Pharmacology Why is "5-MAOI-DMT" so dangerous

[red22]

This is a write-up I made for a Gemini chat (the chat wasn't helpful):

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I'm particularly interested in 5-MeO-DMT's capacity to elevate serotonin because there's evidence that maois render 5-MeO-DMT quite toxic:

"I have heard very mixed reports from trials employing P. harmala and the second of the biotic tryptamines, 5-methoxy-N,N-dimethyl-tryptamine, or 5-MeO-DMT. Apparently, modest amounts of both components gives a modest experience, but I have had two reports of truly toxic crises with larger quantities." Alexander Shulgin. TiHKAL. 1997. Part 1: Chapter 16. Hoasca vs. Ayahuasca, page 302

"I personally had a terrible physical experience from caapi + approx. 5 mg oral of 5-Meo-DMT. I had intense dizzyness/disquilibrium, weakness, alternating extreme hot and cold flashes, overpowering body energy, and intense feelings of malaise. There were no visuals, and I did not feel any kind of ego loss or other psychedelic-like effect." @iom, 2025-04-10, https://www.bluelight.org/community/posts/16249155

"I never had the guts to try this combination again, which I think is probably for the best. When I read Shulgin's TiHKAL in 1999, I read that 5-MeO-DMT in combination with MAOIs has caused some dangerous hypertensive experiences, which certainly fits in with the headaches and pounding heartbeat I experienced." Murple. A Bad Combination. 2000-07-13. https://erowid.org/experiences/exp.php?ID=2362 [This was an experience with 5-MeO-DMT & Peganum harmala]

You might say to this, that's no surprise: MAOIs amplify 5-MeO-DMT's serotonergic action—a well known tight rope in MAOI territory. But Nagai 2007 found that DPT's SRI potency was even stronger than 5-MeO-DMT's SRI potency, and the last person quoted, above, tried DPT with harmine and did not come to the same harsh conclusion:

"Physically, it was a nice trip, after the initial tachycardia passed. I had the usual DPT vibrational feel. I felt very warm and relaxed. The comedown felt very gentle and pleasant." Murple. PropylHuasca. 2000-11-20. https://erowid.org/experiences/exp.php?ID=2383 [This experience also included ketamine, GHB, and cannabis]

Furthermore, he also tried MDMA with P. harmala—more than once—and found it to be a positive combo:

I've mixed MDMA and syrian rue before on several occasions, taking the rue either before or at the same time as the MDMA. I have also mixed Syrian rue with another phenethylamine, mescaline.

Neither caused any problems at all (although when I mixed it with mescaline, I did end up puking, but that happens to me with rue most times anyway, and the mescaline+rue puking was much milder than any tryptamine+rue combination has ever caused). In the case of mixing it with MDMA, it was quite enjoyable and something I will undoubtedly do again. It produces a pretty strong potentiation and adds a new (and quite profound) earthy spiritual dimension to the experience.

The one caution is to use low doses of MDMA. In high enough doses, MDMA itself can kill - as can most amphetamine derivatives. Taking MDMA with an MAOI will lower the overdose threshhold since you are potentiating its effects. If you choose to mix MDMA with Syrian rue, start with no more than half your usual dose of MDMA.

Murple. Combining Ecstasy with Syrian Rue. 2001-07-17. https://erowid.org/experiences/exp.php?ID=8184

Furthermore, I've come across a few people who have used methamphetamine while on an irreversible MAOI without apparent ill effect. One person states that dopamine and norepinephrine amplification is "less of a concern" than serotonin amplification (implying that methamphetamine primarily affects those two chemicals) and "I can personally verify the accuracy of (20mg of vaporized methamphetamine [ … ]) on 30mg nardil not leading to serotonin [toxicity]."[ 1 ] And that's remarkable, as you pointed out that methamphetamine is both an SRI and a serotonin releaser. I also came across someone who had "25 plus instances of combining Nardil with varying amounts of meth, [coke], crack and Ritalin,".[ 2 ] He also said, "I've used [methamphetamine] maybe 20 times, all with no issues, even at much larger doses than the last. The last time I used it in combination with nardil I had a heart attack at 27 and was diagnosed with congenital heart failure"[ 3 ] and "I’ve since smoke lots of crack while still taking the MAOI without any adverse reactions."[ 3 ]

This person puts a big emphasis on these quotes:

"It is, unfortunately, necessary to state clearly from the beginning that much of what is published by doctors in books and journals about MAOIs is either poorly informed, or just plain wrong. As an example, much of the information that comes with MAOIs (the PI, or product information sheet) contains inaccurate material concerning, among other things: serotonin toxicity, drug interactions generally, and dietary tyramine."[ 4 ]

"there is a great deal of misinformation and mythology about their dietary and drug interactions."[ 5 ] 

So, how could 5-MeO-DMT be so threatening, in light of this information?


[ 1 ] PowerHungryGandhi, 2024-01-30, h‍ttps://old.reddit.com/r/harmalas/comments/1aesejh/5meodmt_should_be_combined_with_harmalas_just/kkc5m51/

[ 2 ] No-Tap9133, 2024-04-25, h‍ttps://old.reddit.com/r/MAOIs/comments/1cc8nz9/three_articles_on_combining_stimulants_with_maois/l17vq64/

[ 3 ] No-Tap9133, 2024-05-22, h‍ttps://old.reddit.com/r/MAOIs/comments/1cxinm9/curious_to_hear_from_people_who_have_used_meth/l57ynh0/

[ 4 ] Ken Gillman, M.D. MAOIs (Parnate, Nardil): Misconceptions and Questions No. 1. PsychoTropical Research. 2012-11-14. https://web.archive.org/web/2017042...ical.com/maois-misconceptions-and-questions-1

[ 5 ] Grady M.M., Stahl S.M. Practical guide for prescribing MAOIs: debunking myths and removing barriers. 2012. CNS Spectrums. 17(1):2-10. 10.1017/S109285291200003X
https://www.cambridge.org/core/jour...ing-barriers/29CA109F33F4AEC902C3CE39220AD06C
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Some input from Claude, for what it's worth:

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… looking at the Nagai data honestly [see below], it doesn't help much either — 5-MeO-DMT is actually a weaker SRI than several other drugs in those tables that seem better tolerated with MAOIs.

Which leads me to think the answer probably lives somewhere Nagai doesn't measure at all: receptor binding profiles, particularly 5-HT₁A. MDMA's primary action is transporter-mediated release — it floods the synapse with serotonin, but it's the serotonin acting on receptors, not the drug itself directly. 5-MeO-DMT is a direct, potent 5-HT₁A agonist, and unlike most classical psychedelics whose subjective and physiological effects are dominated by 5-HT₂A activity, 5-MeO-DMT's 5-HT₁A affinity is arguably its dominant feature. 5-HT₁A activation is actually associated with the physiological symptoms in your anecdotes — thermoregulatory disruption, cardiovascular effects, the absence of typical psychedelic visuals.

So the honest answer to your question is: the distinction is probably pharmacodynamic rather than pharmacokinetic, and it's likely about where the excess serotonin activity lands rather than simply how much serotonin is elevated. But I want to be clear that this is a hypothesis built from outside literature, not something the Nagai data can support on its own.
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Table 2. The effects of drugs on monoamine re-uptake into rat brain synaptosome [I selected the 5-HT values. These are IC₅₀ values.]

2C-I	7.9±1.9 × 10⁻⁵
2C-E	7.2±1.6 × 10⁻⁵
2C-C	3.1±0.78 × 10⁻⁵
AMT	3.8±0.74 × 10⁻⁷
5-MeO-AMT	2.9±0.71 × 10⁻⁶
DPT	2.9±0.69 × 10⁻⁶
5-MeO-DiPT	2.2±0.41 × 10⁻⁶
5-MeO-MiPT	6.4±1.8 × 10⁻⁶
5-MeO-DMT	4.1±0.91 × 10⁻⁶

Methamphetamine and cocaine are also included:

Cocaine	2.1±0.52 × 10⁻⁶
Methamphetamine	4.0±0.97 × 10⁻⁶

Nagai, F., Nonaka, R., & Satoh Hisashi Kamimura, K. 2007. The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. European journal of pharmacology, 559(2-3), 132–137. 10.1016/j.ejphar.2006.11.075

 

[red22]

I definitely think that synthetic 5-MeO-DMT should not be combined with MAOI’s at any stage, and again, 5-MeO-DMT is quite strong enough by itself. I am yet to be convinced that any other research chemicals or additives in a changa-like blend are useful or better than natural DMT. However, a herbal blend I dubbed ‘cracker’, containing 5 to 10 percent 5-MeO-DMT, has been found to be a very effective way to dose and smoke 5-MeO, as it contains classic changa herbs such as mullein, mint and blue lotus. I have not found 5-MeO-DMT to be at all positively affected or enhanced by beta-carbolines from ayahuasca vine or Syrian rue and have personally had very negative experiences combining beta-carbolines with 5-MeO-DMT. The Erowid web site has received several reports of people experiencing very troubling side effects with this combination, [Palmer continued that there have been a few reported deaths, but I think there has only been two deaths, see below.]

Julian Palmer. Articulations: On the Utilisation and Meanings of Psychedelics. 2014. Appendix I. Changa: Smoking DMT infused

Contraindication : 5-MeO-DMT and MAOIs Although 5-MeO-DMT is present in some plants used in ayahuasca and in some ayahuasca brews, Erowid has received several reports of very troubling physical reactions in people who have ingested 5-MeO-DMT with MAOI harmala alkaloids. There appears to be the risk of severe hypertensive symptoms, overheating, serotonin syndrome, etc. It is important to note that the profile of these risks are not fully understood, because the long history of use of brews containing some amount the two in combination.

A case of a 17-year-old male was reported to us in December 2002. He ingested an extract of Syrian Rue and then smoked an unknown (but large) dose of powdered, chemical 5-MeO-DMT. He quickly became non-responsive and fell to the ground, began convulsing (myoclonic jerking), and his sitter called an ambulance for help. He was found to have had a pulse of 180, blood pressure 200/125, and temperature 106.0 F. These levels are dangerously high. He was minimally responsive but became wildly agitated upon stimulation (even just speaking to him). He was treated with diazepam and transferred by helicopter to a Boston area hospital. The patient may have suffered lasting damage to his kidneys and rhabdomyolysis. A formal case report of this incident was published in a 2004 issue of the Journal of Toxicology & Clinical Toxicology titled "Monoamine Oxidase Inhibitor Poisoning Resulting from Internet Misinformation on Illicit Substances".

In December 2004, we received an unconfirmed report of a death related to the ingestion of 200 mg of 5-MeO-DMT with some amount of "yage". This death was later described in the case report "A Fatal Intoxication Following the Ingestion of 5-Methoxy-N,N-Dimethyltryptamine in an Ayahuasca Preparation" in the November/December 2005 issue of the Journal of Analytical Toxicology, and the follow-up commentary "A Demand for Clarity Regarding a Case Report on the Ingestion of 5-Methoxy-N,N-Dimethyltryptamine in an Ayahuasca Preparation" was published in the July/August 2006 issue.

We have also received some reports from groups experimenting with making pharmahuasca using 5-MeO-DMT who have said that they had much higher incidence of bad reactions with 5-MeO-DMT than with N,N-DMT. They discontinued using the 5-MeO-DMT.

This is from the WARNINGS section of the HEALTH section of Erowid's 5-MeO-DMT vault.
https://erowid.org/chemicals/5meo_dmt/5meo_dmt_health.shtml

 

[Rectify]

Joe Rogan Liked It.

 

[Didgital]

This is a write-up I made for a Gemini chat (the chat wasn't helpful):

It's a good question. Not sure why...

 

[MedicinalUser247]

Personally, I would just smoke the 5-MeO-DMT and not take it with an MAOI to increase the potency by taking it orally. Smoking 5-MeO-DMT is enough for me.

 

[4DQSAR]

.As a non-selective serotonin agonist, it can trigger serotonin syndrome and unpredictable, overwhelming "whiteout" experiences that leave users vulnerable and unable to move.

Someone gifted me some 5MeO-AMT which I did NOT touch. It came as a sort of bright green film so already alarm-bells were ringing. No dose per cm2 qas known so it seemed to me pure folly to trust that it wouldn't end up with an OD.

I HAVE talked to people who have taken 5MeO-AMT. None wanted to EVER do it again. Nuff said.

It's only when your notice that tryptamines overlay PEAs and thence to realizing that a 5-MeO 7-<something> might be a more selective ligand. But I only know 7,a-DMT is an entactogen at low doses, psychedelic at higher doses. We simply ran out of time as UK law prevented further research.