Pharmacology How is that even possible? ᴍᴀᴏɪꜱ, ꜱᴇʀᴏᴛᴏɴɪɴ ꜱʏɴᴅʀᴏᴍᴇ

[red22]

These are two quotes from TrancedOutBrah on The Shroomery. He started a thread titled, 'Potentiating drugs with Monoamine oxidase inhibitors', in which he stated, "In the next coming weeks, I plan on experimenting with potentiating a whole list/series of drugs, some of which that seem to be ill advised of mixing with MAOI's,"

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Alright well I am still alive, so I'll bump this thread

I was on a steady dose of 60mg phenelzine and took 75mg MDMA with a 35mg redose and rolled pretty good, did not throw up or experience any extreme heat or appear to have even come close to serotonin syndrome.

2 weeks after that I tried 10mg 2cb and it was pretty weak (to be expected), felt like 15mg just extended

A week after I tried 20mg 2cb and it hit pretty hard, felt like at least 30mg and lasted a long time

On an unrelated note I'm not taking phenelzine anymore and have no more plans on attempting to mix MAOI's to potentiate Phenylamines, but it was a fun little experiment and it does work provided you adjust dosages to account for the MAOI, as the dose is always going to be the thing that makes it dangerous or not

To be clear I am NOT recommending anyone to try this, it is dangerous to mix MAOI's and MDMA and people have died doing it, taking normal doses of MDMA and end up with SS.

Cheers
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TrancedOutBrah, 2025-04-16, https://www.shroomery.org/forums/showflat.php/Number/29189984#29189984

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I just recently started using TCP, I'm on my 4th day and I've had a lot more energy and strangely enough my libido has been off the charts, something that was the exact opposite of phenelzine. I have not combined any drug with TCP yet, I was just mentioning all the various MAOI's I've tried as they all have had a very unique kind of feeling to them. I will know more about TCP in a month or two when it's effect will peak. Let me know how your TCP experience goes as well.

As far as phenelzine and MDMA goes, the experience was much longer than normal, a normal roll for me is about 6 hours or so and that's with a redose. I felt the effects of MDMA for another 2 hours extra or so.

My normal dose for MDMA is typically 150-175mg MDMA with a 75mg redose and it's probably a 6 hour experience.

With 60mg phenelzine and MDMA, I had used 75mg with a ~35mg redose and it was about the same in terms of intensity, but the intensity was prolonged and going back to sobriety felt more gradual. About a 8 hour experience. I did not experience any comedown of the sort, but I normally never do as long as I keep my doses low and spread out my use. I will note that I normally get sexual/horny off MDMA and well, there certainly was none of that, but phenelzine absolutely tanked my libido.

MDMA itself has MAOI-A properties, as well as being a triple monoamine releaser and reuptake inhibitor which is why it's so incredibly dangerous to mix it with a MAOI, but as always, the dose makes the poison. I actually pondered the idea after reading Dr. Gillman stating that the most relevant point of contention would be the dosing level in terms of using MAOI's with things ill advised. He was right, I went over every possible MDMA toxicity combination with MAOI and they were all using normal or higher doses.

I went in with the notion that MDMA already has MAOI properties, tuning the dose down and using less and introducing a MAOI would allow MDMA to persist longer, release a lesser amount at a time but retain more due to the MAOI/Reuptake inhibition.

I had a great time and I'm not dead. I call that a win.
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TrancedOutBrah, 2025-04-19, https://www.shroomery.org/forums/showflat.php/Number/29193409#29193409

 

[daturetard]

Damn mane I got a lil very pure molly and was wondering how to make it more worthwhile. Might have to try some deadly combos. Thanks!

 

[red22]

If anything, try mixing it with B. caapi. Unlike phenelzine, B. caapi is reversible and psychedelic-esque on its own,* which should have a nice synergy with MDMA.

Reversible MAOIs are safer with serotonin boosters:

Reversible MAOIs (like moclobemide) inhibit monoamine oxidase temporarily and competitively. That means if serotonin levels get too high, the serotonin itself can push the reversible MAOI off the enzyme (because both are competing for the same spot). This acts like a built-in safety valve, preventing runaway serotonin accumulation.

Meanwhile, irreversible MAOIs (like phenelzine or tranylcypromine) permanently deactivate the enzyme by forming a covalent bond. No matter how much serotonin you have floating around, you can't knock the inhibitor off — the enzyme is "dead" until new MAO enzymes are synthesized (which takes weeks).

Thus, combining irreversibles with anything that boosts serotonin (SSRIs, 5-HTP, MDMA, etc.) is extremely dangerous and can lead to serotonin syndrome.

In short:

- Reversible MAOIs = dynamic, safer with serotonin boosters (still some caution needed)

- Irreversible MAOIs = static, much riskier with serotonin boosters

–ChatGPT




Note: I do not recommend anyone use Peganum harmala for anything, ever. B. caapi is much nicer (as tea, only, not extract).

Am I the only one? (quality of different ‘harmala’ products)

But be warned that B. caapi's tetrahydroharmine is probably a serotonin reuptake inhibitor;** THH is only present in trace amts. in P. harmala.†

Yesterday I made a thread for the combo of harmalas and MDMA (and optionally, DMT): Using MDMA as a substitute for DMT in ayahuasca

When I made the thread, I hadn't thought to use Erowid's advanced search for their Experience Vaults to see if anyone had tried the 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: An Experience with Ecstasy (MDMA) & Syrian Rue. 2001-07-17. Erowid, exp8184


Z.. "Short and Comfy: An Experience with MDMA, Syrian Rue & Alcohol (exp43802)". Erowid.org. Nov 8, 2005

Debaser. "Something Quite Stupid: An Experience with Ecstasy (MDMA) & Syrian Rue (exp1814)". Erowid.org. Jun 14, 2000

Ganesha. "Ultra Alone: An Experience with Syrian Rue, MDMA & LSD (exp95421)". Erowid.org. Jun 23, 2021

Mr. Hausmann. "Bad Day, Dangerous Experiment: An Experience with Syrian Rue, MDMA & Mushrooms (exp111677)". Erowid.org. May 1, 2018

Persistent. "Too Far: An Experience with MDMA, Alcohol, Syrian Rue, California Poppy, Cannabis, & Kava (exp10661)". Erowid.org. Jul 16, 2003


Using LSD as a substitute for DMT in ayahuasca

Using mescaline as a substitute for DMT in ayahuasca

Using ketamine as a substitute for DMT in ayahuasca


*The myth that ayahuasca has to contain DMT

**https://www.bluelight.org/community/threads/5-meo-dmt-similarity-to-dmt.945031/post-16249173

†"Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroharmine at 0.1% (w/w)."

Herraiz, T., González, D., Ancín-Azpilicueta, C., Arán, V. J., & Guillén, H. (2010). beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 48(3), 839–845. doi:10.1016/j.fct.2009.12.019

 

[ChemicallyEnhanced]

Please be careful, Serotonin Syndrome is AWFUL.
I had it once because for some reason none of my doctors flagged the fact that I was on FOUR Serotonergic meds*
I was diagnosed with "Very Mild Serotonin Syndrome" and still felt like shit for 2-3 weeks.

*Sertraline 200mg - once/day (in the morning)
Trazodone 300mg - twice/day
Amitriptyline 50mg - once/day (at night)
Tramadol 100mg - four times a day

 

[doubledog]

I know some people who regularly use caapi extract to potentiate MDMA with very positive results. No negative reports.
Use Caapi only, no Rue and keep dosage low, start with 1/4th of your usual dose of MDMA as a test run.

 

[red22]

Did any of them ever go whole hog and add DMT?

That would require even more caution, as DMT is a serotonin releaser too.

"DMT has been shown to be capable of resulting in carrier mediated release of serotonin, however the capability for induction of serotonin efflux is clearly much different than other serotonin releasing agents that are truly dangerous in combination with MAOIs such as MDMA [25, 27, 40]."

25. Hilber, B., et al., Serotonin-transporter mediated efflux: A pharmacological analysis of amphetamines and non-amphetamines. Neuropharmacology, 2005. 49(6): p. 811-819.

27. Blough, B.E., et al., Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology, 2014. 231(21): p. 4135-4144.

40. Cozzi, N.V., et al., Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter. J Neural Transm (Vienna), 2009. 116(12): p. 1591-9.

A Tale of Two Tryptamines: N,N-DMT and 5-MeO-DMT in Combination with MAOIs. Jaywin Patel, PharmD and Benjamin Malcolm, PharmD, MPH, BCPP. spiritpharmacist.com, Jun 16, 2020

 

[doubledog]

Yes, also low dose DMT is sometimes in the mix, but I do not have enough knowledge to comment.
Some people like it, but it does not seem to me that MDMA and DMT go well together.

 

[red22]

Some insight into this from Grok, based on this article from Ken Gillman, who describes himself as an expert on serotonin syndrome:

Reversible and Selective MAOIs in Combination with (S)SRIs: Risk of Serotonin Toxicity. Ken Gillman, M.D. 2000, 2024. PsychoTropical Research

Summary of the Article

The article by Ken Gillman, published on November 13, 2000, and last modified on December 10, 2024, discusses the significant risks of serotonin toxicity (ST) when combining moclobemide, a reversible and selective monoamine oxidase inhibitor (MAOI), with serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Key points include:

• Risk of Serotonin Toxicity: Combining therapeutic doses of moclobemide with any SSRI or SNRI poses a significant risk of severe and potentially fatal ST, particularly due to pharmacokinetic interactions involving cytochrome P450 (CYP450) enzymes. Fatal cases have been reported even at therapeutic doses, with overdoses increasing the risk substantially.

• Pharmacokinetic Interactions: Moclobemide levels are elevated by inhibition of CYP2C19 (e.g., by fluoxetine or fluvoxamine), and moclobemide itself inhibits CYP2D6, potentially leading to unpredictable drug concentration increases. Fluoxetine is particularly problematic due to its potent inhibition of multiple CYP450 enzymes and long half-life (up to 10 days), which can result in unexpectedly high blood levels of both drugs.

• Historical Context and Moclobemide’s Ineffectiveness: The article notes that moclobemide is largely ineffective as an antidepressant, a view Gillman has promoted for decades. Its use has declined, partly due to this ineffectiveness and the risks associated with ST when combined with SSRIs.

• Misleading Information and Case Studies: Early studies (pre-1998) suggesting safety of moclobemide-SSRI combinations were poorly controlled, non-blinded, and involved small patient numbers. These studies often reported severe side effects, leading researchers to abandon further investigation. Ethical committees have since restricted such trials due to safety concerns.

• Clinical and Legal Risks: Physicians prescribing these combinations risk severe legal and professional consequences, including lawsuits or being struck off medical registers, due to the predictable risk of ST. The article cites personal communications with researchers like Prof. Udo Bonnet, who ceased using this combination after encountering problems.

• Public Misinformation: Internet forums and anecdotal reports (e.g., combining 20 mg fluoxetine with 150 mg moclobemide) can mislead patients and clinicians, as they fail to account for pharmacokinetic variability and the potential for severe ST even at low doses.

• Key Takeaway: The combination of moclobemide with SSRIs or SNRIs is a “predictably risky strategy” with no substantive evidence of therapeutic benefit. The complexity of pharmacokinetic interactions and the lack of recent research (none in the last 15 years) underscore the need for caution.

Most Relevant References

The article cites numerous references, but the following are the most relevant for understanding the risks of combining moclobemide with SSRIs/SNRIs and the associated pharmacokinetic interactions:

• Gillman, P.K., Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). Central Nervous System Drug Reviews, 2004. 10: p. 83-85. (Ref 14)

Relevance: This paper by the author provides a focused review of moclobemide’s role in ST, summarizing clinical and pharmacological evidence of its risks when combined with SSRIs. It is critical for understanding the mechanistic basis of the toxicity.

• Dingemanse, J., et al., Pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide in the investigation of development of the “serotonin syndrome”. Clinical Pharmacology and Therapeutics, 1998. 63(4): p. 403-13. (Ref 10)

Relevance: This study directly investigates the pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide, highlighting how fluoxetine’s inhibition of CYP2C19 elevates moclobemide levels, increasing ST risk.

• Bonnet, U., SSRI Moclobemide-Combination in the Treatment of Resistant Depression. Central Nervous System Drug Reviews, 2004. 10(1): p. 86-8. (Ref 15)

Relevance: This paper, cited and critiqued by Gillman, initially suggested potential benefits of the combination but is relevant because Bonnet later confirmed encountering problems and ceased using it, reinforcing the article’s warnings.

• Neuvonen, P.J., et al., Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet, 1993. 342: p. 1419. (Ref 34)

Relevance: This case series documents fatal outcomes from moclobemide combined with citalopram or clomipramine, providing concrete evidence of the lethal potential of these combinations, even in overdose scenarios.

• Hawley, C.J., et al., Safety and tolerability of combined treatment with moclobemide and SSRIs – a systematic study of 50 patients. International Clinical Psychopharmacology, 1996. 11: p. 187-191. (Ref 12)

Relevance: This study attempted to evaluate the safety of moclobemide-SSRI combinations but reported severe side effects, leading to the cessation of further research. It underscores the practical risks observed in clinical settings.

• Gillman, P.K., Serotonin syndrome: history and risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491. (Ref 38)

Relevance: This review provides a broader context on ST, including historical data and risk factors, making it essential for understanding the evolution of knowledge about moclobemide-SSRI interactions.

• Isbister, G.K., et al., Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. British Journal of Clinical Pharmacology, 2003. 56: p. 441-450. (Ref 60)

Relevance: This study examines moclobemide poisoning cases, detailing toxicokinetic profiles and ST occurrences, which are critical for understanding the dose-response relationship in toxicity.

These references are prioritized because they provide primary data (case reports, clinical studies), mechanistic insights (pharmacokinetic interactions), or authoritative reviews by the author, directly supporting the article’s claims about the dangers of combining moclobemide with SSRIs/SNRIs. They are essential for researchers studying this topic, as they cover clinical outcomes, pharmacological mechanisms, and historical context.

I challenged it by comparing low doses to a Mike's Hard Lemonade and high doses to a hard cocktail; and I said that the lemonade will not magically ferment into a hard cocktail.

Your skepticism about the absolute prohibition of combining serotonin reuptake inhibitors (SRIs) with moclobemide, a reversible monoamine oxidase inhibitor (MAOI), and your analogy to a ["Mike's Hard Lemonade"] versus a "hard cocktail" suggest you’re seeking a nuanced discussion about whether a safe dosage range could exist under specific conditions. While the article by Ken Gillman emphasizes significant risks of serotonin toxicity (ST) with this combination, let’s explore your query by addressing the possibility of a safe dosage range, the limitations of your analogy, and the pharmacological realities, grounded in the article and general pharmacological principles.

Addressing the Possibility of a Safe Dosage Range

1. Theoretical Basis for Low-Dose Combinations:

• The article acknowledges that theoretically, very low doses of an SRI (e.g., 5-10 mg fluoxetine) combined with low doses of moclobemide (e.g., 150 mg) might not immediately precipitate ST in some individuals, as seen in anecdotal reports (e.g., the forum user’s experience with 20 mg fluoxetine and 150 mg moclobemide). This is because ST is dose-dependent, requiring sufficient serotonin elevation to trigger toxicity.

• Moclobemide is a reversible inhibitor of monoamine oxidase A (MAO-A), with a shorter duration of action and less potent MAO inhibition compared to irreversible MAOIs (e.g., phenelzine). This reversibility theoretically reduces the risk of severe ST compared to irreversible MAOIs, especially at lower doses where MAO inhibition is partial.

• SRIs vary in potency and half-life. Less potent SRIs (e.g., citalopram) or those with simpler pharmacokinetics (e.g., sertraline, which has minimal CYP2C19 inhibition) might pose a lower risk than fluoxetine or fluvoxamine when combined with moclobemide at very low doses.

2. Pharmacokinetic Challenges:

• The article highlights that even low doses can become dangerous due to pharmacokinetic variability. Fluoxetine, for example, inhibits CYP2C19, which metabolizes moclobemide, potentially increasing moclobemide levels unpredictably. Moclobemide also inhibits CYP2D6, which can elevate levels of certain SRIs or other co-administered drugs, creating a “two-way street” of interaction (Ref 10: Dingemanse et al., 1998).

• Individual differences in CYP450 enzyme activity (e.g., poor vs. extensive metabolizers of CYP2C19 or CYP2D6) mean that a “safe” dose for one person might be toxic for another. The article notes that drug concentrations at the site of action can vary tenfold or more due to these factors, undermining the predictability of a safe range (Ref 14: Gillman, 2004).

• Fluoxetine’s long half-life (up to 10 days) and self-inhibition of metabolism (Ref 44: Harvey & Preskorn, 2001) can lead to accumulation over time, contradicting your analogy that the “lemonade won’t ferment.” This accumulation could elevate serotonin levels gradually, increasing ST risk even if the initial dose seems safe.

3. Clinical Evidence and Risks:

• The article cites multiple cases of ST, including fatalities, at therapeutic doses (Refs 34, 36: Neuvonen et al., 1993; Spigset et al., 1993). For example, Neuvonen et al. reported five fatal cases with moclobemide combined with citalopram or clomipramine, even in overdose scenarios, indicating that exceeding a narrow therapeutic window is highly dangerous.

• Early studies (Refs 11, 12: Hawley et al., 1996) exploring low-dose combinations reported severe side effects, leading to the abandonment of further research. The lack of recent studies (none in the last 15 years, as per the article) suggests that the risks outweigh potential benefits, and ethical committees have restricted such trials.

• The article’s author corresponded with researchers like Prof. Udo Bonnet (Ref 15), who treated only a few patients with this combination, encountered problems, and ceased its use, reinforcing that even low doses are not reliably safe in practice.

4. Your Analogy: Limitations:

• Your ["Mike's Hard Lemonade"] analogy assumes a stable, predictable effect (low alcohol by volume, ABV) that doesn’t change over time. However, unlike alcohol, the moclobemide-SRI combination involves dynamic pharmacokinetic interactions. The “ABV” equivalent (serotonin levels) can increase unpredictably due to enzyme inhibition, accumulation (especially with long-half-life SRIs like fluoxetine), or external factors like co-administered drugs or dietary influences.

• The “fermentation” risk isn’t magical but rooted in pharmacology: fluoxetine’s accumulation, moclobemide’s variable metabolism, and individual genetic differences can escalate serotonin levels over days or weeks, even at initially low doses. This makes the combination more like a drink with an unstable, potentially spiking ABV.

Could a Safe Dosage Range Exist?

• Hypothetical Conditions for Safety:

• A very low dose of a short-half-life, low-potency SRI (e.g., 5 mg sertraline or citalopram) with a low dose of moclobemide (e.g., 75-150 mg) might minimize ST risk in some patients, particularly those with extensive CYP2C19 and CYP2D6 metabolism.

• Close monitoring (e.g., plasma drug levels, clinical symptoms of ST like tremor or hyperreflexia) and avoiding other serotonergic agents or CYP450 inhibitors could further reduce risk.

• Short-term use (e.g., a few days) under specialist supervision might be less risky than chronic administration, where accumulation becomes a concern.

• Why It’s Not Feasible in Practice:

• Unpredictable Variability: The article emphasizes that pharmacokinetic variability (Refs 10, 14) makes it nearly impossible to define a universally safe dose. A dose safe for one patient could be toxic for another due to genetic or environmental factors.

• Lack of Evidence: No controlled studies have established a safe dosage range, and the few early studies (Refs 11, 12, 23, 24) were small, poorly designed, and reported adverse effects. The absence of recent research reflects a consensus that the risks are too high.

• Medico-Legal Risks: The article warns that physicians prescribing this combination face significant legal and professional consequences (e.g., lawsuits, being struck off), as ST is a predictable adverse event (Ref 1: Gillman, 2006). This deters clinical exploration of low-dose regimens.

• No Therapeutic Justification: Moclobemide’s ineffectiveness as an antidepressant (as argued by Gillman) and the availability of safer alternatives (e.g., other antidepressants or augmentation strategies) reduce the rationale for risking this combination, even at low doses.

Countering Your Skepticism

You might argue that careful titration and monitoring could mitigate risks, and that the article’s blanket condemnation overlooks individual cases where low doses were tolerated (e.g., the forum user’s experience). However:

• Anecdotal Success Isn’t Generalizable: The forum user’s short-term tolerance of 20 mg fluoxetine and 150 mg moclobemide doesn’t account for long-term risks or inter-individual variability. The article notes that such anecdotes are misleading and dangerous (Ref 14).

• Risk-Benefit Imbalance: Even if a narrow safe range exists for some, the lack of evidence for significant therapeutic benefit (Ref 15: Bonnet, 2004) and the availability of safer treatments make the combination unjustifiable.

• Pharmacological Complexity: The “lemonade” analogy underestimates the chess-like complexity of drug interactions (Ref 10). Unlike a static drink, the combination’s effects evolve over time, influenced by accumulation, enzyme inhibition, and external factors.

Conclusion

While a theoretically safe dosage range for combining very low doses of an SRI with moclobemide might exist in specific, tightly controlled conditions, the article and supporting references (Refs 10, 14, 34, 60) demonstrate that pharmacokinetic variability, unpredictable drug accumulation, and documented fatalities make this impractical and hazardous in clinical practice. Your analogy oversimplifies the dynamic nature of these interactions, as the “ABV” (serotonin levels) can indeed “ferment” over time due to pharmacological factors. The consensus, backed by the lack of recent research and ethical restrictions, is that the risks of ST outweigh any potential benefits, and safer alternatives should be pursued.

If you’re exploring this for research or clinical purposes, consider focusing on alternative augmentation strategies (e.g., lithium, atypical antipsychotics) or consulting a pharmacologist for experimental protocols under strict oversight. For further reading, prioritize Refs 10 (Dingemanse et al., 1998) and 14 (Gillman, 2004) for mechanistic insights and Ref 34 (Neuvonen et al., 1993) for clinical consequences. If you have specific scenarios (e.g., a particular SRI or patient profile), I can tailor the analysis further.

A post I recently made about 5-MeO-DMT is relevant. 5-MeO-DMT is an SRI and indeed Erowid and ICEERs published warnings about its usage with harmalas because of reports of toxicity;* interestingly, Murple, quoted above for an MDMA-rue retrospective, said that he wasn't comfortable trying 5-MeO-DMT-rue again.** However, there are some very positive reports of the combo ("I’ve done the combination with quite a few others and all of us had the best experiences ever.") and so I posted credible information that supports both the 5-MeO-DMT-harmala combo and the SRI-MAOI combo.

https://www.bluelight.org/community/threads/945031/post-16248836


*https://www.shroomery.org/forums/showflat.php/Number/28979413#28979413

**"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: An Experience with Pharmahuasca (Syrian Rue & 5-MeO-DMT). 2000-07-13. Erowid, exp2362 Afterword

 

[red22]

Jackpot!

          

In this study, rats were given paroxetine, fluoxetine, imipramine, or clomipramine after being given phenelzine* and only a minority of them died.

Marley, E., & Wozniak, K. M. (1984). Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake. Journal of psychiatric research, 18(2), 173–189. doi: 10.1016/0022-3956(84)90008-6

See 'Fatalities', p. 178.

Furthermore, the doses were ridiculously large. These are the doses after being translated to human doses, according to Grok:

Phenelzine: ~664 mg/day (vs. human therapeutic range of 15–90 mg/day, supratherapeutic).

Paroxetine: ~147 mg/day (vs. 20–50 mg/day, supratherapeutic).

Fluoxetine: ~124 mg/day (vs. 20–80 mg/day, supratherapeutic).

Imipramine: ~113 mg/day (within therapeutic range of 75–150 mg/day).

Clomipramine: ~126 mg/day (within therapeutic range of 75–150 mg/day).


*The same irreversible MAOI that the person quoted in the first post took, which was determined to induce 99% MAO-A inhibitoon by this study.

 

[red22]

Occasionally imipramine and an MAO inhibitor may be combined or one may be substituted for the other in order to produce a more effective therapeutic response. Potentiation or addition of toxic and possibly lethal effects may become a serious practical matter and pose many problems in management.

Luby, E. D., & Domino, E. F. (1961). Toxicity from large doses of imipramine and an MAO inhibitor in suicidal intent. JAMA, 177(1), 68–69. doi: 10.1001/jama.1961.73040270050013b

Summary:

A 30-year-old woman with depression attempted suicide after taking large doses of tranylcypromine (175 mg) and imipramine (275 mg). She became comatose, developed seizures, and had severe hyperthermia (temperature 105.6°F). She eventually recovered, though she had temporary memory loss and confusion. (ChatGPT)


In mental depression, new approaches could also combine both MAO inhibition and serotonin reuptake inhibition to increase extracellular 5-HT concentration at the synapses.

Structural Aspects of Monoamine Oxidase and its Reversible Inhibition. Johan Wouters. 1998. Current Medicinal Chemistry, vol. 5, #2, 136-162 Conclusions and Perspectives, p. 159

 

[red22]

Discussion on 2025-03-05 on reddit ⇩

I did plenty of cocaine last weekend been on Nardil for 3 months. I was actually totally fine and have abstained because I know the risk so took it easy at first. Only because I was drinking but do not plan on drinking for awhile because I was sober up until that point and getting back on the sober train because life’s better that way

No-Arm-4557


wow, ballsy.

I was "this close" to doing it a few months ago while on a bender. somehow stopped myself despite being beyond inebriated. I've regarded it since then as one of the biggest "close calls" of my life.

Wrong-Yak334


Nothing at all happened felt like cocaine before Nardil not recommending it at all but I think it might be abit over exaggerated (you will die) definitely more riskier. But think how many people are on maois and there doctor or psych don’t tell them. My doctor said absolutely nothing about drugs but I was on this forum but think there’s only 7000 in this forum and the amount of people are on maois and not on this forum. I’m sure a lot of prescribers inform them but I think there’d be a fair few like my doctor. Anyways cocaine isn’t really fun anyways hahahha first few then your just chasing the high so no point really risking it

No-Arm-4557


agreed about your last point.

I went through a phase similar to most people that lasted 6-9 months before I realized it's not really a fun drug. highly prefer alcohol personally, which has similar benefits but fewer costs.

Wrong-Yak334


I use to love MDMA but that just sounds way to fucking risky

No-Arm-4557


I took it once on Moclobemide but that was dumb as fuck and I beg anyone reading this not to follow in my idiotic footsteps

BoyBetrayed

⇩

There's also a moclobemide-MDMA report on YouTube:

Blog: Taking MDMA and a MAOI. @clandestinechemistry2861. 2018-08-17. YouTube

The person who uploaded this video included these two reports in the description:

Death following ingestion of MDMA (ecstasy) and moclobemide. Vuori, E., Henry, J. A., Ojanperä, I., Nieminen, R., Savolainen, T., Wahlsten, P., & Jäntti, M. (2003). Addiction (Abingdon, England), 98(3), 365–368. doi:10.1046/j.1360-0443.2003.00292.x

Serotonin toxicity involving MDMA (ecstasy) and moclobemide. Pilgrim, J. L., Gerostamoulos, D., Woodford, N., & Drummer, O. H. (2012). Forensic science international, 215(1-3), 184–188. doi:10.1016/j.forsciint.2011.04.008


I've combined rue with coke, 6-apb, various psychedelics, beer, benzos, amphetamines. Nothing bad has happened yet.

revive_iain_banks, 2024-03-10, https://www.reddit.com/r/harmalas/s/NcVGmfXO1u

 

[red22]

Occasionally imipramine and an MAO inhibitor may be combined or one may be substituted for the other in order to produce a more effective therapeutic response. Potentiation or addition of toxic and possibly lethal effects may become a serious practical matter and pose many problems in management.

Luby, E. D., & Domino, E. F. (1961). Toxicity from large doses of imipramine and an MAO inhibitor in suicidal intent. JAMA, 177(1), 68–69. doi: 10.1001/jama.1961.73040270050013b

Summary:

A 30-year-old woman with depression attempted suicide after taking large doses of tranylcypromine (175 mg) and imipramine (275 mg). She became comatose, developed seizures, and had severe hyperthermia (temperature 105.6°F). She eventually recovered, though she had temporary memory loss and confusion. (ChatGPT)

Comments from ChatGPT with Gillman's reversible MAOI-S(S)RI article (see post #8) used for support⇩

Connection between Luby & Domino (1961) and Gillman (2000/2024):

Both sources are addressing the hidden risk that acute (short-term) use may seem safe, but chronic (long-term) exposure can lead to severe, sudden toxicity.

From Luby & Domino (1961):

"Inasmuch as patients usually take these agents chronically a comparable study in animals using these agents over a period of days or weeks would be indicated."

Meaning:
They observed that a single overdose study underestimated the danger. Because chronic daily use could cause progressive changes (like receptor sensitization or neurotransmitter buildup), they warned that toxicity might appear later, even at regular doses.

From Ken Gillman (2000/2024):

"It is therefore inevitable that in some individuals small changes of blood levels, or dose, of a drug that inhibits P450 could elevate blood levels enough to precipitate ST in someone who previously appeared well and without problems on their previous dosage."

Meaning:
Gillman explains the mechanism behind that late-developing toxicity:

- Chronic use of a reversible MAOI (like moclobemide) + (S)SRI can initially seem safe.

- Subtle pharmacokinetic changes (such as enzyme inhibition from fluoxetine or moclobemide itself) can quietly increase drug levels over time — by twofold, fivefold, even tenfold — without any change in dosage.

- Result: someone tolerating a combo for weeks could suddenly tip into fatal serotonin toxicity — not because they overdosed, but because their body's ability to metabolize the drugs changed.

Key Parallel:

Luby & Domino (1961)	Gillman (2000/2024)
Acute toxicity studies are insufficient; chronic administration is riskier.	Blood concentrations can unpredictably rise over time even with fixed doses.
Chronic exposure may lead to sensitization/toxicity not seen acutely.	Pharmacokinetic shifts (like CYP450 inhibition) make chronic use dangerous.
They recommend chronic animal studies to reveal real risk.	He documents real human fatalities during chronic therapeutic dosing.

In short:
- Luby & Domino suspected delayed, cumulative toxicity from clinical observation and rat studies.
- Gillman confirmed it decades later, with modern pharmacokinetics and clinical case data: chronic dosing masks a growing danger until it suddenly explodes as serotonin syndrome.

Both show that acute safety does not guarantee chronic safety, especially with MAOI + serotonergic combinations.

[Quotes from Gillman's article ⇩]

1.

"It is therefore inevitable that in some individuals small changes of blood levels, or dose, of a drug that inhibits P450 could elevate blood levels enough to precipitate ST in someone who previously appeared well and without problems on their previous dosage."

Directly says: you can seem fine — then crash fatally without changing the dose.

2.

"Even at therapeutic doses, and most definitely following overdoses, one can get quite severe serotonin toxicity reactions and deaths have occurred."

Normal doses are not automatically safe. Toxicity can accumulate and erupt later.

3.

"Although the same dose is being ingested, the concentration of the drug at its site of action can vary by as much as tenfold or even more."

Blood levels can silently skyrocket without warning — a massive destabilizing factor over time.

4.

"This combination of Fluoxetine/Moclobemide is a perfect storm looming on the horizon."

Describes a real clinical situation where the patient is stable — but unseen drug accumulation sets them up for disaster.

5.

"Fluoxetine inhibits its own metabolism and has an unusually long elimination half-life of up to 10 days, thus blood levels can unexpectedly elevate via various mechanisms."

Fluoxetine’s weird kinetics create delayed and unpredictable toxicity — again, chronic use hides risk.

Shortest Summary:
Gillman shows that even if a patient feels fine for days or weeks, small hidden changes in metabolism can magnify drug levels enough to cause sudden, fatal serotonin toxicity without warning.

This is the exact biological mechanism behind the concern that Luby & Domino saw early in 1961 from pure clinical observation — but Gillman, by 2000+, can explain why and how it happens.

 

[red22]

Quotes ⇩

Moclo can be safely coadministered with SSRIs at moderate dosages so long as you monitor for blood pressure and occasionally monitor kidney function. I took moclo and paroxetine together for 2 years, but eventually had to stop because of mildly impaired kidney function. Once I stopped, kidneys immediately went back to normal.

EDIT: With irreversible MAO-A inhibitors like nardil, when combined with serotonin agents like SSRIs or SJW, there is the potential for lethal serotonin toxicity. This is the combination where you need extreme caution.

stinkykoala314, 2024-12-18, reddit.com/r/MAOIs

I should probably not mention this, but the most stupid thing was probably taking 30mg Citalopram in addition to 60mg [tranylcypromine] because I was wondering if I would even get Serotonin syndrome. That certainly didn't feel good. But aside from some nausea I didn't really have any adverse effects. Nothing serious and no myoclonus, either.

itsokaytowishtodie, May 29, 2023, reddit

The thing is, combining an SSRI with an MAOI (reversible or irreversible) has the potential for serotonin toxicity. Sure, there is variability: the degree of MAO inhibition, selectivity, and degree of serotonin reuptake inhibition determine whether ST it will occur. A useful question to ask is: why? Following up with researchers who published studies on such combinations, many patients discontinued because of lack of efficacy, symptoms of ST, or general side effects. (Gillman has posted about this in the past, although it may have been specific to irreversibles, it's been a while).

TechnicalCatch, 2024-12-18, reddit.com/r/MAOIs

Agreed completely with a careful consideration of risk vs reward, and taking the audience into account. But the possibility of serotonin toxicity is, without more context, not necessarily enough to constitute significant risk. My first post notwithstanding, irreversible MAOIs together with SRIs are the combination with known fatal potential, but in the vast majority of other cases, e.g. with paroxetine monotherapy or moclobemide with SRIs, when serotonin toxicity occurs, it is not an emergency situation, and has symptoms that are mild but uncomfortable and enough to signal to the patient / doctor that a change in regimen is warranted. Occasionally it can exhibit with the silent complications that I mention above, which is why I recommend moclo + SRI polytherapy have blood pressure and potassium / kidney function checks periodically.

That said, if you're talking about risk vs reward in my comment about irreversible MAOIs and SRIs, that's a very good point, and made much more effectively than the previous commenter. I'll update my original comment appropriately.

stinkykoala314, 2024-12-18, reddit.com/r/MAOIs

I'm also not sure how to respond. It is an empirical matter, and since we can't always specifically predict each individual's outcome, we have to go off of what is known to make generally correct predictions. Toxicity is dosage mediated, and of course full MAO inhibition isn't necessary; there simply has to be sufficient intrasynaptic serotonin to overwhelm its normal metabolism and allow it to overstimulate 5HT2A receptors. We don't have data on 5HT levels in humans experiencing toxicity, but it's been available and confirmed through the decades in rats. The type and degree of symptoms and the corresponding odds of lethality of various combinations of drugs correlates with what happens in humans. Unsurprisingly, the largest increase of 5HT, and the most lethal combination overall is overdoses of irreversible MAOIs+SSRIs (10,000% increase). Look up the article 'Tranylcypromine in Mind' for measurements of MAO inhibition by TCP. Even lower doses seem to be capable of nearly full inhibition. Irreversible MAOIs+SSRIs is just out of the question. The real question is how would you know what degree of inhibition someone has in order to cautiously administer an SSRI? It's just not possible, especially taking individual patient factors into account.

A reversible like Moclobemide won't be as potent as TCP, but the same principles apply. All that's needed is enough ligand binding occurring at the 2A receptor until progressively a potentially fatal hyperpyrexia develops. Moclobemide can be removed from the MAO enzyme, but this isn't guaranteed to happen at any particular consistent rate, otherwise the drug would be completely useless. We know that life threatening toxicity can happen even at therapeutic doses because it has happened, but individual factors make it impossible to predict at what point it might happen. This makes the risk vs. reward proposition untenable.

The HATS database in Australia has possibly the best collection of toxicology data going back to the 1980's. In a review of patients admitted to hospitals in the region "11 of 21 cases of co-ingestion of moclobemide with an SRI developed ST and in 6 of these 21 severe ST developed with a temperature >38.5°C and muscle rigidity requiring intubation and paralysis and treatment with 5-HT2A antagonists". [Gillman K. (2004). Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). CNS drug reviews, 10(1), 83–88. https://doi.org/10.1111/j.1527-3458.2004.tb00005.x]The real crux of the matter to me is the pharmacokinetic variability that exists. Gillman notes that for this reason the concentration of a drug can vary 10 fold or more between persons. He discusses fluoxetine as the prime example of why Moclobemide+SSRI is a very bad idea:

"First, there is no doubt that a therapeutic level of any SRI combined with a high therapeutic level, or small overdose, of moclobemide is capable of inducing fatal serotonin toxicity...Fluoxetine is the worst possible choice for an SSRI to combine with moclobemide (fluvoxamine comes a close second) because it is a potent inhibitor of several cytochrome P-450 enzymes including 2C19, which is responsible for metabolizing moclobemide. In such situations potently inhibiting these enzymes can increase blood levels of drug to the equivalent of those in persons who have taken a small overdose (and thus produce a risk of severe ST). The situation may be further complicated by other drugs in the patient’s regime which affect blood levels of either fluoxetine or moclobemide, because in this particular instance not only will fluoxetine inhibit moclobemide metabolism but also moclobemide will inhibit the metabolism of fluoxetine making it a two-way street. So any other drug which raises blood levels of either fluoxetine or moclobemide (of which there are plenty) can potentially start the snowball rolling. The chess-like complexity of this situation is yet further magnified by the fact that fluoxetine inhibits its own metabolism and has an unusually long elimination half-life of up to 10 days, thus blood levels can unexpectedly elevate via various mechanisms...A double dose taken by mistake and various other circumstances might easily lead to a fluoxetine or moclobemide level that unexpectedly becomes considerably higher than usual."

Thanks for reading.

vividream29, 2024-12-09, reddit.com/r/MAOIs