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Whole Organisms or Pure Compounds? Entourage Effect Versus Drug Specificity

  • Sidarta Ribeiro
Chapter

Abstract

As the therapeutic use of sacred plants and fungi becomes increasingly 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. 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. Similarly, cannabis contains dozens of psychoactive substances whose specific combinations in different strains correspond to different types of therapeutic and cognitive effects. The “entourage effect” refers to the synergistic effects of the multiple compounds present in whole organisms, which may potentiate clinical efficacy while attenuating side effects. In opposition to this view, mainstream pharmacology is adamant about the need to use purified substances, presumably more specific and safe. In this chapter, I will review the evidence on both sides to discuss the scientific, economic, and political implications of this controversy. The evidence indicates that it is time to embrace the therapeutic complexity of psychedelics.

References

  1. Abrams, D. I. (2016). Integrating cannabis into clinical cancer care. Current Oncology, 23(2), S8–S14.  https://doi.org/10.3747/co.23.3099 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andre, C. M., Hausman, J. F., & Guerriero, G. (2016). Cannabis sativa: The plant of the thousand and one molecules. Frontiers in Plant Science, 7, 19.  https://doi.org/10.3389/fpls.2016.00019 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aso, E., Sanchez-Pla, A., Vegas-Lozano, E., Maldonado, R., & Ferrer, I. (2015). Cannabis-based medicine reduces multiple pathological processes in AbetaPP/PS1 mice. Journal of Alzheimer’s Disease, 43(3), 977–991.  https://doi.org/10.3233/JAD-141014 CrossRefPubMedGoogle Scholar
  4. Attaya, S., Kanthi, Y., Aster, R., & McCrae, K. (2009). Acute profound thrombocytopenia with second exposure to eptifibatide associated with a strong antibody reaction. Platelets, 20(1), 64–67.  https://doi.org/10.1080/09537100802592676 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Augenstein, W. L., Kulig, K. W., & Rumack, B. H. (1988). Captopril overdose resulting in hypotension. JAMA, 259(22), 3302–3305.CrossRefGoogle Scholar
  6. Avraham, H. K., Jiang, S., Fu, Y., Rockenstein, E., Makriyannis, A., Zvonok, A., … Avraham, S. (2014). The cannabinoid CB(2) receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. British Journal of Pharmacology, 171(2), 468–479.  https://doi.org/10.1111/bph.12478 CrossRefPubMedGoogle Scholar
  7. Barceloux, D. G. (2012). Medical toxicology of drug abuse: Synthesized chemicals and psychoactive plants. Hoboken, NJ: Wiley.CrossRefGoogle Scholar
  8. Ben Amar, M. (2006). Cannabinoids in medicine: A review of their therapeutic potential. Journal of Ethnopharmacology, 105(1–2), 1–25.  https://doi.org/10.1016/j.jep.2006.02.001 CrossRefPubMedGoogle Scholar
  9. 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. European Journal of Pharmacology, 353(1), 23–31.CrossRefGoogle Scholar
  10. Bilkei-Gorzo, A., Albayram, O., Draffehn, A., Michel, K., Piyanova, A., Oppenheimer, H., … Zimmer, A. (2017). A chronic low dose of Delta9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nature Medicine, 23(6), 782–787.  https://doi.org/10.1038/nm.4311 CrossRefPubMedGoogle Scholar
  11. Bravo-Ferrer, I., Cuartero, M. I., Zarruk, J. G., Pradillo, J. M., Hurtado, O., Romera, V. G., … Moro, M. A. (2017). Cannabinoid type-2 receptor drives neurogenesis and improves functional outcome after stroke. Stroke, 48(1), 204–212.  https://doi.org/10.1161/STROKEAHA.116.014793 CrossRefPubMedGoogle Scholar
  12. Bregman, T., & Fride, E. (2011). Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice. Journal of Basic and Clinical Physiology and Pharmacology, 22(1–2), 29–32.  https://doi.org/10.1515/jbcpp.2011.004 CrossRefPubMedGoogle Scholar
  13. Buckholtz, N. S., & Boggan, W. O. (1977). Monoamine oxidase inhibition in brain and liver produced by beta-carbolines: Structure-activity relationships and substrate specificity. Biochemical Pharmacology, 26(21), 1991–1996.CrossRefGoogle Scholar
  14. Cannabis-based medicines--GW pharmaceuticals: High CBD, high THC, medicinal cannabis--GW pharmaceuticals, THC:CBD. (2003). Drugs R D, 4(5), 306–309.Google Scholar
  15. Cao, C., Li, Y., Liu, H., Bai, G., Mayl, J., Lin, X., … Cai, J. (2014). The potential therapeutic effects of THC on Alzheimer’s disease. Journal of Alzheimer’s Disease, 42(3), 973–984.  https://doi.org/10.3233/JAD-140093 CrossRefPubMedGoogle Scholar
  16. Coons, J. C., Barcelona, R. A., Freedy, T., & Hagerty, M. F. (2005). Eptifibatide-associated acute, profound thrombocytopenia. Annals of Pharmacotherapy, 39(2), 368–372.  https://doi.org/10.1345/aph.1E244 CrossRefPubMedGoogle Scholar
  17. 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.  https://doi.org/10.7717/peerj.2727 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dakic, V., Nascimento, J. M., Sartore, R. C., Maciel, R. M., de Araujo, D. B., Ribeiro, S., … Rehen, S. K. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-methoxy-N,N-dimethyltryptamine. BioRxiv.  https://doi.org/10.1101/108159
  19. Dawson, W. (1934). Studies in the Egyptian medical texts: III. The Journal of Egyptian Archaeology, 20(1/2), 41–46.CrossRefGoogle Scholar
  20. Dawson, A. H., Harvey, D., Smith, A. J., Taylor, M., Whyte, I. M., Johnson, C. I., … Roberts, M. J. (1990). Lisinopril overdose. Lancet, 335(8687), 487–488.CrossRefGoogle Scholar
  21. de Araujo, D. B., Ribeiro, S., Cecchi, G. A., Carvalho, F. M., Sanchez, T. A., Pinto, J. P., … Santos, A. C. (2012). Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion. Human Brain Mapping, 33(11), 2550–2560.  https://doi.org/10.1002/hbm.21381 CrossRefPubMedPubMedCentralGoogle Scholar
  22. de Lago, E., Moreno-Martet, M., Cabranes, A., Ramos, J. A., & Fernandez-Ruiz, J. (2012). Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB1 receptor-mediated anti-inflammatory effects. Neuropharmacology, 62(7), 2299–2308.  https://doi.org/10.1016/j.neuropharm.2012.01.030 CrossRefPubMedGoogle Scholar
  23. de Mello Schier, A. R., de Oliveira Ribeiro, N. P., Coutinho, D. S., Machado, S., Arias-Carrion, O., Crippa, J. A., … Silva, A. C. (2014). Antidepressant-like and anxiolytic-like effects of cannabidiol: A chemical compound of Cannabis sativa. CNS & Neurological Disorders-Drug Targets, 13(6), 953–960.CrossRefGoogle Scholar
  24. Di Forti, M., Morgan, C., Dazzan, P., Pariante, C., Mondelli, V., Marques, T. R., … Murray, R. M. (2009). High-potency cannabis and the risk of psychosis. The British Journal of Psychiatry, 195(6), 488–491.  https://doi.org/10.1192/bjp.bp.109.064220 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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.  https://doi.org/10.1007/s00213-011-2434-x CrossRefGoogle Scholar
  26. Elsohly, M. A., & Slade, D. (2005). Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sciences, 78(5), 539–548.  https://doi.org/10.1016/j.lfs.2005.09.011 CrossRefPubMedGoogle Scholar
  27. Fabisiak, A., & Fichna, J. (2017). Cannabinoids as gastrointestinal anti-inflammatory drugs. Neurogastroenterology & Motility, 29(3).  https://doi.org/10.1111/nmo.13038 CrossRefGoogle Scholar
  28. 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.  https://doi.org/10.1016/j.neuropharm.2004.08.009 CrossRefPubMedGoogle Scholar
  29. Fakhoury, M. (2016). Could cannabidiol be used as an alternative to antipsychotics? Journal of Psychiatric Research, 80, 14–21.  https://doi.org/10.1016/j.jpsychires.2016.05.013 CrossRefPubMedGoogle Scholar
  30. Farnsworth, D. L. (1976). What is the evidence for an amotivational syndrome in cannabis users? Annals of the New York Academy of Sciences, 282(1), 1.CrossRefGoogle Scholar
  31. Fasinu, P. S., Phillips, S., ElSohly, M. A., & Walker, L. A. (2016). Current status and prospects for cannabidiol preparations as new therapeutic agents. Pharmacotherapy, 36(7), 781–796.  https://doi.org/10.1002/phar.1780 CrossRefPubMedGoogle Scholar
  32. Ferreira, S. H. (1965). A bradykinin-potentiating factor (bpf) present in the venom of bothrops jararaca. British Journal of Pharmacology and Chemotherapy, 24(1), 163–169.  https://doi.org/10.1111/j.1476-5381.1965.tb02091.x CrossRefPubMedPubMedCentralGoogle Scholar
  33. Fetterman, P. S., & Turner, C. E. (1972). Constituents of Cannabis sativa L. I. Propyl homologs of cannabinoids from an Indian variant. Journal of Pharmaceutical Sciences, 61(9), 1476–1477.CrossRefGoogle Scholar
  34. Flather, M. D., Yusuf, S., Kober, L., Pfeffer, M., Hall, A., Murray, G., … Braunwald, E. (2000). Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: A systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet, 355(9215), 1575–1581.CrossRefGoogle Scholar
  35. Formukong, E. A., Evans, A. T., & Evans, F. J. (1988). Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation, 12(4), 361–371.CrossRefGoogle Scholar
  36. Forsyth, A. J. M. (2001). Distorted? A quantitative exploration of drug fatality reports in the popular press. The International Journal of Drug Policy, 12(5–6), 435–453.  https://doi.org/10.1016/S0955-3959(01)00092-5 CrossRefGoogle Scholar
  37. Gallant, M., Odei-Addo, F., Frost, C. L., & Levendal, R. A. (2009). Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes. Phytomedicine, 16(10), 942–949.  https://doi.org/10.1016/j.phymed.2009.02.013 CrossRefPubMedGoogle Scholar
  38. Gertsch, J., Pertwee, R. G., & Di Marzo, V. (2010). Phytocannabinoids beyond the Cannabis plant – do they exist? British Journal of Pharmacology, 160(3), 523–529.  https://doi.org/10.1111/j.1476-5381.2010.00745.x CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gloss, D. (2015). An overview of products and bias in research. Neurotherapeutics, 12(4), 731–734.  https://doi.org/10.1007/s13311-015-0370-x CrossRefPubMedPubMedCentralGoogle Scholar
  40. Guy, G. W., Whittle, B. A., & Robson, P. (2004). The medicinal uses of cannabis and cannabinoids. Chicago, IL: Pharmaceutical Press.Google Scholar
  41. Guzman, M. (2003). Cannabinoids: Potential anticancer agents. Nature Reviews Cancer, 3(10), 745–755.  https://doi.org/10.1038/nrc1188 CrossRefPubMedGoogle Scholar
  42. Hamblin, M. W., Leff, S. E., & Creese, I. (1984). Interactions of agonists with D-2 dopamine receptors: Evidence for a single receptor population existing in multiple agonist affinity-states in rat striatal membranes. Biochemical Pharmacology, 33(6), 877–887.CrossRefGoogle Scholar
  43. Hookana, E., Ansakorpi, H., Kortelainen, M. L., Junttila, M. J., Kaikkonen, K. S., Perkiomaki, J., & Huikuri, H. V. (2016). Antiepileptic medications and the risk for sudden cardiac death caused by an acute coronary event: A prospective case-control study. Annals of Medicine, 48(1–2), 111–117.  https://doi.org/10.3109/07853890.2016.1140225 CrossRefPubMedGoogle Scholar
  44. Hu, S. S., & Mackie, K. (2015). Distribution of the endocannabinoid system in the central nervous system. Handbook of Experimental Pharmacology, 231, 59–93.  https://doi.org/10.1007/978-3-319-20825-1_3 CrossRefPubMedGoogle Scholar
  45. Huff, J., & Chan, P. (2000). Antitumor effects of THC. Environmental Health Perspectives, 108(10), A442–A443.CrossRefGoogle Scholar
  46. 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.  https://doi.org/10.1007/s002130100879 CrossRefGoogle Scholar
  47. Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V., & Mechoulam, R. (2009). Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends in Pharmacological Sciences, 30(10), 515–527.  https://doi.org/10.1016/j.tips.2009.07.006 CrossRefPubMedGoogle Scholar
  48. Jiang, W., Zhang, Y., Xiao, L., Van Cleemput, J., Ji, S. P., Bai, G., & Zhang, X. (2005). Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. The Journal of Clinical Investigation, 115(11), 3104–3116.  https://doi.org/10.1172/JCI25509 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Jin, K., Xie, L., Kim, S. H., Parmentier-Batteur, S., Sun, Y., Mao, X. O., … Greenberg, D. (2004). Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Molecular Pharmacology, 66(2), 204–208.  https://doi.org/10.1124/mol.66.2.204 CrossRefPubMedGoogle Scholar
  50. Johnson, J. R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E. D., Potts, R., & Fallon, M. T. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Journal of Pain and Symptom Management, 39(2), 167–179.  https://doi.org/10.1016/j.jpainsymman.2009.06.008 CrossRefPubMedGoogle Scholar
  51. Johnson, J. R., Lossignol, D., Burnell-Nugent, M., & Fallon, M. T. (2013). An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. Journal of Pain and Symptom Management, 46(2), 207–218.  https://doi.org/10.1016/j.jpainsymman.2012.07.014 CrossRefPubMedGoogle Scholar
  52. Keating, G. M. (2017). Delta-9-Tetrahydrocannabinol/Cannabidiol oromucosal spray (Sativex(R)): A review in multiple sclerosis-related spasticity. Drugs, 77(5), 563–574.  https://doi.org/10.1007/s40265-017-0720-6 CrossRefPubMedGoogle Scholar
  53. Kekecs, Z., Szollosi, A., Palfi, B., Szaszi, B., Kovacs, K. J., Dienes, Z., & Aczel, B. (2016). Commentary: Oxytocin-gaze positive loop and the coevolution of human-dog bonds. Frontiers in Neuroscience, 10, 155.  https://doi.org/10.3389/fnins.2016.00155 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Koehler, J. (2014). Who benefits most from THC:CBD spray? Learning from clinical experience. European Neurology, 71(Suppl 1), 10–15.  https://doi.org/10.1159/000357743 CrossRefPubMedGoogle Scholar
  55. Labate, B. C., & Cavnar, C. (2013). The therapeutic use of ayahuasca. New York, NY: Springer.Google Scholar
  56. Labate, B. C., & Cavnar, C. (2014a). Ayahuasca shamanism in the Amazon and beyond. New York, NY: Oxford University Press.CrossRefGoogle Scholar
  57. Labate, B. C., & Cavnar, C. (2014b). Prohibition, religious freedom, and human rights: Regulating traditional drug use. New York, NY: Springer.CrossRefGoogle Scholar
  58. Labigalini, E., Jr., Rodrigues, L. R., & Da Silveira, D. X. (1999). Therapeutic use of cannabis by crack addicts in Brazil. Journal of Psychoactive Drugs, 31(4), 451–455.  https://doi.org/10.1080/02791072.1999.10471776 CrossRefPubMedGoogle Scholar
  59. Ladin, D. A., Soliman, E., Griffin, L., & Van Dross, R. (2016). Preclinical and clinical assessment of cannabinoids as anti-cancer agents. Frontiers in Pharmacology, 7, 361.  https://doi.org/10.3389/fphar.2016.00361 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Letyagin, A. Y., Savelov, A. A., & Polosmak, A. A. (2014). High field magnetic resonance imaging of a mummy from Ak-Alakha-3 mound 1, Ukok plateau, Gorny Altai: Findings and interpretations. Archaeology Ethnology & Anthropology of Eurasia, 42(4), 83–91.CrossRefGoogle Scholar
  61. Lewis, D. Y., & Brett, R. R. (2010). Activity-based anorexia in C57/BL6 mice: Effects of the phytocannabinoid, Delta9-tetrahydrocannabinol (THC) and the anandamide analogue, OMDM-2. European Neuropsychopharmacology, 20(9), 622–631.  https://doi.org/10.1016/j.euroneuro.2010.04.002 CrossRefPubMedGoogle Scholar
  62. Liu, W. M., Fowler, D. W., & Dalgleish, A. G. (2010). Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids. Current Clinical Pharmacology, 5(4), 281–287.CrossRefGoogle Scholar
  63. Lombard, C., Nagarkatti, M., & Nagarkatti, P. S. (2005). Targeting cannabinoid receptors to treat leukemia: Role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. Leukemia Research, 29(8), 915–922.  https://doi.org/10.1016/j.leukres.2005.01.014 CrossRefPubMedGoogle Scholar
  64. Maccarrone, M., Maldonado, R., Casas, M., Henze, T., & Centonze, D. (2017). Cannabinoids therapeutic use: What is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others? Expert Review of Clinical Pharmacology, 10(4), 443–455.  https://doi.org/10.1080/17512433.2017.1292849 CrossRefPubMedGoogle Scholar
  65. 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.CrossRefGoogle Scholar
  66. McPartland, J. M., & Guy, G. W. (2004). The evolution of Cannabis and coevolution with the cannabinoid receptor—a hypothesis. In G. Guy, B. A. Whittle, & P. Robson (Eds.), The medicinal use of cannabis and cannabinoids (pp. 71–101). Grayslake, IL: Pharmaceutical Press.Google Scholar
  67. Mechoulam, R., Hanus, L. O., Pertwee, R., & Howlett, A. C. (2014). Early phytocannabinoid chemistry to endocannabinoids and beyond. Nature Reviews Neuroscience, 15(11), 757–764.  https://doi.org/10.1038/nrn3811 CrossRefPubMedGoogle Scholar
  68. Moldrich, G., & Wenger, T. (2000). Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides, 21(11), 1735–1742.CrossRefGoogle Scholar
  69. Molina-Holgado, F., Pinteaux, E., Moore, J. D., Molina-Holgado, E., Guaza, C., Gibson, R. M., & Rothwell, N. J. (2003). Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. Journal of Neuroscience, 23(16), 6470–6474.CrossRefGoogle Scholar
  70. 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.  https://doi.org/10.1038/npp.2010.58 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 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]. The British Journal of Psychiatry, 197(4), 285–290.  https://doi.org/10.1192/bjp.bp.110.077503 CrossRefPubMedGoogle Scholar
  72. Nagarkatti, P., Pandey, R., Rieder, S. A., Hegde, V. L., & Nagarkatti, M. (2009). Cannabinoids as novel anti-inflammatory drugs. Future Medicinal Chemistry, 1(7), 1333–1349.  https://doi.org/10.4155/fmc.09.93 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Nutt, D. J., King, L. A., Phillips, L. D., & Independent Scientific Committee on Drugs. (2010). Drug harms in the UK: A multicriteria decision analysis. Lancet, 376(9752), 1558–1565.  https://doi.org/10.1016/S0140-6736(10)61462-6 CrossRefPubMedGoogle Scholar
  74. Ohtsuka, Y., Yoshinaga, H., & Kobayashi, K. (2000). Refractory childhood epilepsy and factors related to refractoriness. Epilepsia, 41(Suppl 9), 14–17.CrossRefGoogle Scholar
  75. Osorio, L., Sanches, R. F., Macedo, L. R., Santos, R. G., Maia-de-Oliveira, J. P., Wichert-Ana, L., … Hallak, J. E. (2015). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A preliminary report. Revista Brasileira de Psiquiatria, 37(1), 13–20.  https://doi.org/10.1590/1516-4446-2014-1496 CrossRefGoogle Scholar
  76. Palhano-Fontes, F. (2017). Os efeitos antidepressivos da ayahuasca, suas bases neurais e relação com a experiência psicodélica [The antidepressant effects of ayahuasca, its neural bases and relation with the psychedelic experience] (Doctoral dissertation). Federal University of Rio Grande do Norte, Natal. Retrieved from https://repositorio.ufrn.br/jspui/handle/123456789/24156
  77. Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M., Pessoa, J., … de Araujo, D. B. (2017). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: A randomised placebo-controlled trial. BioRxiv.  https://doi.org/10.1101/103531
  78. Parakh, S., Naik, N., Rohatgi, N., Bhat, U., & Parakh, K. (2009). Eptifibatide overdose. International Journal of Cardiology, 131(3), 430–432.  https://doi.org/10.1016/j.ijcard.2007.07.132 CrossRefPubMedGoogle Scholar
  79. Park, H., Purnell, G. V., & Mirchandani, H. G. (1990). Suicide by captopril overdose. Journal of Toxicology: Clinical Toxicology, 28(3), 379–382.PubMedGoogle Scholar
  80. Parker, H. G., Dreger, D. L., Rimbault, M., Davis, B. W., Mullen, A. B., Carpintero-Ramirez, G., & Ostrander, E. A. (2017). Genomic analyses reveal the influence of geographic origin, migration, and hybridization on modern dog breed development. Cell Reports, 19(4), 697–708.  https://doi.org/10.1016/j.celrep.2017.03.079 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Patti, F. (2016). Health authorities data collection of THC:CBD oromucosal spray (L’Agenzia Italiana del Farmaco Web Registry): Figures after 1.5 years. European Neurology, 75(Suppl 1), 9–12.  https://doi.org/10.1159/000444236 CrossRefPubMedGoogle Scholar
  82. Phillips, D. R., & Scarborough, R. M. (1997). Clinical pharmacology of eptifibatide. American Journal of Cardiology, 80(4A), 11B–20B.CrossRefGoogle Scholar
  83. Pollan, M. (2001). The botany of desire: A plant’s eye view of the world (1st ed.). New York, NY: Random House.Google Scholar
  84. Price, M. R., Baillie, G. L., Thomas, A., Stevenson, L. A., Easson, M., Goodwin, R., … Ross, R. A. (2005). Allosteric modulation of the cannabinoid CB1 receptor. Molecular Pharmacology, 68(5), 1484–1495.  https://doi.org/10.1124/mol.105.016162 CrossRefPubMedGoogle Scholar
  85. Radwan, M. M., Elsohly, M. A., Slade, D., Ahmed, S. A., Wilson, L., El-Alfy, A. T., … Ross, S. A. (2008). Non-cannabinoid constituents from a high potency Cannabis sativa variety. Phytochemistry, 69(14), 2627–2633.  https://doi.org/10.1016/j.phytochem.2008.07.010 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Rekand, T. (2014). THC:CBD spray and MS spasticity symptoms: Data from latest studies. European Neurology, 71(Suppl 1), 4–9.  https://doi.org/10.1159/000357742 CrossRefPubMedGoogle Scholar
  87. Rickli, A., Moning, O. D., Hoener, M. C., & Liechti, M. E. (2016). Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology, 26(8), 1327–1337.  https://doi.org/10.1016/j.euroneuro.2016.05.001 CrossRefPubMedGoogle Scholar
  88. Rimonabant: Depression and suicide. (2009). Prescrire International, 18(99), 24.Google Scholar
  89. Robbe, D., Montgomery, S. M., Thome, A., Rueda-Orozco, P. E., McNaughton, B. L., & Buzsaki, G. (2006). Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nature Neuroscience, 9(12), 1526–1533.  https://doi.org/10.1038/nn1801 CrossRefPubMedGoogle Scholar
  90. Rocha e Silva, M. (1963). The physiological significance of bradykinin. Annals of the New York Academy of Sciences, 104, 190–210.CrossRefGoogle Scholar
  91. Romeo, B., Choucha, W., Fossati, P., & Rotge, J. Y. (2015). Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Research, 230(2), 682–688.  https://doi.org/10.1016/j.psychres.2015.10.032 CrossRefPubMedGoogle Scholar
  92. Rosenberg, E. C., Tsien, R. W., Whalley, B. J., & Devinsky, O. (2015). Cannabinoids and epilepsy. Neurotherapeutics, 12(4), 747–768.  https://doi.org/10.1007/s13311-015-0375-5 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Russo, E. B. (2011). Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163(7), 1344–1364.  https://doi.org/10.1111/j.1476-5381.2011.01238.x CrossRefPubMedPubMedCentralGoogle Scholar
  94. Sanches, R. F., de Lima Osorio, F., Dos Santos, R. G., Macedo, L. R., Maia-de-Oliveira, J. P., Wichert-Ana, L., … Hallak, J. E. (2016). Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A SPECT study. Journal of Clinical Psychopharmacology, 36(1), 77–81.  https://doi.org/10.1097/JCP.0000000000000436 CrossRefPubMedGoogle Scholar
  95. Sastre-Garriga, J., Vila, C., Clissold, S., & Montalban, X. (2011). THC and CBD oromucosal spray (Sativex(R)) in the management of spasticity associated with multiple sclerosis. Expert Review of Neurotherapeutics, 11(5), 627–637.  https://doi.org/10.1586/ern.11.47 CrossRefPubMedGoogle Scholar
  96. Sawler, J., Stout, J. M., Gardner, K. M., Hudson, D., Vidmar, J., Butler, L., … Myles, S. (2015). The genetic structure of marijuana and hemp. PLoS One, 10(8), e0133292.  https://doi.org/10.1371/journal.pone.0133292 CrossRefPubMedPubMedCentralGoogle Scholar
  97. Schmits, E., & Quertemont, E. (2013). Les drogues dites “douces”: Cannibas et syndrome amotivationnel [So called “soft” drugs: cannabis and the amotivational syndrome]. Revue Médicale de Liège, 68(5–6), 281–286.PubMedGoogle Scholar
  98. 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. Molecular Cancer Therapeutics, 13(12), 2955–2967.  https://doi.org/10.1158/1535-7163.MCT-14-0402 CrossRefPubMedGoogle Scholar
  99. Sherif, M., Radhakrishnan, R., D’Souza, D. C., & Ranganathan, M. (2016). Human laboratory studies on Cannabinoids and psychosis. Biological Psychiatry, 79(7), 526–538.  https://doi.org/10.1016/j.biopsych.2016.01.011 CrossRefPubMedGoogle Scholar
  100. Silva, T. B., Balbino, C. Q., & Weiber, A. F. (2015). The relationship between cannabidiol and psychosis: A review. Annals of Clinical Psychiatry, 27(2), 134–141.PubMedGoogle Scholar
  101. Solt, K., Ruesch, D., Forman, S. A., Davies, P. A., & Raines, D. E. (2007). Differential effects of serotonin and dopamine on human 5-HT3A receptor kinetics: Interpretation within an allosteric kinetic model. Journal of Neuroscience, 27(48), 13151–13160.  https://doi.org/10.1523/JNEUROSCI.3772-07.2007 CrossRefPubMedGoogle Scholar
  102. Sznitman, S. R., & Lewis, N. (2015). Is cannabis an illicit drug or a medicine? A quantitative framing analysis of Israeli newspaper coverage. International Journal of Drug Policy, 26(5), 446–452.  https://doi.org/10.1016/j.drugpo.2015.01.010 CrossRefPubMedGoogle Scholar
  103. Thomas, G., Lucas, P., Capler, N. R., Tupper, K. W., & Martin, G. (2013). Ayahuasca-assisted therapy for addiction: Results from a preliminary observational study in Canada. Current Drug Abuse Reviews, 6(1), 30–42.CrossRefGoogle Scholar
  104. Topol, E. J., Bousser, M. G., Fox, K. A., Creager, M. A., Despres, J. P., Easton, J. D., … Investigators, C. (2010). Rimonabant for prevention of cardiovascular events (CRESCENDO): A randomised, multicentre, placebo-controlled trial. Lancet, 376(9740), 517–523.  https://doi.org/10.1016/S0140-6736(10)60935-X CrossRefPubMedGoogle Scholar
  105. Tsou, K., Brown, S., Sanudo-Pena, M. C., Mackie, K., & Walker, J. M. (1998). Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience, 83(2), 393–411.CrossRefGoogle Scholar
  106. U’Prichard, D. C. (1980). Multiple CNS receptor interactions of ergot alkaloids: Affinity and intrinsic activity analysis in in vitro binding systems. Advances in Biochemical Psychopharmacology, 23, 103–115.PubMedGoogle Scholar
  107. van Vliet, S. A., Vanwersch, R. A., Jongsma, M. J., Olivier, B., & Philippens, I. H. (2008). Therapeutic effects of Delta9-THC and modafinil in a marmoset Parkinson model. European Neuropsychopharmacology, 18(5), 383–389.  https://doi.org/10.1016/j.euroneuro.2007.11.003 CrossRefPubMedGoogle Scholar
  108. Verty, A. N., Evetts, M. J., Crouch, G. J., McGregor, I. S., Stefanidis, A., & Oldfield, B. J. (2011). The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia. Neuropsychopharmacology, 36(7), 1349–1358.  https://doi.org/10.1038/npp.2011.19 CrossRefPubMedPubMedCentralGoogle Scholar
  109. Wacker, D., Wang, S., McCorvy, J. D., Betz, R. M., Venkatakrishnan, A. J., Levit, A., … Roth, B. L. (2017). Crystal structure of an LSD-bound human serotonin receptor. Cell, 168(3), 377–389. e312.  https://doi.org/10.1016/j.cell.2016.12.033 CrossRefPubMedPubMedCentralGoogle Scholar
  110. Weber, M., Goldman, B., & Truniger, S. (2010). Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: A randomised, double-blind crossover trial. Journal of Neurology, Neurosurgery & Psychiatry, 81(10), 1135–1140.  https://doi.org/10.1136/jnnp.2009.200642 CrossRefGoogle Scholar
  111. Winkelman, M. (2014). Psychedelics as medicines for substance abuse rehabilitation: Evaluating treatments with LSD, peyote, ibogaine and ayahuasca. Current Drug Abuse Reviews, 7(2), 101–116.CrossRefGoogle Scholar
  112. Xapelli, S., Agasse, F., Sarda-Arroyo, L., Bernardino, L., Santos, T., Ribeiro, F. F., … Malva, J. O. (2013). Activation of type 1 cannabinoid receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures. PLoS One, 8(5), e63529.  https://doi.org/10.1371/journal.pone.0063529 CrossRefPubMedPubMedCentralGoogle Scholar
  113. Yu, Y. Z., Liu, S., Wang, H. C., Shi, D. Y., Xu, Q., Zhou, X. W., … Huang, P. T. (2016). A novel recombinant 6Abeta15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer’s disease-like pathology, cognitive decline and synaptic loss in aged 3 x Tg-AD mice. Scientific Reports, 6, 27175.  https://doi.org/10.1038/srep27175 CrossRefPubMedPubMedCentralGoogle Scholar
  114. Zani, A., Braida, D., Capurro, V., & Sala, M. (2007). Delta9-tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors. British Journal of Pharmacology, 152(8), 1301–1311.  https://doi.org/10.1038/sj.bjp.0707514 CrossRefPubMedPubMedCentralGoogle Scholar
  115. Zarate, C. A., Jr., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., … Manji, H. K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 63(8), 856–864.  https://doi.org/10.1001/archpsyc.63.8.856 CrossRefPubMedGoogle Scholar
  116. Zettl, U. K., Rommer, P., Hipp, P., & Patejdl, R. (2016). Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis. Therapeutic Advances in Neurological Disorders, 9(1), 9–30.  https://doi.org/10.1177/1756285615612659 CrossRefPubMedPubMedCentralGoogle Scholar
  117. Zuardi, A. W., Crippa, J. A., & Hallak, J. E. (2010). Cannabis sativa: A planta que pode produzir efeitos indesejáveis e também tratá-los [Cannabis sativa: The plant that can induce unwanted effects and also treat them]. Revista Brasileira de Psiquiatria, 32(Suppl 1), S1–S2.CrossRefGoogle Scholar
  118. 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: 30 years of a translational investigation. Current Pharmaceutical Design, 18(32), 5131–5140.CrossRefGoogle Scholar
  119. Zurier, R. B. (2003). Prospects for cannabinoids as anti-inflammatory agents. Journal of Cellular Biochemistry, 88(3), 462–466.  https://doi.org/10.1002/jcb.10291 CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Brain InstituteFederal University of Rio Grande do NorteNatalBrazil

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