5-MeO-DMT, Toad Secretions, and the Entourage Effect

5-MeO-DMT is only part of the story for understanding the effect of toad secretions.

May 16, 2019 -

Both the plant and animal worlds are sources of the psychoactive tryptamine compound 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine). It was first described in plants in a member of the family Rutaceae called Dictyoloma incanescens.1 It is also found in high concentrations in the parotid gland secretions of the Colorado River toad Bufo alvarius.2,3 A 2010 review article cites several references indicating 5-MeO-DMT has been detected in human urine, blood, and cerebrospinal fluid and may also be synthesized in the retina, pineal gland.2 In fact, elevated levels of 5-MeO-DMT and its analogs have been detected in the body of fluids of people suffering from psychiatric disorders such as schizophrenia.

Interestingly, researchers are finding that 5-MeO-DMT is only one of many compounds in so-called toad venoms. Just like psilocybin mushrooms, it’s the influence of all the compounds in toad secretions that is responsible for the overall psychedelic experience for the user. For example, a 2018 study found that a 50 mg dose of vaporized bufotoxin secretions (containing about 5-7 mg of 5-MeO-DMT) from B. alvarius gave the same intensity of mystical experience as a high dose (30 mg/70 kg) of pure psilocybin.4 However, there was a significant increase in the intensity of the mystical experience from the vaporized toad secretions compared to a moderate/high dose (20 mg/70kg) of pure psilocybin.  The latter result shows that the mixture of compounds in the toad secretions was more potent than the moderate/high dose of pure psilocybin in creating a full mystical experience. Therefore, an experience with 5-MeO-DMT alone would not be expected to have all the effects and possible benefits of the complete, naturally-occurring mixture of compounds in toad secretions.

Here are two examples of the different compounds found in the secretions of B. alvarius. As part of the first study, the researchers analyzed five samples of secretions for the levels of several compounds. The ranges of each compound per 1 gram of dried secretion were:3

  • Tryptamines –
    • 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) = 203.6 – 307.3 mg/g
    • Bufotenin (5-HO-DMT) = 0.600 – 3.530 mg/g
    • DET (N,N-dimethyltryptamine) = 0.415 µg/g (detected in only one sample)
    • DMT (N,N-dimethyltryptamine) = 0.016 – 0.041 mg/g
    • NMe-5-HT (N-methylserotonin) = 0.014 – 0.171 mg/g
  • Steroid Lactones –
    • Bufogenin = 0.005 – 0.013 mg/g (four samples)
  • Tryptophols –
    • 5-MeO-tryptophol (5-MTOH or 5-methoxytryptophol) = 0.696 – 3.053 µg/g

Secondly, a 1967 study found the following compounds in the skin of B. alvarius:5

  • bufotenin
  • bufoviridine
  • O-methylbufotenine (another name for 5-MeO-DMT)
  • 5-hydroxytryptophol
  • 5-hydroxyindoleacetic acid
  • 5-methoxytryptophol
  • 5-methoxyindoleacetic acid

In addition, Alexander and Ann Shulgin documented that B. alvarius secretions can be up to 15% 5-MeO-DMT.1 Also, they say that 5-MeO-NMT, N-methyl-5-methoxytryptamine, and bufotenine are other components of the secretions of this species.

Evidence Supporting the Entourage Effect in Toad Secretions

The entourage effect is a term that originated in medical marijuana research. It describes a phenomenon where compounds act together synergistically to modulate the overall effects. In other words, compounds can increase (or decrease) the potency of others (and have other influences) by acting as allosteric modulators of receptors, molecular transporters, and enzymes. At this time, there is no direct evidence supporting that the entourage effect is at work with toad secretions. However, there is indirect evidence supporting the hypothesis.

The entourage effect exists in the world of magic mushrooms. In one of his papers, researcher Jochen Gartz saw the entourage effect emerge around the compound aeruginascin when he studied the data from 24 accidental mushroom poisonings.6 He concluded, “Aeruginascin seems to modify the pharmacological action of psilocybin to give an always euphoric mood during ingestion of the mushrooms.”

G-protein coupled receptors (GPCRs) are some of the most ubiquitous receptors in nature, and the scientific literature is brimming with studies that show their role in the allosteric modulation of cellular functions. The compounds in marijuana, magic mushrooms, and toad secretions all have an affinity for GPCRs, some more than others. In particular, magic mushroom compounds bind to serotonin 5-HT2A receptors which elicits their psychedelic effects,7 5-MeO-DMT is also known to work primarily via 5-HT2A,8 and there is experimental evidence that shows cannabidiol interacts with GPCRs.9 And, other compounds in toad secretions like bufotenin are agonists of 5-HT2A receptors.2

To sum it up, the entourage effect almost certainly plays a role in the effects of toad secretions. This is because several of the compounds are known to be agonists of the serotonin 5-HT2A receptor, which is subject to allosteric modulation like other GPCRs. Also, studies have shown that the effects of chemically similar compounds like serotonin and other tryptamines can be changed through allosteric modulation of GPCRs like 5-HT2A. The fact that the entourage effect has been documented in nature for other compounds like those found in magic mushrooms and cannabis also adds credence to extrapolating this theory to toad secretions.

Conclusion

Ingesting 5-MeO-DMT alone is not the same as the complete, naturally-occurring cocktail of compounds in toad secretions. Researchers are finding more compounds in the secretions of B. alvarius, including steroid lactones, tryptophols, and additional tryptamines. The consistencies that scientists see in the natural world suggest the entourage effect that modulates the effects of compounds in marijuana and psilocybin mushrooms is probably also at work in toad secretions.

    References
  1. Shulgin A, Shulgin A. TiHKAL: The Continuation. First Edition. Berkeley, California: Transform Press; 2002.
  2. Shen H-W, Jiang X-L, Winter JC, Yu A-M. Psychedelic 5-Methoxy-N,N-dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions. Curr Drug Metab. 2010;11(8):659-666.
  3. Uthaug MV, Lancelotta R, van Oorsouw K, et al. A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms. Psychopharmacology. April 2019. doi:10.1007/s00213-019-05236-w
  4. Barsuglia JP, Davis AK, Palmer R, et al. Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study. Front Psychol. 2018;9. doi:10.3389/fpsyg.2018.02459
  5. Erspamer V, Vitali T, Roseghini ML, Cei JM. 5-Methoxy- and 5-hydroxyindoles in the skin of Bufo alvarius. Biochemical pharmacology. 1967;16(7):1149-1164. doi:10.1016/0006-2952(67)90147-5
  6. Gartz J. Analysis of aeruginascin in fruit bodies of the mushroom Inocybe aeruginascens. International Journal of Crude Drug Research. 1989;27(3):141-144. doi:10.3109/13880208909053954
  7. Nichols DE. Structure–activity relationships of serotonin 5-HT2A agonists. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 2012;1(5):559-579. doi:10.1002/wmts.42
  8. Krebs-Thomson K, Ruiz EM, Masten V, Buell M, Geyer MA. The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats. Psychopharmacology. 2006;189(3):319-329. doi:10.1007/s00213-006-0566-1
  9. Laun AS, Shrader SH, Brown KJ, Song Z-H. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacologica Sinica. 2019;40(3):300. doi:10.1038/s41401-018-0031-9