Hoasca, dimethyltryptamine (DMT), and the US Supreme Court

As we approach 100,000 visitors since joining ScienceBlogs I am amazed to still be getting 500-700 visits per month at the old home of Terra Sigillata, all without any promotion or new posts. The most-visited of the old posts is the following which appeared originally on 21 February 2006.

Much of humankind's experience with pharmacologically-active natural products has been through the mind-altering effects of plants used in religious ceremonies.

Today [21 Feb 2006], the US Supreme Court upheld a decision to permit a New Mexico sect of a Brazilian religious order to continue using an herbal hallucinogenic tea for religious purposes despite the fact that the tea contains a US DEA Schedule I controlled substance (N,N'-dimethyltryptamine). Schedule I substances are classified as compounds that have no recognized medical value in the United States.

I had heard that the Supreme Court was moving toward support of faith-based groups, but this one was a surprise to me, particularly given the unanimous decision in favor of the defendants (8-0 since the recently-confirmed Justice Alito could not participate in rendering the decision).

The precedent for protecting these rights is the 1993 Religious Freedom Restoration Act.

The Wikipedia entry on the case is pretty accurate and a great reference on the political side of this story. But let's address the fascinating pharmacology of this ethnobotanical hallucinogen (entheogen).

The Hoasca hallucinogenic tea, more appropriately called Ayahuasca, is made from stems of the vine Banisteriopsis caapi together with the leaves of Psychotropia viridis (in Brazil, Peru, and Ecuador) or Diplopterys cabrerana (in Ecuador and Colombia). The latter two plants contain the hallucinogen, DMT, a serotonin analog that stimulates 5-HT_2A receptors similar to LSD. However, DMT alone would normally be very quickly metabolized in the liver by monoamine oxidase A (MAO-A) such that little of the compound, if any, could get to the brain.

Hoasca or Ayahuasca
The key plant is B. caapi which is not hallucinogenic on its own. Instead, B. caapi contains beta-carboline compounds that inhibit the liver's ability to destroy the DMT. Most important among these is a compound called harmine, a well-characterized MAO inhibitor. In pharmacology, one would say that harmine potentiates the hallucinogenic effect of DMT. As a scientist, I am in awe of the South American cultures that discovered this concoction long before we had HPLCs and mass spectrometers.

The bottom line is that without harmine, one does not hallucinate from ingesting DMT orally. But before my counterculture friends start converting to the Santo Daime or Uniao do Vegetal, there are some very serious considerations.

Although hallucinogens are rarely associated with fatal events directly, there has been at least one well-documented death associated with this herbal concoction. The cause of death was undetermined in this case, but one might hypothesize a scenario whereby the cause related more to the MAO inhibitor part of the herbal cocktail than to the hallucinogen itself.

MAO does not exist in our livers (and in the mitochondria of our neurons) to allow us to experience hallucinations. The primary purpose of MAO is to destroy blood pressure-raising chemicals from both our diet and our own nervous systems that, if allowed to accumulate, could kill us. One of the dietary forms of these chemicals is called tyramine.

If your MAO is inhibited and you eat foods rich in tyramine (such as aged cheeses or red wines), you could conceivably go into a hypertensive crisis and die.

A Modern Confounder of Risk-Free Hallucinations
But, there is a modern contributor to this well-known drug-food interaction that might be underestimated. Many antidepressant drugs inhibit another liver enzyme that breaks down harmine...it's called CYP2D6. Many antidepressant drugs known as SSRIs act to inhibit CYP2D6 and some of these could thereby prolong the MAO inhibitory action of harmine.

So, let's say you're battling with the dog of depression and taking an SSRI like Prozac or Paxil and you're fond of red wine and cheese. Not uncommon, especially in academia.

But let's say you also get religion...the South American kind...the kind that uses Ayahuasca in their Nativity celebrations. You take a batch of the ceremonial tea and the harmine inhibits DMT metabolism by MAO - good thing: religious hallucinations.

However, the SSRIs you're taking also inhibit the liver's breakdown of harmine by CYP2D6. It's possibly that you might experience longer or more intense hallucinations than someone not taking an SSRI. Not a problem until you reach for the 1990 Chateau Montrose and some nicely aged pecorino (I know it's a stretch but bear with me..there's only been one reported death thus far). Massive amounts of tyramine get into your bloodstream, speeding your heart rate while also causing your blood vessels to constrict. As pathologists are fond of saying, this is a situation that is incompatible with life.

In fact, this was not such a far fetched scenario 20 years ago since MAO inhibitors were used widely as antidepressant drugs (and still are in some very serious cases) and patients would be given a long list of foods to avoid for this very reason.

This issue can be even more complicated since some of us are already set up genetically to be slow or fast metabolizers of drugs like harmine. CYP2D6 activity varies quite a bit across ethnic groups and individuals, with some people being much more sensitive to harmine overload. Not surprisingly, the high priest-equivalent in the Uniao do Vegetal faith gets to know fellow worshipers well enough to provide them with the proper dose of hallucinogen based upon past experiences.

Yes, you've got it: ancient South American religions knew about pharmacogenetics long before we knew the structure of DNA.

So, the health danger of this hallucinogenic tea is real, albeit rare. But isn't it surprising that an inappropriate mix of ancient and modern culture and medicine could theoretically lead to fatal outcomes for a practice meant to bring one closer to their god?

Hearty congratulations to the faithful who have won this battle, but caution to those wishing to exploit this win for recreational purposes.