreational Ecstasy user provides any protection against MDMA-induced hyperthermia.
The prolongation of the elevated body temperature that was the excuse for using “Potentiates” in the title? Doesn’t support a strong conclusion at this stage but it certainly brings up some other scenarios for risk with subsequent dosing.
*Actually it is not entirely true that one might expect this. This is well below the doses used in the clinical trials. One of the initial results seems to imply not just that mean temp did not significantly increase but that no individual experienced a 1 deg Celsius increase in temperature. Liechti and Vollenweider (2000) reported no effect of 1.5 mg/kg oral MDMA on axillary temperature. Nevertheless in a dedicated experiment using an ingested remote device to measure gastric (“core”) temperature Freedman and colleagues (2005) found that 2 mg/kg oral MDMA did increase body temperature under cool and warm laboratory conditions.

No Responses Yet to “Wait…Cannabis potentiates the effects of Ecstasy?”

  1. D. C. Sessions Says:

    Thanks for the reminder, DM. I don’t miss the 60s, despite the jokes.


  2. No wonder I always enjoyed firing up a fat..wait, wut? Never mind.


  3. leigh Says:

    that’s the problem with using rats in these types of studies… the rat physiological effects aren’t always relevant, and neither are the doses.


  4. daedalus2u Says:

    Usually cannabis is smoked which includes inhaling combustion products including CO. CO binds to the P450 enzymes too (that is even the source of the P450 reference). What does CO do the the relative activity of the enzymes that metabolize MDMA?


  5. becca Says:

    rats are not furry people- round eleventy
    daedalus2u- in the study, they used “vaporized” THC. And a placebo.
    However, the P450 connection seems feasible.
    CYP3A4 seems to metabolize both THC and MDMA (as well as *binding* to grapefruit, and starfruit, saint john’s wort and prozac and testosterone, and estradiol, and…).
    (In contrast, my very limited understanding from de la Torre + wikipedia is that CYP2D6 binds MDMA but is blocked by it, so if you want to actually effectively metabolize MDMA you need CYP3A4)
    COMT is another reasonable bet. Apparently rat COMT is more effective than human COMT, at least for several substrates.
    I tried to see if there was UGT crossover, but it doesn’t seem so (THC seems to eventually route to 1A1 and 1A3; for MDMA I could only find info on 2B15). So if any of the difference is at phase II, it’s probably a stupid GST or something else I don’t know as much about, so I can’t say anything about specific polymorphisms or species differences.


  6. juniorprof Says:

    THC, partial agonist, sucks for hypothermia. These humans should have taken Win55,212-2, that would have done the trick, I would imagine.


  7. becca Says:

    Win55,212-2? *Googles* Neato, wanna play!
    But… antiinflammatory? I thought U0126 reduced TNF-alpha? Whiskey…? Tango…? Foxtrot…?
    Curse you ERK for being so counterintuitive, CURSE YOU! *shakes fist*


  8. leigh Says:

    thc works well enough for hypothermia in rats, hence the issue raised here. but win2 in humans… whoa. dude, that is badass.
    (aside: ever try dissolving that stuff in injectable solution?)
    oh yes, and then there’s the absorption/first-pass metabolism difference with inhalation vs i.p. injection.


  9. juniorprof Says:

    leigh, I’ve got one word for you… carboxymethylcellulose (CMC). It s bit milky but it does the trick. I actually doubt its ever been given to humans though (WIN that is, I had plenty of CMC tonight in my ice cream)… however, for hypothermia in rats its about a log step left of thc. And thc is such a weak partial agonist that it can act as an antagonist at sufficient concentrations against WIN… gotta love those pharm tricks!! On the other hand, I think that CP55,940 (or whatever the telephone number on that one is) has been given to humans. That one’s pretty potent. Wonder what it would do? All of which raises an interesting question. Anyone ever wonder which THC effects are actually due to antagonist activity (due to partial agonism) against endocannabinoids? 2-AG levels can go pretty high in membrane microdomains and the 2-AG site in CB1 is intramembrane or very close to. Just sayin.
    And Becca, where the heck does U0126 come from with WIN55,212-2. WIN is a CB1/2 agonist, I’ve never heard of it influencing ERK. And just to be a pharmacology purist, U0126 is a MEK inhibitor.


  10. becca Says:

    Blame wikipedia for me knowing about it.
    (Bouaboula et al, Biochem J. 1995.
    phosphorylation of p42/44 (ERK1/2) after exposure to WIN in CB1 transfected CHO cells.)
    Granted it’s wonky cell culture.
    Maj et al European J Neurosci 2007 is probably representative of a much more meaningful cell signaling pattern
    (they used prenatal exposure to WIN and found the adult animals ended up with low BNDF in the hippocampus and frontal cortext accompanied by low phospho ERK1/2).
    “And just to be a pharmacology purist, U0126 is a MEK inhibitor.”
    Fine. And just to be an ice cream purist, if you are ingesting milky gunk with CMC, you need get real ice cream!


  11. S. Rivlin Says:

    Most cannabis users do not use pure THC. One can wonder about THC’s antagonistic effect as a partial agonist, however, all the other cannabinoids in smoked cannabis are probably more potent in either potentiating or inhibiting any agonistic or antagonistic effect of THC.


  12. leigh Says:

    JP, it also goes into a very rain-dancey dissolution resulting in a final ratio of 18:1:1 saline:ethanol:emulphor that will dissolve most cannabinoid drugs if you really hammer on em.
    the antagonist theory is out there being discussed… i recently saw a talk about it, and i wasn’t particularly convinced by the data used to support the idea. while 2-AG is a full agonist, AEA is not. and then we get into differences in agonist efficacy in homeostatic regulation pathways of the CB1 receptor, which do significantly alter the functional downtream coupling of the system after THC but not so much after full agonist. there are some other holdups i have about it that i won’t go into here.
    however, the effects of THC can be framed in this general light as deregulating the normal mechanisms of CB1-mediated control of presynaptic NT release, which does not exclude the possibility that it is acting as an antagonist to compete with 2-AG.


  13. daedalus2u Says:

    DM, I just came across this paper but have only seen the abstract.
    These changes are suggestive of changes to NO physiology and changes to energy physiology brought about by a reduction in ATP levels.
    NO regulates the ATP level via their combined action on sGC. Low NO lowers the ATP concentration, which is one of the mechanisms behind ischemic preconditioning. Low ATP pushes the mitochondrial potential higher, which increases superoxide levels and lowers ATP concentration still more. The potential rate of formation of ATP increases as the ATP concentration goes down. If that increased mitochondrial potential is not used to generate an increased ATP production flux it gets dissipated as heat.
    Metabolism of substrates by P450 enzymes is accompanied by production of superoxide which will pull down the NO level, leading to an acceleration of metabolism (via the effect of low NO on ATP levels). This acceleration could be quite local depending on the expression profile of P450 enzymes with affinities for MDMA. Low NO will potentiate the effects of everything metabolized through the P450 enzymes.
    I think that euphoria from hypoxia, ischemia, stimulant abuse, solvent huffing and MDMA all have the final common pathway of low ATP. Low ATP is the consequence of excitotoxicity. It is the low ATP of the metabolic stress of excitotoxicity that causes cell death. I see that as a “feature”, that “prunes” specific cells to reduce the metabolic demands of that volume element of brain.
    Apoptosis could be removing neurons with a single dose of MDMA. The perceived “therapeutic” benefits of MDMA may be due to apoptosis. It is hard to imagine an acute effect of any drug that has long term and complex neurological activity acting via a different mechanism. You can’t make new neurons or new connections that rapidly, you can only prune them.


  14. Jale Raisme Says:

    still ‘waiting’, let me know when to stop and go on reading the rest of the post.


  15. […] precise dose and pattern folks exposed themselves to, the environmental conditions, co-administered psychoactive substances and even the identity of the drugs being consumed as […]


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