Since the therapeutic use of sacred plants and fungi began to be accepted by Western medicine, a tug of war has been taking place between those who advocate the traditional consumption of whole organisms, and those who defend exclusively the utilization of purified compounds or chemicals. Quoting the lyrics of the Brazilian composer and singer Caetano Veloso, something has gone out of order.
As a professional neuroscientist with an interest in psychedelic medicines, it is clear to me that the attempt to reduce organisms to single active principles is challenged by the sheer complexity of traditional medicine. Ayahuasca, for example, is a concoction of at least two plant species containing multiple psychoactive substances with complex interactions.[1. Dos Santos, R. G., Grasa, E., Valle, M., Ballester, M. R., Bouso, J. C., Nomdedeu, J. F., Riba, J. (2012). Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology (Berl), 219(4), 1039–1053. doi:10.1007/s00213-011-2434-x] [2. Mckenna, D. J., Towers, G. H. N., & Abbott, F. (1984). Monoamine-oxidase inhibitors in South-American hallucinogenic plants: Tryptamine and beta-carboline constituents of ayahuasca. Journal of Ethnopharmacology, 10, 195–223.] Similarly, cannabis contains dozens of psychoactive substances whose specific combinations in different strains correspond to distinct types of therapeutic and cognitive effects.[3. Mechoulam, R., Hanus, L. O., Pertwee, R., & Howlett, A. C. (2014). Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci, 15(11), 757–764. doi:10.1038/nrn3811]
My understanding of the medicinal use of whole organisms was greatly illuminated by the notion of entourage effect, a term coined in 1998 by chemists Raphael Mechoulam and Simon Ben-Shabat[4. Ben-Shabat, S., Fride, E., Sheskin, T., Tamiri, T., Rhee, M. H., Vogel, Z., Mechoulam, R. (1998). An entourage effect: Inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol, 353(1), 23–31.] to refer to the cooperative effects of the multiple compounds present in whole organisms, which may potentiate clinical efficacy while attenuating side effects. One clear example of such entourage effect is the additive effect of cannabidiol (CBD) and 9-tetrahydrocannabinol (THC), two main constituents of cannabis, in the enhancement of radiotherapy for the treatment of glioma.[5. Scott, K. A., Dalgleish, A. G., & Liu, W. M. (2014). The combination of cannabidiol and Delta9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther, 13(12), 2955–2967. doi:10.1158/1535-7163.MCT-14-0402] The perfumed organic compounds called terpenoids, chemically similar to cannabinoids and abundant in cannabis, may facilitate the passage of chemicals through the blood-brain barrier, and counterbalance memory deficits induced by THC.[6. Russo, E. B. (2011). Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol, 163(7), 1344–1364. doi:10.1111/j.1476-5381.2011.01238.x]
From the psychiatric point of view, CBD and THC also have very different and, in fact, complementary effects,[7. Fadda, P., Robinson, L., Fratta, W., Pertwee, R. G., & Riedel, G. (2004). Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats. Neuropharmacology, 47(8), 1170–1179. doi:10.1016/j.neuropharm.2004.08.009] [8. Morgan, C. J., Freeman, T. P., Schafer, G. L., & Curran, H. V. (2010). Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology, 35(9), 1879–1885. doi:10.1038/npp.2010.58] [9. Morgan, C. J., Schafer, G., Freeman, T. P., & Curran, H. V. (2010). Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: Naturalistic study: Naturalistic study (corrected). Br J Psychiatry, 197(4), 285–290. doi:10.1192/bjp.bp.110.077503] with relaxation and sedation following CBD intake, and excitation being produced after THC intake. CBD is anxiolytic and anti-psychotic, while THC is pro-psychotic and anxiogenic.[10. Fakhoury, M. (2016). Could cannabidiol be used as an alternative to antipsychotics? J Psychiatr Res, 80, 14–21. doi:10.1016/j.jpsychires.2016.05.013] [11. Sherif, M., Radhakrishnan, R., D’Souza, D. C., & Ranganathan, M. (2016). Human laboratory studies on cannabinoids and psychosis. Biol Psychiatry, 79(7), 526–538. doi:10.1016/j.biopsych.2016.01.011] [12. Zuardi, A. W., Crippa, J. A., Hallak, J. E., Bhattacharyya, S., Atakan, Z., Martin-Santos, R., Guimaraes, F. S. (2012). A critical review of the antipsychotic effects of cannabidiol: Thirty years of a translational investigation. Curr Pharm Des, 18(32), 5131–5140] In isolation and high doses, these substances may have negative health effects, especially for people in the risk groups. On the other hand, the presence of both compounds in cannabis results in a buffered effect that is anything but unsafe from the patient’s perspective.
In stark opposition to this view, mainstream pharmacology is adamant about the need to use purified substances for medical treatment, because these are presumably more specific and safe. This position is defended fiercely in the media and also in academic publications, as if there was much more clinical knowledge accumulated about the effects of the purified compounds than about the effects of whole organisms. However, this is simply not the case. The traditional use of whole organisms has centuries and, in some cases, millennia of cultural experience, while purified compounds only recently started to be investigated. Rimonabant, an anti-obseity medicine based on an antagonist of a cannabinoid receptor, is the most infamous example of the potential dangers of a single compound, being removed from the market in 2008 due to the association with suicide cases. The whole cannabis plant, however, with various proportions of THC, CBD, and many other cannabinoids, is clinically safe for people outside risk groups, and can even be used in these risk groups provided that adequate, specific strains of cannabis are used. For example, CBD-rich cannabis is safe for psychotic patients and can be used as psychiatric treatment.[13. Zuardi, A. W., Crippa, J. A., Hallak, J. E., Bhattacharyya, S., Atakan, Z., Martin-Santos, R., Guimaraes, F. S. (2012). A critical review of the antipsychotic effects of cannabidiol: Thirty years of a translational investigation. Curr Pharm Des, 18(32), 5131–5140]
In the case of ayahuasca, the advantage of compound combination is related not to the safety of the consumption, but to the fact that the N-N-Dimethyltryptamine (DMT) contained in the plant Psychotria viridis is entirely degraded by the monoamine-oxidases (MAO) present in the gastrointestinal tract in the absence of pharmacological protection.[14. Buckholtz, N. S., & Boggan, W. O. (1977). Monoamine oxidase inhibition in brain and liver produced by beta-carbolines: Structure-activity relationships and substrate specificity. Biochem Pharmacol, 26(21), 1991–1996] Indeed, the DMT contained in ayahuasca would be innocuous if the brew did not include another plant, the liana Banisteriopsis caapi, which is rich in inhibitors of MAO and therefore allows the psychedelic experience to occur. These substances by themselves increase the levels of dopamine and other neurotransmitters,[15. Iurlo, M., Leone, G., Schilstrom, B., Linner, L., Nomikos, G., Hertel, P., . . . Svensson, H. (2001). Effects of harmine on dopamine output and metabolism in rat striatum: Role of monoamine oxidase-A inhibition. Psychopharmacology (Berl), 159(1), 98-104. doi:10.1007/s002130100879] and induce the formation of new neurons.[16. Dakic, V., Maciel, R. M., Drummond, H., Nascimento, J. M., Trindade, P., & Rehen, S. K. (2016). Harmine stimulates proliferation of human neural progenitors. PeerJ, 4, e2727. doi:10.7717/peerj.2727]
We should not forget that the traditional shamanic use of whole organisms such as cannabis co-evolved with the plant itself.[17. McPartland, J. M., & Guy, G. W. (2004). The evolution of cannabis and coevolution with the cannabinoid receptor: A hypothesis. In G. W. Guy, B. A. Whittle, & P. J. Robson (Eds.), The medicinal use of cannabis and cannabinoids (pp. 71–101). London, Chicago: Pharmaceutical Press] [18. Pollan, M. (2001). The botany of desire: A plant’s eye view of the world (1st ed.). New York City, NY: Random House] The artificial selection of cannabis, performed systematically around the Himalaya in the past six thousand years, led to strains characterized by cannabinoid mixtures, rather than strains dominated by a single cannabinoid. If purified compounds were indeed best for therapy, single-compound strains should have been favored over time; but the opposite happens to be true. We should listen to our ancestors here.
The core issue at stake is the fact that the phyto-therapeutic approach to psychedelic medicine is successful in multiple countries, and quite scalable due to the low cost of home-growing whole organisms. Purified compounds, on the other hand, are much more expensive to make, and necessarily reach the final consumer at much higher prices than whole organisms. The clinical use of purified compounds for subjects with low socio-economic status is further hampered by Big-Pharma patent rights, and marketing strategies. Still, the large margin of profit for the commercialization of purified compounds has motivated, in recent years, a strong corporative push for the adoption of purified compounds as the golden standard for medical practice involving psychedelic substances. In medical marijuana, for instance, cannabis in natura versus isolated cannabinoids is a billion-dollar question.
We are living in the era of psychedelic revival. Science finally caught up with the wisdom and curiosity of healers and psychonauts, and new questions are becoming as widespread as new answers. Now is the prime time to discuss the potential advantages and disadvantages of therapeutics based on whole organisms versus purified compounds; a debate with major economic, social, and philosophical implications for the future of human health.
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