Entheogen and hallucinogen, N,N’-dimethyltryptamine (DMT), identified as endogenous ligand for sigma-1 receptors

Welcome 4 March readers of The Daily Grail – please be sure to also click on the original post about the DMT article by my colleague, Laura Mariani.
ResearchBlogging.orgThanks to Dave Munger & Co’s ResearchBlogging.org, I just found a fabulous neuroscience grad student blogger from Emory University: Laura E Mariani at Neurotypical?
Doctor-to-be Mariani blogged last Monday about a paper in Science where the endogenous ligand of the orphan sigma-1 receptor was identified as the hallucinogen, N,N’-dimethyltryptamine, or DMT. The work originated with the group of Arnold Ruoho and colleagues at the University of Wisconsin’s Depts of Pharmacology and Physiology, together with a collaborator at the Isfahan University of Technology in Iran.
As an aside, what blows me away is that the first author on this publication, Dominique Fontanilla, is a graduate student in the UW Molecular and Cellular Pharmacology training program. The funding acknowledgment suggests that she was on an NIH institutional training grant and then scored her own individual predoctoral NRSA from the National Institute on Drug Abuse. It appears that she also has a background in synthetic chemistry that extends back to her Sigma Xi-recognized undergraduate work at Carleton College in Minnesota. If anyone is looking for a stellar postdoc candidate in this field (*cough* DrugMonkey), you’d better get in line now.
Anyway, as a neuroscientist, Laura tells the story far better than I can so you should go to her post to read the details.
Where a natural products cancer pharmacologist gets interested in this story is its intersection with plant-derived medicines – 25% of today’s pharmaceuticals can be traced to natural sources, I recognize that the history of my discipline lies in the ethnobotany of indigenous cultures and their religious and ritual use of plant compounds with hallucinogenic effects of other activities in modulating the central nervous system. Hallucinogens used culturally in religious rituals are often called entheogens (loosely translated as “creating god within”).

DMT is a naturally-occurring analog of serotonin, or 5-hydroxytryptamine, the neurotransmitter we try to manipulate with many antidepressant therapies. Many serotonin-like molecules, the most famous being LSD, have the potential to more dramatically influence our perception of reality than the neurotransmitter itself. Interestingly, we make very small but detectable amounts of DMT.
Where DMT is most famous, however, is as part of plant-derived hallucinogen cocktail called ayahuasca or hoasca used by the religious group, the União do Vegetal (more precisely the Centro Espírita Beneficente União do Vegetal or UDV.). I wrote awhile back about New Mexico-based UDV community that won the right to use their traditional plant brew containing DMT in a 21 Feb 2006 US Supreme Court decision citing protection of the group’s activities under the 1993 Religious Freedom Restoration Act.
Here was my description at the time of the Ayahuasca tea:

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-HT2A 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.
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 reader will note that I cited DMT’s effect at serotonin 5-HT2A receptors. In other recent work, DMT has also been found to act on trace amine-associated receptors, or TAARs. However, it appears that a combination of in vitro and in vivo results, particularly behaviorial hypermobility studies in sigma-1 receptor knockout mice, is suggestive that DMT acts primarily on sigma-1 receptors.
I’m not qualified to delve too much into the therapeutic potential of these discoveries but the sigma-1 receptor may represent a unique opportunity to develop new drugs for schizophrenia and other debilitating psychotic disorders. For example, it was news to me from the Ruoho paper that the antipsychotic drug haloperidol (Haldol®) binds with very high affinity to sigma-1 receptors even though its therapeutic activity has long been attributed to its antagonism of dopamine at central dopamine D2 receptors.
Finally, Fontanilla et al. hypothesize that other dimethylated serotonin-like compounds may also exert their effects at sigma-1 receptors. For example, N,N’-dimethylserotonin, or bufotenine, is another compound with hallucinogenic activity that has been also been observed at elevated concentrations in the urine of patients with schizophrenia.
If the prefix “bufo” rings a bell to you, you’ll think of the genus name for toads: bufotenine (and 5-methoxy-DMT) is secreted from the skin of many toads (Cane, Colorado River, Sonoran Desert toads). Toad licking or smoking of toad skin is a favorite hallucinogenic pastime of individuals in the desert southwest US, Mexico, and Australia.
I’ll leave a scholarly treatment of toad licking and toad smoking for another day.
The fact that we are now finding a common mechanism for entheogens and hallucinogens reveals once again the awesome power of natural products in the discovery of the pathophysiology and pharmacotherapeutics of human diseases.

D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, A. E. Ruoho (2009). The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science, 323 (5916), 934-937 DOI: 10.1126/science.1166127


6 thoughts on “Entheogen and hallucinogen, N,N’-dimethyltryptamine (DMT), identified as endogenous ligand for sigma-1 receptors

  1. Thanks for this post.
    In your cited (previous) post, you wrote “As a scientist, I am in awe of the South American cultures that discovered this concoction long before we had HPLCs and mass spectrometers.” I feel the same way. As I recall, manioc was the staple starch for an ancient culture. The stuff can only be (safely) eaten after the sap is squeezed out of it. Who discovered that?
    On the other hand, the Chinese project that looked at traditional remedies for malaria screened more than 100 herbs and only found one that could be effective (http://www.ncbi.nlm.nih.gov/pubmed/16722826?ordinalpos=21&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum). I say “could” because it is notable that the active ingredient (artemisinin) is not always produced by the plant.
    Finding a useful drug from 1% of products tested is great, going to a traditional healer and only having a 1% chance of receiving an effective product is not great.
    My point is that traditional preps truly have delivered some astonishing stuff; but, I suspect they provide many more misses than hits. That goes for everything- bloodletting, scalding, purgatives …; the list is long.
    Is there a summary of the reliability of ethnobotany for discovering drugs identified as such by ethnobotanists. (I do not count drugs that are useful against A that were promoted as remedial for B.) Do we have any idea?

  2. Great blog!
    For those who want to see molecular pictures of bufotenin and some other 5HT2A ligands, see – http://www.bio-balance.com/5HTPICTSmall.htm and for those who are interested in how they bind to their target receptors to produce a response, see – http://www.bio-balance.com/BB5.html ,and more generally, http://www.bio-balance.com/Ref.htm and http://www.bio-balance.com/GPCR_Activation.pdf
    This is definitely a fascinating area of pharmacology that will be explored for many years to come. Just the fact that a miniscule amount of a particular chemical substance can radically alter our physiology is both a scientific and philosophical issue that needs further exploration for us to truly understand these very complex issues.

  3. As a researcher don´t you feel any responsability.You remind me of the LSD-professors of some US Universities in the beginning of the sixties.You MD:s always think you are so smart.Cocain against hangovers.The invention of amphetamin,LSD,destilled alcohol,barbiturates,heroin,morfin,pills that make you happy,and alot of other dangerous drugs.Now it is DMT.If the state pays you to write some propaganda against cannabis many of you will.This plant is the devil and what you promote is the gate to heaven.You may fool the world but not me.Say Hi to your alien friends but don´t experiment with people that already have problems with the conception of reality.I like to smoke weed if it doesn´t suit you nobody forces you.But if you work for big buissiness or the state you can manipulate people with dangerous drugs.I wouldn´t even by a headache pill from somebody like you,DMT the strongest psychedelic drug to mental patients.Who is insane?You?Me?Your patients?

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