Is it possible that cannabis could reduce negative long-term effects on the brain's serotonin system caused by MDMA? Several researchers have sought to answer this question by administering THC to rodents immediately prior to MDMA, and the results hint at the possibility of neuroprotective effects.

In 2010, a team of researchers led by Clara Touriño published their work with mice showing that high doses of THC can block damage from very high doses of MDMA, prompting questions from ecstasy users about whether smoking (or eating) cannabis along with MDMA might provide some lasting benefit, or at least mitigate hangovers. Though a review of the current science shows it is too early to provide definitive answers, this interesting research demonstrates how much there is still to learn about MDMA neurotoxicity and potential prophylactic strategies in humans.

MDMA and cannabis act quite differently in the brain and body. Delta-9-tetrahydrocannabinol (Δ9-THC), the chief psychoactive compound in cannabis, activates endocannabinoid (CB) receptors (CB1 and CB2) in the brain and body.1,2,3 MDMA stimulates the neurotransmitter systems for serotonin, norepinephrine, and dopamine, triggering a complex reaction of transmitter release and altered reuptake activity.4,5,6,7 MDMA initially increases serotonin activity in the brain; however, it is also associated with lasting serotonin reductions.

Research indicates that MDMA may produce long-term reductions in serotonin activity and other changes in the brain, either through toxicity (damage) to the brain cells that release serotonin or by changing the brain's response to serotonin.2,8 Researchers found lower brain serotonin levels in rats and monkeys weeks or months after repeated high doses of MDMA.9,10,11 MDMA dosage and ambient temperature both appear to play important roles in these findings.11,12,13 Decreased serotonin activity may result from damage to parts of serotonin neurons called axons, or possibly the brain responding to the flood of serotonin by reducing the number of serotonin receptors.14,15,16,17

Controversy persists over the significance of these findings despite over 20 years of research. Some findings raise serious questions about whether most animal studies have employed doses of MDMA truly matching those used by humans.18 One opinion among researchers holds that the evidence clearly demonstrates long-term toxicity, while others think the evidence shows that the brain is withdrawing or deactivating the protein that transports serotonin back into neurons. Brain researchers have used radioactively tagged drugs to estimate the amount of serotonin transporters available in regular ecstasy users. These scientists find that relatively heavy MDMA use is associated with fewer serotonin transporter sites, though lower serotonin transporter levels are not seen in people reporting low or moderate use.19,20 Interestingly, not all researchers using the same radioactive drug detected fewer serotonin transporters in ecstasy users.21

One of the leading explanations for the mechanism by which MDMA may harm serotonin neurons is that the drug or its metabolites produce "free radicals".22,23 Free radicals are chemicals that interact with other molecules and produce oxidative stress, which injures cellular machinery and causes inflammation. If this hypothesis is correct, then any drug or activity that reduces oxidative stress or inflammation should reduce MDMA toxicity, an effect that has been demonstrated with vitamins C and E in rats.24,25

There is evidence that cannabis possesses antioxidant and anti-inflammatory properties, with THC playing a role in some of these effects.26 Researchers have found that when rats and mice received both MDMA and THC, they had a smaller rise in body temperature than after MDMA alone.27 Morley and colleagues also found, when compared to rats given MDMA alone, that rats given MDMA and THC had less of a reduction in brain serotonin and its metabolite 5-hydroxyacetic acid (5HIAA). They concluded that THC lessened the lasting effects of MDMA on brain serotonin by activating the CB1 subtype of endocannabinoid receptors, because when they gave rats a different drug that only activated the CB1 receptors, that drug also attenuated the lasting reduction in brain serotonin after MDMA. Conversely, a drug that prevented activation of CB1 receptors (an antagonist) did not stop the reduction in brain serotonin after MDMA.

Touriño's research team examined whether THC and cannabinoid activity can reduce brain damage from high doses of MDMA. They used mice that had been genetically engineered to lack one or both CB receptors to study the effects of MDMA on brain dopamine.28 In mice, MDMA toxicity causes lasting reductions in dopamine levels instead of the lasting reductions in serotonin levels seen in rats and primates. The researchers tested mice lacking the endocannabinoid CB1 receptor (mostly found in the brain), the CB2 receptor (mostly found on immune cells), or both. All mice received four separate doses of 20 mg/kg MDMA (a very high dose) at two-hour intervals. Some mice in all three groups received 3 mg/kg THC (also a very high dose) prior to MDMA. Giving mice THC beforehand prevented them from overheating (hyperthermia), prevented reductions in brain dopamine, and reduced microglial activation, considered a marker for inflammation. However, mice without CB1 receptors did not benefit from receiving THC; they grew hot and had reduced brain dopamine. Likewise, blocking CB1 receptor activity with another drug eliminated the benefits of THC. In mice lacking CB2 receptors, THC still helped reduce body temperature and lessen reductions in brain dopamine, although it did not stop increased microglial activation. These results suggest that cannabinoids like THC can mitigate the lasting, harmful effects of high-dose MDMA on the brain, perhaps through lowering body temperature and antioxidant and anti-inflammatory activity.

Despite this intriguing evidence for the neuroprotective potential of cannabis in helping stave off some long-term effects of MDMA, there are a number of reasons for taking the data with a grain of salt. Most importantly, Touriño and colleagues' work, like the vast majority of studies of MDMA effects in animals, used an interspecies scaling formula to calculate MDMA doses to mimic those used by humans. However, research on blood levels of MDMA in rodents and monkeys has found that this scaling formula results in overly high doses to animals.29,18 Hence it is not clear whether the lower doses of MDMA used by people actually reduce brain serotonin, let alone whether these effects are due to oxidative stress and whether they can be countered by antioxidants such as THC. Because animal studies with THC used dosages resulting in much higher blood levels of MDMA than found in humans, it is unclear whether these findings can be extrapolated to humans with any validity.

Various lasting problems have reportedly been associated with ecstasy use, including depression, anxiety, impulsivity, and loss of enjoyment of taking MDMA. The most consistent cognitive deficit reported in the literature in humans is a small decline in verbal memory (word recall) performance.30 Anxiety or depression prior to use, as well as heavy use of other recreational drugs, may be a contributory factor,31,32,33,34 but there is also sufficient evidence to suggest that heavy ecstasy use causes memory problems.35,36 Unfortunately, there is little strong evidence for attributing these effects to serotonin neurotoxicity in humans,19,37,38 and therefore it is unknown whether they could be reduced by blocking neurotoxic effects.

Lastly, some studies suggest that cannabis use itself is associated with problems in ecstasy users. These include increased likelihood of psychological problems such as anxiety and depression,39,40 as well as reduced performance in some memory tests.41 The correlation between cannabis use and these problems may result from a greater likelihood for specific behaviors and characteristics in such users, including intensity of substance use or pre-existing traits such as impulsivity.34

More research is needed into the actions of antioxidants and anti-inflammatory compounds in heavy ecstasy users before conclusions can be made about THC's ability to mitigate damage caused by MDMA. Specifically, animal research using doses of MDMA and THC equivalent to those used recreationally by humans is necessary to judge possible prophylactic effects. Further, since cannabis contains many cannabinoids other than THC (including some that have neuroprotective properties in their own right), research with THC alone may produce misleading results. In short, Touriño's group reports intriguing findings that unfortunately offer little concrete insight into whether cannabis provides protective effects in brains of human ecstasy users.

Ilsa Jerome is a research and information specialist for the Multidisciplinary Association for Psychedelic Studies (MAPS); her particular focus is on literature relating to MDMA.