Human adaptations to San Pedro use, as revealed by flies
Padró et al. employ fruit fly genetics to probe indigenous population genomes for adaptations to San Pedro
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Ortholog genes from cactophilic Drosophila provide insight into human adaptation to hallucinogenic cacti
Why they did it
Our beloved species set out from Africa about 100,000 years ago and settled into new and different environments around the world. 🗺
Human groups developed unique genetic and cultural identities in response to their specific environments. We classify these groups as ethnicities.
We know a fair bit about how lifestyle and dietary changes lead to genetic changes. For example many of us can digest lactose well into adulthood, a direct adaptation to dairy farming. 🤠🐄
What about ancient religious traditions? Could the consumption of entheogenic plants/fungi have also led to unique genetic signatures?
In this remarkable study, Julian Padró and colleagues sought insight into how the shamanistic use of mescaline-containing cacti could have lead to genetic changes in indigenous Central Andean populations.
They approached this question by examining diet-induced gene expression changes in Drosophila buzzattii, a fruit fly species that lives in central South America. 🪰
D. buzzattii primarily feeds on prickly pear cacti, but they also feed on San Pedro cacti. This makes them a useful model for understanding the genetic transition to chemical tolerance of new and potentially harmful plant alkaloids. 🌵
The San Pedro-safe genetic signature of D. buzzattii is an excellent starting point to determine what genetic changes may also have occurred among human populations that use San Pedro in their religious practices.
What they did
To determine how the cactus diet of D. buzzattii impacts gene expression, they raised larvae on a food bed mixed with either prickly pear tissue, San Pedro tissue, or San Pedro tissue with an extra boost of alkaloids (i.e. more mescaline/related alkaloids).
The thought here is that certain fly genes will be transcribed at a higher or lower rate in response to the heightened alkaloid content of the San Pedro diet and boosted San Pedro diet. These genes are called differentially expressed genes (DEGs).
DEGs are measured by extracting and measuring the RNA content of the larvae. There will be more RNA of a given gene if it is over-expressed, and vice versa. 🧬
They compared these fly DEGs to the human genome to search for human orthologs. Orthologs are genes existing in two different species which originate from the species’ last common ancestor. Orthologs typically retain the same structure and function in the different species.
Meanwhile, they compiled genomic datasets from indigenous populations within the area of Andean shamanic influence (Quecha & Aymara populations), as well as populations outside of this area to use as references (Yukpa, Bari, Yanesha, and Wichi populations)
Finally, they scanned their indigenous genomic data to see if any of the human orthologs are undergoing positive selection. Positive selection occurs on genes that are generally advantageous, and thus increasing in frequency in a population. 📈
Their results, summarized below, is a list of genes that may have been selected for in these populations due to the increased consumption of hallucinogenic cacti.
What they found
In flies fed a hallucinogenic cactus diet, overexpressed genes were involved in the processing of foreign substances, neurotransmitter clearance, serotonin mechanisms, energy metabolism, and ATP synthesis. Underexpressed genes were involved in general metabolism, as well as some developmental processes.
Out of the entire list of differentially expressed fly genes, 70 had a moderate to high orthology match with human genes. These human genes are involved in such processes as neurotransmitter regulation, nervous system development, oxidative stress, alkaloid detox, and response to narcotics.
Of these 70 genes, 10 of them seem to be undergoing positive selection in the Quecha and Aymara populations when compared to three of the reference populations (Bari, Yukpa, and Wichi), but not to the Yanesha population.
They found evidence that the Yanesha population is not as genomically different from the Quecha and Aymara populations, which explains why the candidate genes in the latter populations do not show significant positive selection when compared to the former.
The 10 genes undergoing positive selection likely due to Andean shamanistic practices are listed in Table 1.
Caveats
Our knowledge of the shamanistic use of San Pedro does not come from ancient texts. It is inferred (and generally agreed upon) based on archeological evidence such as evidence of cactus trade and the presence of shells from the cactus-eating snail Scutalus proteus, allegedly used for concentrating cactus alkaloids. Think, mescaline escargot.
As for the genomic data, it cannot be ruled out that the selection signals are due to other selection pressures on human health. 🩺
Drosophila is useful for pinpointing candidate genes as in this study, but they are flies and we are humans, and so there is always a chance that some important genes are overlooked because, after millions of years of evolution in different species, they have different functions.
It is possible that some fly candidate genes were not captured in the genomes of the populations they studied due to low sampling in that area. A larger collection of whole genomes from individuals in this area may increase the number of orthologs found between cactus-eating flies and cactus-eating humans. 🔬
My Take
Our bodies contain a suite of enzymes that break down large and/or harmful molecules into small, digestible, and sometimes psychoactive parts. Across the entire human genome, gene variants code slightly different versions of enzymes, which function slightly different from on another. We’ve learned about this here already from a paper which found CYP variants break down LSD at different rates, thus influencing the subjective experience of the drug. Since this gene has variation, it is amenable to natural selection.
Padró and colleagues have demonstrated how natural selection can shape a gene pool in a population of humans that regularly consumes a psychedelic cactus. As these groups settled around the Andes and began incorporating San Pedro in to their cultural traditions, their bodies had to digest new molecules. Individuals with enzyme variants that were better at metabolizing cactus alkaloids had a greater quantity and/or more successful offspring (i.e. better evolutionary fitness). Over time, the genes encoding enzymes that conferred a fitness advantage became more prevalent in the population, and genes that did not help fitness became less prevalent.
Although more research is needed to directly link this psychedelic selection pressure with the observed genetic signature, there are new questions to be asked. First, what is the significance of the genes that changes in frequency? Some are obvious, such as the increased expression of detox genes. Why exactly is a gene like ALDH2 upregulated? This gene is associated with alcohol dependence, regulation of serotonergic and dopaminergic systems which can protect against opioid addiction, AND it interacts with the 5HT2a receptor. ATP2A1 is a downregulated gene involved in maintaining calcium homeostasis during cardiac arrhythmia. Seems…not great.
On a social level, what are the public health consequences, whether good or bad, of the shamanistic San Pedro genetic signature? What could the genetic signature of our own society look like if we mass adopt psychedelics?
Personally, I am interested in how our genetic roots influence our subjective experience of altered states of consciousness. As more studies are done on the interactions between psychedelic, genetics, and mind, we may need to consider amending “set & setting” to “set, setting, & ancestry”.
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📃 Here’s the paper:
Padró, J., De Panis, D. N., Luisi, P., Dopazo, H., Szajnman, S., Hasson, E., & Soto, I. M. (2022). Ortholog genes from cactophilic Drosophila provide insight into human adaptation to hallucinogenic cacti. Scientific Reports, 12(1), 13180.
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Really appreciate the article. Based on my experience with psychoactive plant medicines, including San Pedro cactus, I believe these plants allow our brains to take in more and/or an altered version of our reality that our minds cannot process in a non-psychedelic induced state. When peoples hundreds of thousands of years ago started ingesting these plants, over time our brains chemical makeup evolved to deliver the "reality" we all live in today. Who knows, but fun to think about. Thanks again!