Towards a safer MDMA protocol

Editor's note: As previously discussed, MDMA may be physiologically harmful when used regularly (though it appears to be less harmful than alcohol (a), cf. this critique of comparative-harm analysis (a)).

The research below was prepared by an anonymous collaborator, and published here with the author's permission.

This post is about my personal take on the best psychedelic stack and protocol after reviewing the relevant literature, consulting with neuro-focused medical researchers, comparing to existing protocols in use by psychedelic therapy training programs, and conducting some experiments.

I was dissatisfied with the scattered nature of the relevant info online. This post is obviously for educational purposes only. If at some point in the far future such substances were legalized this could be a useful guide to using such things for self-administered or peer-assisted therapy if a reliable facilitator is not available.

MDMA pharmacology:

Rick Doblin, founder of MAPS, recently gave an inspiring TED talk. From the talk:

Now, how does MDMA work? How did MDMA help Marcela? People who have PTSD have brains that are different from those of us who don't have PTSD. They have a hyperactive amygdala, where we process fear. They have reduced activity in the prefrontal cortex, where we think logically. And they have reduced activity in the hippocampus, where we store memories into long-term storage. MDMA changes the brain in the opposite way. MDMA reduces activity in the amygdala, increases activity in the prefrontal cortex and increases connectivity between the amygdala and the hippocampus to remit traumatic memories to move into long-term storage.

You may have heard that MDMA has been granted breakthrough treatment status for PTSD, and that [the Usona Institute and Compass Pathways are] working on similar Phase 3 trials for psilocybin for treatment-resistant depression. Obviously in the medical trials these substances are being tested separately, but I actually think they're highly synergistic.

Here's why: a large proportion of the psychedelic effects of MDMA seem to come from its conversion in the body to MDA (Kalant 2001). Obviously people like these effects, but the problem is that MDA appears to be many times more neurotoxic than MDMA (Colado et al. 1995, Hearn et al. 1988).

Though the reality is more complicated and other metabolites are in play, the relevant causal mechanisms are covered by what we're doing here so we don't need to get into it.

One could inhibit the conversion of MDMA to MDA by taking a CYP3A4 inhibitor, but where would one get something this exotic?

[Editor's note: A neuropharmacology expert notes that people have widely varying levels of CYP3A4 activity. For people who have low CYP3A4 activity, inhibiting CYP3A4 may actually increase the toxicity of MDMA. This expert is generally supportive of using supplements with MDMA, but skeptical of using CYP3A4 inhibitors to improve MDMA safety.]

Luckily some of the enzymes in grapefruit juice/peel are quite potent in this regard, and appear to block about 90% of the conversion (Kolbrich et al. 2009). Preventing the conversion of MDMA-to-MDA also means that there is more MDMA circulating in your system. Which means one can reduce the dosage, and potentially mitigate any other dose dependent neurotoxic effects we might not know about. Based on surveys, people report the best effects with 80 mg (as opposed to the 100-150 mg doses often taken recreationally).

[Note that grapefruit juice interacts with many medications in ways that can sometimes produce serious side effects. Definitely check for interactions with grapefruit if you take other medications.]

MDMA paired with psilocybin:

Now the problem is that without said conversion, the MDMA isn't going to have the same psychedelic kick as before, though it will still have an emotional effect. If we presume that the psychedelic effect is at least partially responsible for the good effects of MDMA therapy we wouldn't like to lose this, so what do we do? You can probably guess what comes next. Stacking the MDMA with low-dose psilocybin allows us to precisely control how strong we want the psychedelic effect to be without any of the downsides of MDA (my guess is that MDA is more responsible for MDMA hangovers than the MDMA itself).

To do psychotherapeutic work, one wants to be lucid enough to be able to follow chains of emotional reasoning and be able to communicate with one's facilitator. People respond differently, but this generally corresponds to about 10-20 mg of psilocybin (Griffiths et al. 2011). This also corresponds to about 1-2 grams of dry weight mushrooms, though obviously this can vary a bit too depending on conditions.

Other supplements:

There is milder evidence for some other supplements lowering signs of neurotoxicity, and they're harmless and cheap enough to take. They are:

There are companies selling stacks for convenient though expensive dosing:

Body temperature & other approaches:

Keeping core temperature cool also seems to ameliorate toxicity effects. Staying hydrated and not being excessively active (e.g. not dancing for hours) helps a lot with this.

If one finds oneself overheating, cool (not too cold) water on the palms/wrists rapidly lowers core body temperature. Gel packs kept in the fridge rather than the freezer are also about the right temperature to rapidly cool without being so cold that they activate the bodies natural "preserve heat" response which is counterproductive.

Some people try to optimize the timing of all sorts of peak blood concentration curves for various substances based on various pieces of available evidence. I don't see compelling evidence this makes much a difference. You can take it all at the same time (except the melatonin).

What about 5-htp at night or the next day? I'm pretty underwhelmed by this supplement, to be honest. Why is a long complicated topic, suffice to say if you're doing everything else right I think any benefits from this would be quite small and not worth the mild risks.

(Tangent: in studies on the neurotoxocity of MDMA one of the comparisons they use is the known to be highly neurotoxic methamphetamine. If you or someone you know is on it, I'd recommend they take l-tyrosine along with the above on a regular basis. People report it helps with adderall hangovers. While I worry that sharing such info will actually make people more likely to stay on adderall, I can't justify not sharing things that impact brain health and leaving the decisions to them.)


Trip reports of people using this stack say that they did not experience a hangover, and in fact experienced the opposite, a pleasant afterglow that lasted for several days.

I think both the emotional component and the psychedelic component of an MDMA trip are important. Why?

The emotional component creates the space to have self-compassion (one person reported that on MDMA they felt like they actually understood the idea of self care for the first time, that they deserved as much consideration as they would give to others facing a difficult situation).

The psychedelic component creates the possibility of seeing things from a broader perspective and the neuroplasticity for this new perspective to stick. [See Carhart-Harris & Friston 2019 for a possible mechanism of this neuroplasticity boost.]