The ethnobotany of psychoactive plant use: a phylogenetic perspective

Introduction

Plants constantly evolve to produce various defensive secondary metabolites against their equally adaptive predators (Polya, 2003; Wink, 2003; Wink, 2016). Some well-known psychoactive compounds such as atropine, caffeine, cocaine, nicotine and morphine are believed to have been products of this evolutionary arms race (Howe & Jander, 2008; Fürstenberg-Hägg, Zagrobelny & Bak, 2013). Psychoactive, alternatively psychotropic, substances act on the nervous system affecting mental processes and behavior (Spinella, 2001; Rätsch, 2005). They include hallucinogens that distort reality, sedatives/narcotics that induce sleep, calmative or anxiolytics, antidepressants, and stimulants that wake the mind (Spinella, 2001; Rätsch, 2005; Van Wyk & Wink, 2014). Interestingly, humans have exploited alternate uses for plants containing psychoactive phytochemicals that have purportedly evolved to ward off plant predators. However, the affinity of these phytochemicals within the hominid nervous system may also indicate some kind of mutualistic co-evolution, with ancient humans seeking and perhaps cultivating plant psychotropics to facilitate survival, by alleviating starvation, fatigue and pain (Sullivan & Hagen, 2002).

Psychoactive compounds have specific molecular targets in the nervous system, and interact in a particular way with neuronal receptors to produce various psychoactive effects (Spinella, 2001; Polya, 2003). For instance, morphine in opium poppy (Papaver somniferum, Papaveraceae) eliminates pain by binding to opioid receptors (Polya, 2003), but simultaneously promotes sedation and euphoria, by disinhibiting dopamine-containing neurons in the limbic system (Johnson & North, 1992). Dopamine is ultimately responsible for feelings of elation and satisfaction, which occur after some rewarding act like sex or food satiety. Addiction arises from wanting to re-experience the pleasure due to the drug’s ability to cause dopamine buildup (Lüscher & Ungless, 2006). Compounds that mimic serotonin and act as receptor agonists like mescaline in the peyote cactus (Lophophora williamsii, Cactaceae), trigger hallucinations and cognitive breakdown (Polya, 2003). Stimulating substances, such as the alkaloid nicotine in tobacco, Nicotiana tabacum (Solanaceae), mimic the endogenous neurotransmitter acetylcholine stimulating muscle contractions and cholinergic areas of the brain involved in arousal and attention (Polya, 2003). Yet, the confamilial Atropa belladonna, contains a chemically different alkaloid, atropine, which promotes sedation and incapacitation via its action as muscarinic acetylcholine antagonist, blocking neuromuscular communication (Spinella, 2001).

It is well established that all cultures, ancient or modern, have some kind of drug culture, relying on psychoactives for recreational, ritual and/or medicinal uses (Schultes, 1976; Schultes, Hofmann & Rätsch, 2001; Rätsch, 2005). Shamanistic religions have existed in the Old World of Europe, Asia and Africa, believing that psychoactive plants are capable of healing through divine power. Marijuana (Cannabis spp., Cannabaceae) and opium poppy are among the most popular psychoactive plants used by Old World shamans. Marijuana was used in ancient China for various afflictions like malaria and constipation, and even as a narcotic in surgeries. In India, the plant was considered sacred promoting pleasurable sensations in the user (Clarke & Merlin, 2013). Tetrahydrocannabinol (THC) in marijuana, exerts these actions by binding to cannabinoid receptors, mediating sensory pleasure (Mahler, Smith & Berridge, 2007). Another familiar psychoactive, opium poppy was used for medicinal and recreational purposes. It probably originated in the Mediterranean, but widespread use has confounded its evolutionary origin (Merlin, 2003). It was recorded in the Eber papyrus, an ancient Egyptian scroll, that opium poppy was used to stop the excessive crying of children (Vetulani, 2001). The plant contains morphine and codeine that are responsible for its hypnotic and analgesic properties (Heinrich et al., 2012).

Indigenous people of the New World have also used psychotropic substances, including tobacco, ayahuasca, and coca, even more so than cultures of the Old World (Schultes, 1976). Tobacco from the leaves of N. tabacum has long been used in the Americas, with cultivation in pre-Columbian Mexico or Peru (Rätsch, 2005). American Indians believed in the medicinal power of tobacco, and it was smoked in ceremonial peace pipes to seal covenants. In the Amazon Basin of South America, the hallucinogenic beverage, ayahuasca, is made by healers from the boiled crushed stems of the caapi, Banisteropsis caapi (Malpighiaceae), along with the leaves of chacruna, Psychotria viridis (Rubiaceae). Chacruna contains serotonergic N, N-dimethyltryptamine (DMT), that is activated by the beta-carbolines in caapi (McKenna, 1996). In the Andes, indigenous peoples chew coca leaves of Erythroxylum coca (Erythroxylaceae) to cope with hard labor, removing symptoms of fatigue and hunger (Nigg & Seigler , 1992). Its cocaine content prevents dopamine reuptake producing increased energy and mood elevation (Spinella, 2001).

The ubiquity of psychoactive plants in various cultures motivates investigation of the commonalities among these plants, in which a phylogenetic framework may be insightful. Information is assigned to nodes of the phylogeny, instead of one species at a time, facilitating the study of trait distributions (Saslis-Lagoudakis et al., 2015). Phylogenetic studies of culturally diverse medicinal plants have repeatedly shown that medicinal uses and phytochemical traits are not randomly distributed on the phylogeny, but are shared by closely related plants, regardless of these plants’ cultural and geographic designations (Saslis-Lagoudakis et al., 2012; Saslis-Lagoudakis et al., 2015; Xavier & Molina, 2016). In this study we aimed to understand if there is a similar pattern of cultural convergence (Xavier & Molina, 2016) in psychoactive plants using phylogenetic analysis—does the phylogeny of culturally important psychoactive plants reveal a preference for certain plant families and for specific psychoactive effects (hallucinogenic, sedative, stimulant, etc.)? Additionally, we sought to understand if there is also a pattern of mechanistic convergence, such that unrelated plants with similar psychoactive effects ultimately affect similar neurotransmitter systems. Our study provides insight into the ethnobotanical origins of psychoactive plant use and suggests new plant sources of psychopharmacological drugs.

Materials and Methods

Pyschoactive taxa of seed plants (126 genera) used by various indigenous groups were compiled for this study (Table 1), but plants with psychoactive uses only after alcoholic fermentation were excluded (e.g., wine from grapes, Vitis vinifera). Congeneric species were only represented once in the phylogeny, e.g., Datura spp. included D. discolor Bernh., D. ferox L., D. innoxia Mill., D. metel L., D. stramonium L., D. wrightii Regel. This is to account for taxonomic uncertainties that are common in species circumscriptions, and also not to visually bias the phylogeny towards a certain family with multi-species genera (e.g., Datura). The plants’ names were verified in (The Plant List, 2013), a working list of all known plant species that is maintained by the Royal Botanic Gardens and the Missouri Botanical Garden. The psychoactive uses of each plant were categorized as follows: hallucinogen, sedative (=narcotic/hynotic), stimulant, anxiolytic (=relaxant), and antidepressant. As psychotropic plants may also exert analgesia and/or aphrodisiac effects, these effects were determined for each plant in addition to their original psychoactive use. Multiple effects based on literature were not uncommon. Thus, plants were assigned multiple psychoactive attributes, if applicable. For congeneric taxa, uses for each species were all noted.

The 126 psychoactive plant taxa were categorized according to the ethnic groups they were associated with: Native American (including North, Central and South America, 49 genera), European (15), Temperate Asian (including China, Russia, 10), Middle Eastern and African (19), Indomalayan (including India and Southeast Asia, 10), Australasia (including Australia, New Guinea, New Zealand, Pacific Islands, 4). Taxa with traditional psychoactive uses in at least two of these groups were designated multi-cultural (19). The uses of the plants were based on the originating indigenous cultures. For example, harmal, Peganum harmala (Nitrariaceae), is native in the Mediterranean (Europe), but it was used as a stimulant in the Middle East and in Africa, so harmal was assigned to the latter. Guava, Psidium guajava (Myrtaceae), is native to tropical America, but was only used as psychoactive in Africa (Rätsch, 2005). Argyreia nervosa (=A. speciosa), though of Indian origin, is considered multi-cultural here. It has been used in Ayurvedic medicine as an analgesic and aphrodisiac (Galani, Patel & Patel, 2010), but Hawaiians (Australasia) have been using it as alternative to marijuana (Rätsch, 2005). Cultural designations for each plant were all noted, with overlapping origins, if applicable, indicated.

To construct the phylogeny, the sequence of rbcL (the gene that codes for the photosynthetic enzyme rubisco; Clegg, 1993) for each psychoactive plant taxon was obtained from the GenBank database (http://www.ncbi.nlm.nih.gov/genbank) using BLASTN (e-value = 0, query coverage >50%; Altschul et al., 1990). If there are multiple species within the genus, only the genus name was indicated. The rbcL sequences were not available in GenBank for the following species: Calea ternifolia, Calliandra anomala, Crocus sativus, Horsfieldia australiana, Iochroma fuchsioides, Juniperus recurva, Justicia pectoralis, Lactuca virosa, Ledum palustre, Lonchocarpus violaceus, Nymphaea ampla, Pachycerus pectenaboriginum, Psychotria viridis, Ptychopetalum olacoides, Psidium guajava, Rhynchosia pyramidalis, Sassafras albidum, Sceletium tortuosum, Tanaecium nocturnum, Tilia tomentosa, Urtica urens, Veratrum album, and Virola elongata. In these cases, the rbcL sequence for any species within the corresponding genus was downloaded instead.

The rbcL sequences of the psychoactive plants were aligned using default parameters in MAFFT v.7 (Katoh & Standley, 2013). PhyML (Guindon & Gascuel, 2003) was utilized to reconstruct the phylogeny applying the general time reversible (GTR) DNA model (Tavaré, 1986) with aLRT (approximate likelihood ratio test) Shimodaira-Hasegawa-like (SH-like) branch support (Simmons & Norton, 2014) and 100 bootstrap replicates. ITOL (Interactive Tree of Life, http://itol.embl.de), a web-based tool used for the display and manipulation of phylogenetic trees (Letunic & Bork, 2006), was used to highlight and map the traits in Table 1 (indigenous culture, psychoactive uses). Affected neurotransmitter (NT) systems (Table 2) for the main psychoactive families were also added to the phylogeny. Cosmetic editing of the ITOL results was completed in Adobe Illustrator CS4.

Results

The 126 psychoactive seed plant taxa belong to 56 families and 31 orders (Table 1) and together comprise 1.6% of the total generic diversity for these families. The phylogeny reflects expected relationships (The Angiosperm Phylogeny Group, 2016). Within eudicots there seems to be cultural bias of psychotropic use toward asterid members (61) vs. rosids (31). Nonetheless, the scattered distribution of psychoactive taxa throughout the angiosperm phylogeny suggests that psychoactive phytochemicals have evolved multiple times throughout angiosperm evolution. However, certain families are more diverse with at least 3 or more genera: Myristicaceae, Papaveraceae, Malvaceae, Fabaceae, Cactaceae, Asteraceae, Convolvulaceae, Solanaceae, Lamiaceae, Rubiaceae, Apocynaceae. However, psychoactive diversity within these families may be positively correlated with the family’s generic diversity. To test this, a Pearson’s product moment correlation coefficient was calculated to test the relationship between the number of psychoactive genera in our study versus the generic diversity of each family (from Christenhusz & Byng, 2016). Taxonomically diverse families like Asteraceae and Rubiaceae (>500 genera each) did not always have proportionally higher number of psychoactive genera with the correlation coefficient very weakly positive (r = 0.004). However, Myristicaceae (4 psychoactive genera out of 21 total), Papaveraceae (4/42), Cactaceae (5/127), Convolvulaceae (4/53), Solanaceae (16/100), Lamiaceae (8/241), Apocynaceae (7/366) have a disproportionate number (>1.6%) of their family’s generic diversity psychoactive. We focused on the neurotransmitter systems affected by psychotropic members of these families as well as psychoactive members in the inherently diverse families of Fabaceae, Malvaceae, Rubiaceae, and Asteraceae (Fig. 1).

Unrelated families may exert similar psychoactive effects (Fig. 1). Cactaceae, Fabaceae, Myristicaceae, Convolvulaceae, and Solanaceae are mainly hallucinogens, though they are unrelated. Of the five cultural groups, Native Americans have traditionally used the most psychoactives (49/126) with predilection for hallucinogens (Fig. 2) in Cactaceae, Fabaceae, Convolvulaceae. These families mainly work as serotonin receptor agonists (Fig. 1; Table 2), the same mechanism as hallucinogenic Myristicaceae that has been used in Australasia and Indomalaya. Members of Solanaceae have also been used as hallucinogens, predominantly by Native Americans and Europeans, but act via a different mechanism—as acetylcholine antagonists. Hallucinogenic asterids are also often used as aphrodisiacs (16∕30 = 53% vs. 4∕18 = 22% hallucinogenic rosids).

The unrelated Papaveraceae and Lamiaceae similarly show sedative/narcotic qualities, another popular psychoactive effect among different cultural groups (Fig. 2). However, they affect different neurotransmitter systems with Papaveraceae working mainly as opioid receptor agonists. Lamiaceae work as receptor agonists of gamma-amino butyric acid (GABA), which also mediates the family’s anxiolytic effects. Psychoactive members of these families also tend to exhibit analgesic effects.

Plants with anxiolytic and antidepressant properties are relatively sparse (Figs. 1 and 2), with Europeans showing slightly increased use of these plants. Members of Apocynaceae and Rubiaceae that show an antidepressant effect facilitate this effect by increasing synaptic levels of monoamine neurotransmitters (serotonin, dopamine, noradrenaline; Fig. 1 and Table 2). In contrast, plants with stimulating effects are numerous and randomly distributed throughout the phylogeny, exhibiting varying mechanisms of action (see Malvaceae and Rubiaceae, Fig. 1 and Table 2).

Discussion

The phylogenetic distribution of psychoactive plants shows multiple evolutionary origins and provides evidence for the adaptive benefit of phytochemicals that are psychoactive in animals. It has been hypothesized that mammals may have sought plants with these phytochemicals that were chemically similar to endogenous neurotransmitters to augment their nutrition, as well as to facilitate survival, alleviating pain and hunger (Sullivan & Hagen, 2002). Whether this phylogenetic distribution, showing multiple independent origins of psychoactive plants, is due to co-evolutionary mutualism with animals remains to be tested. However, it is clear that certain psychoactive effects are concentrated in certain groups, which demonstrates that psychoactive phytochemicals are phylogenetically clustered. Phylogenetic clustering of certain secondary metabolites (Wink, 2003; Wink et al., 2010; Wink, 2013) and of medicinal traits (Saslis-Lagoudakis et al., 2012; Saslis-Lagoudakis et al., 2015; Xavier & Molina, 2016) have also been revealed in other studies.

In the phylogeny, 11 of 56 plant families have more psychoactive genera (three or more) compared to others. Accounting for these families’ total generic diversity shows that Myristicaceae, Papaveraceae, Cactaceae, Convolvulaceae, Solanaceae, Lamiaceae, and Apocynaceae have a disproportionate number of psychoactive genera. The psychoactive diversity of the other families, Fabaceae, Malvaceae, Asteraceae, and Rubiaceae, may be an artifact of their overall higher generic diversity. Nonetheless, we see a pattern where these plant families are being used for similar psychoactive applications by different cultures, a pattern of cultural convergence (Xavier & Molina, 2016) with bias, interestingly, for plants with hallucinogenic and sedative/narcotic potential.

Conclusion

Phylogenetic analysis has demonstrated multiple evolutionary origins of traditionally used psychoactive plant groups. Whether this pattern is due to repeated co-evolutionary mutualism with animals remains to be tested. Psychoactive diversity of some highlighted families is probably due to the inherent elevated diversity in these families. However, other plant families have a disproportionate number of psychoactive genera, and their phytochemical and psychoactive traits show phylogenetic clustering, with different cultures converging on geographically-disparate members of these families for similar uses: Myristicaceae, Cactaceae, Convolvulaceae, and Solanaceae as hallucinogens; Papaveraceae, Lamiaceae for analgesia and sedation; Apocynaceae for antidepressant effects. In certain unrelated families with the same psychoactive effect, the same neurotransmitter systems were also affected, i.e., mechanistic convergence. However, this was not the case for plants with stimulant effects, where confamilial taxa possess chemically diverse stimulant alkaloids, and chemically similar stimulant alkaloids exist in diverse lineages. Endophytic fungi can also produce some active metabolites originally attributed to plants (Wink, 2008; Wink et al., 2010; Nicoletti & Fiorentino, 2015), and this should be considered when interpreting the phylogeny.

Though we may have missed other psychotropic taxa, our study still provides insight into the ethnobotanical origins of psychoactive plant use. The addition of these missing taxa may only serve to corroborate our conclusion of widespread human dependence on psychoactive plants and highlight other important psychoactive families and their pharmacology. The brain is perhaps the most complex domain of the human body (Singer, 2007), and therefore brain disorders are complex pathologies themselves (Margineanu, 2016). Ethnobotanical research on how various human cultures have exploited herbal therapy through time to treat neurological afflictions will continue to provide insight into the etiology of these diseases and the success of folkloric treatments. Yet, the astounding diversity of plant-based medicines may be better appreciated within an evolutionary context that can reveal phylogenetic patterns that may guide future drug discovery (Saslis-Lagoudakis et al., 2012; Xavier & Molina, 2016). Though chemically similar psychoactive chemicals may exist in phylogenetically unrelated lineages, suggesting convergent evolution or differential gene regulation of common metabolic pathways (Wink, 2003; Wink, 2008; Wink et al., 2010), the majority of traditionally used psychoactive plants generally display phylogenetic conservatism in phytochemistry and pharmacology, and may be explored as novel therapeutics for neurological disorders such as depression, anxiety, pain, insomnia and sexual dysfunction, reinforcing the potential of plant psychoactives as “springboards for psychotherapeutic drug discovery” (McKenna, 1996).