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Modified from the section on drug interactions in Chapter 6 (mescaline pharmacology):

Harmine was said to augment the effects of mescaline in animals by Kapadia & Fayez 1970 citing Hoshikawa 1962

While not yet obtaining a copy of Hoshikawa 1962, two interesting points were made in the 1964 Chemical Abstracts.

One is that mescaline accelerates conditioned avoidance responses in rats and was antagonistic to many tranquilizers' effects on conditioned avoidance response. Harmine (termed an extrapyramidal poison) augmented mescaline's acceleration of conditioned avoidance responses.

The other is that mescaline showed a marked antagonism to harmine in terms of both motility and tremors.

There are many statements in the literature concerning the danger of mixing phenethylamines with MAO inhibitors. This is similarly true for cheese, alcohol, pickled foods, smoked foods, many herbal products and a long list of common food items that can cause this potentially fatal reaction when mixed with prescription MAOIs. The emphasis on phenethylamines, to the exclusion of everything else, is a most peculiar bias.

This is due to the potential of a `hypertensive crisis'. There is at least one case on record of an emergency room admission involving a prescription MAOI combined with ecstasy. While this is not a good combination, it should be pointed out that no deaths have been reported from this particular combination (at least none that I are aware of; if in error, I welcome being corrected.). Clearly the effects were found quite distressing by the people who combined them, as well as extremely alarming to those who observed them.

I do not suggest this combination, and while strongly discouraging it, I do want to point out that the published assertion that combining Ecstasy and MAOIs will "kill your ass real quick" are at the very least hyperbole [See Note 1].

Perhaps it is pertinent to note that there have been a several instances where several people have deliberately combined the reversible MAOI moclobemide with MDMA. No adverse reactions appear to have been reported (other than a strong per dose increase in activity) but this is still a relatively unexplored area based largely on anonymous reports.

One case, appearing in the literature, was reported in the 1987 Journal of Toxicology. Clinical Toxicology, authored by Martin J. Smilkstein, Susan C. Smolinske and Barry H. Rumack; entitled "A Case of MAO Inhibitor / MDMA Interaction: Agony After Ecstasy."

It is interesting reading although it might be added that this person combined MDMA along with their prescription (irreversible) MAOI as well as alcohol.

The potential of danger from sharp and high peaks of blood pressure induced from this combination is real. (Possibly inducing such undesirable and potentially fatal things as aneurysms.) [This reaction results from an excessive release of serotonin and noradrenaline. Potentially serious problems resulting from such MAOI and sympathomimetic amine interactions include hypertensive crisis, hypertonicity, severe hyperthermia and intracranial hemorrhage. See Smilkstein et al. 1987]

However, while not recommending careless or random experimentation, the automatic assumption that the danger also applies to harmine (or moclobemide) has not been proven. The presented notion that it is better to err on the side of caution is indeed a good one to serve in practice but does not substitute as proof.

[Jonathan Ott also discusses this and has been taken to task as being irresponsible for doing so, quite unjustifiably, by some good intentioned but underinformed individuals with publication access.]

Several things indicate that such a blanket assumption is in need of a closer evaluation.

First, prescription MAO inhibitors are mostly nonspecific, meaning they inactivate all forms of MAO. Harmine is highly specific, acting only appreciably on one type of MAO (MAO-A). Similarly mescaline apparently exerts its effects only on one subclass of postsynaptic receptors, the 5-HT₂ receptors. It does not share the broad receptor interactions that are observed in drugs like LSD, or even Ecstasy.

Second, many MAOIs are non reversible and thus long lasting. They actually covalently bond to MAO, not simply inactivating them but requiring the body to synthesize entirely new enzymes as their replacement. The action therefore persists for weeks; even after the drug is discontinued. (This lengthy time to clear the system is also true for SSRIs)

Harmine is highly reversible as it does not covalently bind to the enzyme and its effects last only a few hours. Cheese reactions to harmine have been demonstrated not to occur [The limited data points seem to support this See Note 2] (Drugs which do cause this dangerous interaction affect both MAO-A and MAO-B.)

(Caution should be urged in combining any suspected food or drug, most especially alcohol, with any MAOI, even with harmine. But I would urge caution not rampant paranoia.)

However, the most important point that could possibly be made on this subject has been already made by Jonathan Ott. Namely, that phenethylamines such as mescaline are known to have been nonfatal in combination with harmine by humans.

Jonathan Ott 1994 "Ayahuasca Analogues." mentions that a European psychonaut had conducted two separate trials combining mescaline with 150 mg. of harmaline hydrochloride (2 mg/kg) [determined to actually be a mixture of harmaline-harmine (2:1)]. They obtained sub-threshold effects using a dose of 60 mg. (0.78 mg/kg) of mescaline hydrochloride and definite threshold effects with 100 mg. (1.32 mg/kg) of mescaline hydrochloride. [They had also combined harmaline with 2,4,5-trimethoxyphenethylamine for no effect.] See also Shulgin & Shulgin 1997, pages 451-452, or more details.

Similarly Claudio Naranjo 1973 [in Harner (ed.); page 180] reported on the visionary experience of a subject who had combined "a fairly large amount of harmaline with the addition of mescaline." [Amount was not specified for either alkaloid.]

Ayahuasca Analogs and Plant-based Tryptamines, several bioassays were described in which the psychonauts combined harmala alkaloids with San Pedros. All reported a rough doubling of effects and the introduction of a, to be expected, sedative component.

While this demonstrates that some people have combined the two successfully with no apparent toxic effects this still is not proof that it is safe. There is presently a small pool of successful bioassays but it is not large enough to predict adverse reactions. Only once the number gets into the hundreds of thousands of such REPORTED experiences will we be able to get a good overview. Until then, a slow and cautious approach is urged, with all practitioners attempting to share their experiences, good or bad, however they can.

An important point concerning Smilkstein's observations concerning the MDMA/MAOI interaction which ended up in the emergency room was that, despite showing common signs of MAOI overdose (slurred speech, diaphoresis, hypertension and hypertonicity), and despite their attempted treatment being ineffective, their patient showed a complete and uneventful recovery after a 5-6 hr total duration of adverse effects.

Another point is that this person's reaction involved an irreversible MAOI. And also an unspecified amount of alcohol.

Multiple human evaluations involving the combination of the reversible MAOI moclobemide with 2C-B and also with MDMA have occurred and apparently none have resulted in any adverse reactions. There is one report of a bad experience when a person combined it with 150 mg of DMT but 150 mg of DMT can and should be expected to be an unpleasant dosage level for most people even without an MAOI.

Accounts of synergy between moclobemide and cocaine, and also moclobemide and methamphetamine, have also been reported. This is still fairly new territory and should be approached with some caution

This does not suggest reckless or casual experimentation is in order, just that the aforementioned drug combinations have occurred without apparent problems.

If someone doesn't do it first, the plan is to evaluate a 200 milligram mescaline equivalency of San Pedros or crystalline mescaline with harmine/harmaline isolated from Peganum harmala. The question, of whether potentiation of a sub-threshold dosage of mescaline by harmine would be enable it to be fully active, is really intriguing.

Ott 1994 also notes that an Epiphyllum species and an Opuntia species are used by the Peruvian Sharanahua as ayahuasca additives. Both are mentioned in Rivier & Lindgren's 1972 listing of ayahuasca admixtures. [See Note 3]

Rivier & Lindgren mention that the Sharanahua call the Opuntia "Tchai" and consider it to be hallucinogenic. It is apparently cultivated for this purpose. The plant was said to have been originally brought to Marcos (Peru) by the Amahuaca living on the Inuya River. No voucher was made nor has chemical analysis been performed. The mixture is said to be very strong and to never be used medicinally.

Bianchi & Samorini 1993 state that its current use as an ayahuasca additive has apparently died out for being "too intense" and it's raw juice is now used on its own for hallucinogenic purposes, by some Shipibo and Amahuaca shamans. A photograph of the plant can be found on page 38 of their article.

More recently R. Stuart undertook an expedition to Peru visiting the source of Bianchi's information. He was able to locate the plant, obtain herbarium vouchers and positively identify it as Brasiliopuntia brasiliensis (AKA Opuntia brasiliensis)
After multiple bioassays (guided and independent) plus an additional bioassay using a good dose of Peganum harmala seeds, yielded no effects, Stuart surmised that the ethnobotanists had been provided with false information.

Small amounts of mescaline have been identified in a number of Opuntia species at levels too low to normally be physiologically active. See under Opuntia in "Mescaline Containing Species." above. [Rivier & Lindgren 1972 also refer to Lewin 1888.]

Very few members of the enormous genus Opuntia have been analyzed. With the exceptions of hordenine being observed in the Uruguayan Opuntia aurantiaca Lindley and O. maldonesis Engelmann, by DeVries and coworkers 1971, and 3-methoxytyramine in the Chilean O. subulata (Mühlenpfordt) Engelmann, by Meyer and associates 1980, all Opuntias analyzed have been North American (some species of which occur as far south as Central America). ...

...many Tephrocacti resemble a number of depictions of spotted and small jointed Opuntias found depicted in ritual or supernatural context on ceramic vessels, and should be targeted for assay. Interestingly, the small globose species of Opuntias have, thus far, shown the highest alkaloid levels.

When describing the work of Federico Falco and Sebastian Hilburg, who examined a number of Argentinean Opuntias, the 1949 Chemical Abstracts notes; "The presence of alkaloid was demonstrated in every sample." No further analysis or characterization appears to have been done.

Only one leaf of the Epiphyllum species is used as an additive to ayahuasca or else its unboiled juice is drank along with the prepared hoasca. The Sharanahua are said to call it "Pokere" and the Culina to refer to it as "Wamapanako". Homer Pinkley 1969 notes that there is an herbarium voucher of the Epiphyllum (made by L. Rivier and I. Rüff) present in the Economic Herbarium of Oakes Ames at Harvard and that the Sharanahua call it "Pukara".

On page 12 of the 1997 Summer Solstice issue of the Entheogen Review a reader noted that in the aphrodisiac section of "Mastering Herbalism" it was claimed that "high doses" of a water extract of Epiphyllum oxypetalum could cause hallucinations. This turned out to be in reference to another cactus entirely (personal communication with Jon R. Hanna) and the original source was a vaguely worded comment in Grieve's Herbal so we would suggest it may be meaningless.

Epiphyllum spp. have not been determined to contain mescaline but none appear to have been looked at in recent times. Heffter's turn of the century screening is the sole entry in the literature I have been able to examine. They are quite popular for their flowers; and intense and competitive hybridization has focused on this genus.

While mescaline itself has not been identified in either plant, it IS noteworthy that when alkaloids do occur in cacti it is most often as phenethylamines.
Many of the most commonly reported ones have far greater pressor effects than does mescaline. This factor also holds true for peyote alkaloids other than mescaline, most of which are far more toxic and some of which show greater pressor effects than does mescaline.

Further, they would interact with a broader range of receptors, are present far more commonly in physiologically active concentrations than mescaline is and, if using the exact same rationale currently contraindicating mescaline, would pose considerably more risk if combined with a Monoamine Oxidase inhibitor.)

Due to the use of the grass Phalaris arundinacea as a component of modern ayahuasca analogs, it is almost certain that hordenine, a not infrequent alkaloid present in decent amounts in numerous strains of this species, has been ingested as a component of brewed ayahuasca. While this is a subject that is unlikely to have generated any documentable proof, a disturbing percentage of its consumers appear oblivious to the fact that a number of distinct chemical species exist in this species and, overall, relatively few of its suppliers have any real clue what is in the generic version of this species of grass they sell seeds for. As a result a wide variety of Phalaris species and strains are being grown and ingested, often without the desired results.

On the other hand, an increasing number of people DO know what they have and focus on propagating the better strains. In most cases they will be named but some appear to be in-house strains selected based on bioassays.

A variety of mostly phenethylamine type alkaloids, including mescaline and b-hydroxymescaline, have been detected, also in similarly low amounts, from a number of the more primitive epiphytic cactus species. [i.e. Pereskia spp. (See in Ch. 4; "Mescaline Containing Species." )

b-hydroxymescaline is thought to be inactive as a hallucinogen but has apparently seen no evaluations in humans (at least none that were published)

It has been determined to be pharmacologically active, but not hallucinogenic, using animal models.

Similarly a Pereskiopsis sp. has been found to contain a variety of alkaloids including low concentrations of mescaline. [In spite of their primitive nature (as with Pereskia they also still bear distinct leaves), Pereskiopsis species are more closely allied with Opuntias than with Pereskia.]