Skip to main content Accessibility help
Hostname: page-component-7bb4899584-j8xrj Total loading time: 0.764 Render date: 2023-01-26T22:21:19.408Z Has data issue: true Feature Flags: { "useRatesEcommerce": false } hasContentIssue true

Using evolutionary tools to search for novel psychoactive plants

Published online by Cambridge University Press:  25 October 2016

Morten Halse-Gramkow
Natural History Museum of Denmark, Faculty of Science, University of Copenhagen, Sølvgade 83S, DK1307 Copenhagen K, Denmark
Madeleine Ernst
Natural History Museum of Denmark, Faculty of Science, University of Copenhagen, Sølvgade 83S, DK1307 Copenhagen K, Denmark
Nina Rønsted
Natural History Museum of Denmark, Faculty of Science, University of Copenhagen, Sølvgade 83S, DK1307 Copenhagen K, Denmark
Robert R. Dunn
Natural History Museum of Denmark, Faculty of Science, University of Copenhagen, Sølvgade 83S, DK1307 Copenhagen K, Denmark Department of Applied Ecology and Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC 27695, USA
C. Haris Saslis-Lagoudakis*
Natural History Museum of Denmark, Faculty of Science, University of Copenhagen, Sølvgade 83S, DK1307 Copenhagen K, Denmark
*Corresponding author. E-mail:


Bioprospecting is the search for valuable products from natural sources. Given that most species are poorly known, a key question is where to search. Ethnodirected bioprospecting approaches use traditional knowledge in the process of selecting plants to screen for desired properties. A complementary approach is to utilize phylogenetic analyses based on traditional uses or known chemistry to identify lineages in which desired properties are most likely to be found. Novel discoveries of plant bioactivity from these approaches can aid the development of treatments for diseases with unmet medical needs. For example, neurological disorders are a growing concern, and psychoactive plants used in traditional medicine may provide botanical sources for bioactivity relevant for treating diseases related to the brain and nervous system. However, no systematic study has explored the diversity and phylogenetic distribution of psychoactive plants. We compiled a database of 501 psychoactive plant species and their properties from published sources. We mapped these plant attributes on a phylogenetic tree of all land plant genera and showed that psychoactive properties are not randomly distributed on the phylogeny of land plants; instead certain plant lineages show overabundance of psychoactive properties. Furthermore, employing a ‘hot nodes’ approach to identify these lineages, we can narrow down our search for novel psychoactive plants to 8.5% of all plant genera for psychoactivity in general and 1–4% for specific categories of psychoactivity investigated. Our results showcase the potential of using a phylogenetic approach to bioprospect plants for psychoactivity and can serve as foundation for future investigations.

Research Article
Copyright © NIAB 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Abbas, G, Naqvi, S, Erum, S, Ahmed, S and Dar, A (2013) Potential antidepressant activity of Areca catechu nut via elevation of serotonin and noradrenaline in the hippocampus of rats. Phytotherapy Research 27: 3945.CrossRefGoogle ScholarPubMed
Andersen, G, Vestergaard, K and Lauritzen, L (1994) Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 25: 10991104.CrossRefGoogle ScholarPubMed
Balandrin, MF, Kinghorn, AD and Farnsworth, NR (1993) Plant-derived natural products in drug discovery and development: an overview. In: Kinghorn AD and Balandrin MF (eds.) Human Medicinal Agents from Plants, Washington, D.C. USA: American Chemical Society, pp. 2–12. doi: 10.1021/bk-1993-0534.ch001 Google Scholar
Balick, MJ and Cox, PA (1996) Plants, people, and culture: the science of ethnobotany. Scientific American Library, vol. 60. New York: W H Freeman & Co.Google Scholar
Barnes, PM, Bloom, B and Nahin, RL (2008) Complementary and Alternative Medicine use Among Adults and Children: United States, 2007. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics Hyattsville, MD.Google ScholarPubMed
Bay-Smidt, MGK, Jäger, AK, Krydsfeldt, K, Meerow, AW, Stafford, GI, Van Staden, J and Rønsted, N (2011) Phylogenetic selection of target species in Amaryllidaceae tribe Haemantheae for acetylcholinesterase inhibition and affinity to the serotonin reuptake transport protein. South African Journal of Botany 77: 175183. doi: CrossRefGoogle Scholar
Benishin, CG (1992) Actions of ginsenoside Rb 1 on choline uptake in central cholinergic nerve endings. Neurochemistry International 21: 15.CrossRefGoogle Scholar
Binder, MD, Hirokawa, N and Windhorst, U (2009) Encyclopedia of Neuroscience, vol. 3166. Berlin, Heidelberg: Springer.CrossRefGoogle Scholar
Boyer, EW and Shannon, M (2005) The serotonin syndrome. New England Journal of Medicine 352: 11121120.CrossRefGoogle ScholarPubMed
Brummitt, N and Bachman, S (2010) Plants under Pressure a Global Assessment. The First Report of the IUCN Sampled Red List Index for Plants. London, UK: Natural History Museum.Google Scholar
Carlini, EA (2003) Plants and the central nervous system. Pharmacology Biochemistry and Behavior 75: 501512. doi: CrossRefGoogle ScholarPubMed
Chamberlain, S and Szocs, E (2013) taxize: taxonomic search and retrieval in R. F1000 Res 2: 191. doi: 10.12688/f1000research.2-191.v2 Google Scholar
Chatterjee, SS, Bhattacharya, SK, Wonnemann, M, Singer, A and Müller, WE (1998) Hyperforin as a possible antidepressant component of Hypericum extracts. Life Sciences 63: 499510.CrossRefGoogle ScholarPubMed
Chugani, DC, Muzik, O, Rothermel, R, Behen, M, Chakraborty, P, Mangner, T, Da Silva, EA and Chugani, HT (1997) Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Annals of Neurology 42: 666669.CrossRefGoogle ScholarPubMed
Contestabile, A (2011) The history of the cholinergic hypothesis. Behavioural Brain Research 221: 334340.CrossRefGoogle ScholarPubMed
Cragg, GM and Newman, DJ (2009) Nature: a vital source of leads for anticancer drug development. Phytochemistry Reviews 8: 313331.CrossRefGoogle Scholar
Cragg, GM, Grothaus, PG and Newman, DJ (2009) Impact of natural products on developing new anti-cancer agents. Chemical Reviews 109: 30123043.CrossRefGoogle ScholarPubMed
Craig, LA, Hong, NS and McDonald, RJ (2011) Revisiting the cholinergic hypothesis in the development of Alzheimer's disease. Neuroscience & Biobehavioral Reviews 35: 13971409.CrossRefGoogle ScholarPubMed
Dahlgren, R (1980) A revised system of classification of the angiosperms. Botanical Journal of the Linnean Society 80: 91124.CrossRefGoogle Scholar
DeFeudis, FV (1998) Ginkgo Biloba Extract (EGb 761): from Chemistry to the Clinic. Wiesbaden, Germany: Ullstein Medical Wiesbaden.Google Scholar
Ernst, M, Saslis-Lagoudakis, CH, Grace, OM, Nilsson, N, Toft Simonsen, H, Horn, JW and Rønsted, N (2016) Evolutionary prediction of medicinal properties in the genus Euphorbia L. Scientific Reports 6: 30531. doi: 10.1038/srep30531.CrossRefGoogle ScholarPubMed
Fabricant, DS and Farnsworth, NR (2001) The value of plants used in traditional medicine for drug discovery. Environmental Health Perspectives 109: 69.CrossRefGoogle ScholarPubMed
Farnsworth, NR, Akerele, O, Bingel, AS, Soejarto, DD and Guo, Z (1985) Medicinal plants in therapy. Bulletin of the World Health Organization 63: 965.Google ScholarPubMed
Forest, F, Grenyer, R, Rouget, M, Davies, TJ, Cowling, RM, Faith, DP, Balmford, A, Manning, JC, Procheş, Ş, van der Bank, M, Reeves, G, Hedderson, TAJ and Savolainen, V (2007) Preserving the evolutionary potential of floras in biodiversity hotspots. Nature 445: 757760.CrossRefGoogle ScholarPubMed
Foulds, J (2006) The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. International Journal of Clinical Practice 60: 571576.CrossRefGoogle ScholarPubMed
Francis, PT, Palmer, AM, Snape, M and Wilcock, GK (1999) The cholinergic hypothesis of Alzheimer's disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry 66: 137147.CrossRefGoogle ScholarPubMed
Fritz, SA and Purvis, A (2010) Selectivity in mammalian extinction risk and threat types: a new measure of phylogenetic signal strength in binary traits. Conservation Biology 24: 10421051.CrossRefGoogle ScholarPubMed
Geula, C and Mesulam, M-M (1995) Cholinesterases and the pathology of Alzheimer disease. Alzheimer Disease & Associated Disorders 9: 2328.CrossRefGoogle ScholarPubMed
Gorinova, NI, Atanassov, AI and Velcheva, MP (1999) Physochlaina species: in vitro culture and the production of physochlaine and other tropane alkaloids. In: Bajaj, YPS (ed.) Medicinal and Aromatic Plants XI. Berlin Heidelberg, Berlin, Heidelberg: Springer, pp. 350363. doi: 10.1007/978-3-662-08614-8_21.CrossRefGoogle Scholar
Gottlieb, OR (1982) Ethnopharmacology versus chemosystematics in the search for biologically active principles in plants. Journal of Ethnopharmacology 6: 227238.CrossRefGoogle ScholarPubMed
Grace, OM, Buerki, S, Symonds, MR, Forest, F, van Wyk, AE, Smith, GF, Klopper, RR, Bjorå, CS, Neale, S and Demissew, S (2015) Evolutionary history and leaf succulence as explanations for medicinal use in aloes and the global popularity of Aloe vera . BMC Evolutionary Biology 15: 29.CrossRefGoogle Scholar
Gurib-Fakim, A (2006) Medicinal plants: traditions of yesterday and drugs of tomorrow. Molecular Aspects of Medicine 27: 193.CrossRefGoogle ScholarPubMed
Gyllenhaal, C, Kadushin, M, Southavong, B, Sydara, K, Bouamanivong, S, Xaiveu, M, Xuan, L, Hiep, N, Hung, N and Loc, P (2012) Ethnobotanical approach versus random approach in the search for new bioactive compounds: support of a hypothesis. Pharmaceutical Biology 50: 3041.CrossRefGoogle ScholarPubMed
Hagan, J, Jansen, J and Broekkamp, C (1987) Blockade of spatial learning by the M1 muscarinic antagonist pirenzepine. Psychopharmacology 93: 470476.CrossRefGoogle ScholarPubMed
Hao, W, Xing-Jun, W, Yong-Yao, C, Liang, Z, Yang, L and Hong-Zhuan, C (2005) Up-regulation of M 1 muscarinic receptors expressed in CHOm 1 cells by panaxynol via cAMP pathway. Neuroscience Letters 383: 121126.CrossRefGoogle ScholarPubMed
Harmon, LJ, Weir, JT, Brock, CD, Glor, RE and Challenger, W (2008) GEIGER: investigating evolutionary radiations. Bioinformatics 24: 129131.CrossRefGoogle Scholar
Heinrich, M and Teoh, HL (2004) Galanthamine from snowdrop—the development of a modern drug against Alzheimer's disease from local Caucasian knowledge. Journal of Ethnopharmacology 92: 147162.CrossRefGoogle ScholarPubMed
Hieronymus, F, Emilsson, JF, Nilsson, S and Eriksson, E (2016) Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Molecular Psychiatry 21: 523530.CrossRefGoogle ScholarPubMed
Hinchliff, CE and Smith, SA (2014) Some limitations of public sequence data for phylogenetic inference (in plants). PLoS ONE 9: e98986.CrossRefGoogle Scholar
IFPMA (2012) Mental and Neurological Disorders, Adressing a Global Health Priority. Position Paper.Google Scholar
iPlant Collaborative. Taxonomic Name Resolution Service v4.0. Available at (accessed 20 November 2015).Google Scholar
Kembel, SW, Cowan, PD, Helmus, MR, Cornwell, WK, Morlon, H, Ackerly, DD, Blomberg, SP and Webb, CO (2010) Picante: R tools for integrating phylogenies and ecology. Bioinformatics 26: 14631464.CrossRefGoogle ScholarPubMed
Khafagi, IK and Dewedar, A (2000) The efficiency of random versus ethno-directed research in the evaluation of Sinai medicinal plants for bioactive compounds. Journal of Ethnopharmacology 71: 365376.CrossRefGoogle ScholarPubMed
Kish, SJ, Tong, J, Hornykiewicz, O, Rajput, A, Chang, L-J, Guttman, M and Furukawa, Y (2008) Preferential loss of serotonin markers in caudate versus putamen in Parkinson's disease. Brain 131: 120131.Google ScholarPubMed
Klockgether-Radke, A (2002) FW Serturner and the discovery of morphine. 200 years of pain therapy with opioids. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie 37: 244249.CrossRefGoogle ScholarPubMed
Lachowicz, JE, Duffy, RA, Ruperto, V, Kozlowski, J, Zhou, G, Clader, J, Billard, W, Binch, H, Crosby, G and Cohen-Williams, M (2001) Facilitation of acetylcholine release and improvement in cognition by a selective M 2 muscarinic antagonist, SCH 72788. Life Sciences 68: 25852592.CrossRefGoogle Scholar
Larsen, MM, Adsersen, A, Davis, AP, Lledó, MD, Jäger, AK and Rønsted, N (2010) Using a phylogenetic approach to selection of target plants in drug discovery of acetylcholinesterase inhibiting alkaloids in Amaryllidaceae tribe Galantheae. Biochemical Systematics and Ecology 38: 10261034. doi: CrossRefGoogle Scholar
Lee, T, Shiao, Y-J, Chen, C-F and Wang, LC (2001) Effect of ginseng saponins on b-amyloid-suppressed acetylcholine release from rat hippocampal slices. Planta Medica 67: 634637.CrossRefGoogle ScholarPubMed
Lendvai, B, Kassai, F, Szájli, Á and Némethy, Z (2013) α7 nicotinic acetylcholine receptors and their role in cognition. Brain Research Bulletin 93: 8696.CrossRefGoogle ScholarPubMed
Lenz, RA, Pritchett, YL, Berry, SM, Llano, DA, Han, S, Berry, DA, Sadowsky, CH, Abi-Saab, WM and Saltarelli, MD (2015) Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease. Alzheimer Disease & Associated Disorders 29: 192199.CrossRefGoogle ScholarPubMed
Li, JW-H and Vederas, JC (2009) Drug discovery and natural products: end of an era or an endless frontier? Science 325: 161165.CrossRefGoogle ScholarPubMed
Lukhoba, CW, Simmonds, MS and Paton, AJ (2006) Plectranthus: a review of ethnobotanical uses. Journal of Ethnopharmacology 103: 124.CrossRefGoogle ScholarPubMed
McChesney, JD, Venkataraman, SK and Henri, JT (2007) Plant natural products: back to the future or into extinction? Phytochemistry 68: 20152022.CrossRefGoogle ScholarPubMed
McClatchey, W (2005) Medical Bioprospecting and Ethnobotanical Research. Ethnobotany Research and Applications 3: 189190.CrossRefGoogle Scholar
Newman, DJ and Cragg, GM (2007) Natural products as sources of new drugs over the last 25 years. Journal of Natural Products 70: 461477.CrossRefGoogle ScholarPubMed
Olincy, A, Harris, JG, Johnson, LL, Pender, V, Kongs, S, Allensworth, D, Ellis, J, Zerbe, GO, Leonard, S and Stevens, KE (2006) Proof-of-concept trial of an α7 nicotinic agonist in schizophrenia. Archives of General Psychiatry 63: 630638.CrossRefGoogle Scholar
Orme, D, Freckleton, R, Thomas, G, Petzoldt, T, Fritz, S, Isaac, N and Pearse, W (2013) Caper: Comparative analyses of phylogenetics and evolution in R. R package version 052. (accessed 18 February 2016).Google Scholar
Ott, J (1996) Pharmacotheon: Entheogenic Drugs, their Plant Sources and History. 2nd edn., Kennewick, WA, USA: Natural Products Co.Google Scholar
Palhano-Fontes, F, Andrade, KC, Tofoli, LF, Santos, AC, Crippa, JAS, Hallak, JE, Ribeiro, S and de Araujo, DB (2015) The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS ONE 10: e0118143.CrossRefGoogle ScholarPubMed
Paradis, E, Claude, J and Strimmer, K (2004) APE: analyses of phylogenetics and evolution in R language. Bioinformatics 20: 289290.CrossRefGoogle ScholarPubMed
Peigen, X and Liyi, H (1982) Przewalskia tangutica – a tropane alkaloid-containing plant . Planta Medica 45: 112115.CrossRefGoogle ScholarPubMed
Pittler, MH and Ernst, E (2003) Kava extract versus placebo for treating anxiety. Cochrane Database of Systematic Reviews 1:CD003383.Google Scholar
R Core Team (2015) R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing.Google ScholarPubMed
Raskin, I, Ribnicky, DM, Komarnytsky, S, Ilic, N, Poulev, A, Borisjuk, N, Brinker, A, Moreno, DA, Ripoll, C and Yakoby, N (2002) Plants and human health in the twenty-first century. Trends in Biotechnology 20: 522531.CrossRefGoogle ScholarPubMed
Rätsch, C (2005) The Encyclopedia of Psychoactive Plants: Ethnopharmacology and its Applications. Rochester, Vermont, USA: Inner Traditions/Bear & Co.Google Scholar
Reyes-García, V, Guèze, M, Luz, AC, Paneque-Gálvez, J, Macía, MJ, Orta-Martínez, M, Pino, J and Rubio-Campillo, X (2013) Evidence of traditional knowledge loss among a contemporary indigenous society. Evolution and Human Behavior 34: 249257.CrossRefGoogle ScholarPubMed
Robson, P (2001) Therapeutic aspects of cannabis and cannabinoids. The British Journal of Psychiatry 178: 107115.CrossRefGoogle ScholarPubMed
Rønsted, N, Savolainen, V, Mølgaard, P and Jäger, AK (2008) Phylogenetic selection of Narcissus species for drug discovery. Biochemical Systematics and Ecology 36: 417422.CrossRefGoogle Scholar
Rønsted, N, Symonds, MR, Birkholm, T, Christensen, SB, Meerow, AW, Molander, M, Mølgaard, P, Petersen, G, Rasmussen, N and Van Staden, J (2012) Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of Amaryllidaceae. BMC Evolutionary Biology 12: 182.CrossRefGoogle ScholarPubMed
Roz, N and Rehavi, M (2003) Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane. Life Sciences 73: 461470.CrossRefGoogle ScholarPubMed
Saslis-Lagoudakis, CH, Klitgaard, BB, Forest, F, Francis, L, Savolainen, V, Williamson, EM and Hawkins, JA (2011) The use of phylogeny to interpret cross-cultural patterns in plant use and guide medicinal plant discovery: an example from Pterocarpus (Leguminosae). PLoS ONE 6: e22275.CrossRefGoogle Scholar
Saslis-Lagoudakis, CH, Savolainen, V, Williamson, EM, Forest, F, Wagstaff, SJ, Baral, SR, Watson, MF, Pendry, CA and Hawkins, JA (2012) Phylogenies reveal predictive power of traditional medicine in bioprospecting. Proceedings of the National Academy of Sciences of the United States of America 109: 1583515840.CrossRefGoogle ScholarPubMed
Schippmann, U, Leaman, DJ and Cunningham, A (2002) Impact of Cultivation and Gathering of Medicinal Plants on Biodiversity: Global Trends and Issues. Rome, Italy: FAO Biodiversity and the Ecosystem Approach in Agriculture, Forestry and Fisheries.Google Scholar
Shultes, RE (1976) Hallucinogenic Plants. New York: Golden Press.Google Scholar
Slish, DF, Ueda, H, Arvigo, R and Balick, MJ (1999) Ethnobotany in the search for vasoactive herbal medicines. Journal of Ethnopharmacology 66: 159165.CrossRefGoogle ScholarPubMed
ThePlantList (2016). Available at (accessed 18 February 2016).Google Scholar
Webb, CO, Ackerly, DD and Kembel, SW (2008) Phylocom: software for the analysis of phylogenetic community structure and trait evolution. Bioinformatics 24: 20982100.CrossRefGoogle ScholarPubMed
Wickham, H (2011) The split-apply-combine strategy for data analysis. Journal of Statistical Software 40: 129.CrossRefGoogle Scholar
Wink, M (2003) Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry 64: 319.CrossRefGoogle ScholarPubMed
Wink, M and Van-Wyk, BE (2008) Mind-Altering and Poisonous Plants of the World. 1st edn., Portland, OR, USA: Timber Press.Google Scholar
World Health Organization (2015a) Psychoactive Substance Definition. Available at (accessed 18 February 2016).Google Scholar
World Health Organization (2015b) WHO Traditional Medicine Strategy 2014–2023. 2013. Geneva: World Health Organization.Google Scholar
Xiang, Z, Thompson, AD, Jones, CK, Lindsley, CW and Conn, PJ (2012) Roles of the M1 muscarinic acetylcholine receptor subtype in the regulation of basal ganglia function and implications for the treatment of Parkinson's disease. Journal of Pharmacology and Experimental Therapeutics 340: 595603.CrossRefGoogle Scholar
Zhu, F, Qin, C, Tao, L, Liu, X, Shi, Z, Ma, X, Jia, J, Tan, Y, Cui, C and Lin, J (2011) Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting. Proceedings of the National Academy of Sciences of the United States of America 108: 1294312948.CrossRefGoogle ScholarPubMed
Supplementary material: File

Halse-Gramkow supplementary material

Supplementary Figures and Tables

Download Halse-Gramkow supplementary material(File)
File 1 MB
Cited by

Save article to Kindle

To save this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the or variations. ‘’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Using evolutionary tools to search for novel psychoactive plants
Available formats

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Using evolutionary tools to search for novel psychoactive plants
Available formats

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Using evolutionary tools to search for novel psychoactive plants
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *