Therapeutic Potential of Natural Psychoactive Drugs for Central Nervous System Disorders: A Perspective from Polypharmacology (original) (raw)

In the drug development, the formation of highly selective ligands has been unsuccessful in the treatment of central nervous system disorders. Multi-target ligands, from the polypharmacology paradigm, are being proposed as treatments for these complex disorders, since they offer enhanced efficacy and a strong safety profile. Natural products are the best examples of multi-target compounds, so they are of high interest within this paradigm. Additionally, recent research on psychoactive drugs of natural origin, such as ayahuasca and cannabis, has demonstrated the promising therapeutic potential for the treatment of some psychiatric and neurological disorders. In this text, we describe how research on psychoactive drugs can be effectively combined with the polypharmacology paradigm, providing ayahuasca and cannabis research as examples. The advantages and disadvantages are also discussed.

Keywords: Polypharmacology, multi-target, psychoactive, ayahuasca, cannabis, plant, therapeutic.

[10]

Treede, R.D.; Rief, W.; Barke, A.; Aziz, Q.; Bennett, M.I.; Benoliel, R.; Cohen, M.; Evers, S.; Finnerup, N.B.; First, M.B.; Giamberardino, M.A.; Kaasa, S.; Kosek, E. Lavandʼhomme, P.; Nicholas, M.; Perrot, S.; Scholz, J.; Schug, S.; Smith, B.H.; Svensson, P.; Vlaeyen, J.W.; Wang, S.J. A classification of chronic pain for ICD-11. Pain , 2015, 156(6), 1003-1007.
[http://dx.doi.org/10.1097/j.pain.0000000000000160] [PMID: 25844555]

[14]

Dos Santos, R.G.; Bouso, J.C.; Alcázar-Córcoles, M.Á.; Hallak, J.E.C. Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews. Expert Rev. Clin. Pharmacol. , 2018, 11(9), 889-902.
[http://dx.doi.org/10.1080/17512433.2018.1511424] [PMID: 30102078]

[15]

Horrobin, D.F. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat. Rev. Drug Discov. , 2003, 2(2), 151-154.
[http://dx.doi.org/10.1038/nrd1012] [PMID: 12563306]

[20]

Escott-Price, V.; Nalls, M.A.; Morris, H.R.; Lubbe, S.; Brice, A.; Gasser, T.; Heutink, P.; Wood, N.W. H ardy, J.; Singleton, A.B.; Williams, N.M. International Parkinson’s disease genomics consortium; IPDGC consortium members. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann. Neurol. , 2015, 77(4), 582-591.
[http://dx.doi.org/10.1002/ana.24335] [PMID: 25773351]

[21]

Hagenaars, S.P.; Radaković, R.; Crockford, C.; Fawns-Ritchie, C.; Harris, S.E.; Gale, C.R.; Deary, I.J. International FTD-genomics consortium (IFGC). Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function. PLoS One , 2018, 13(6)e0198187
[http://dx.doi.org/10.1371/journal.pone.0198187] [PMID: 29856801]

[22]

Purcell, S.M.; Wray, N.R.; Stone, J.L.; Visscher, P.M.; O’Donovan, M.C.; Sullivan, P.F.; Sklar, P. International Schizophrenia consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature , 2009, 460(7256), 748-752.
[http://dx.doi.org/10.1038/nature08185] [PMID: 19571811]

[25]

Setola, V.; Roth, B.L. Why mice are neither miniature humans nor small rats: a cautionary tale involving 5-hydroxytryptamine-6 serotonin receptor species variants. Mol. Pharmacol. , 2003, 64(6), 1277-1278.
[http://dx.doi.org/10.1124/mol.64.6.1277] [PMID: 14645656]

[29]

Agoston, V.; Csermely, P.; Pongor, S. Multiple weak hits confuse complex systems: a transcriptional regulatory network as an example. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. , 2005, 71(5 Pt 1)051909
[http://dx.doi.org/10.1103/PhysRevE.71.051909] [PMID: 16089573]

[37]

Aixalà, M.; Ona, G.; Parés, Ò.; Bouso, J.C. Patterns of use, desired effects, and mental health status of a sample of natural psychoactive drug users. Drugs Educ. Prev. Policy , 2019, 27(3), 191-198.
[http://dx.doi.org/10.1080/09687637.2019.1611739]

[42]

Berthoux, C.; Barre, A.; Bockaert, J.; Marin, P.; Bécamel, C. Sustained activation of postsynaptic 5-HT2A receptors gates plasticity at prefrontal cortex synapses. Cereb. Cortex , 2019, 29(4), 1659-1669.
[http://dx.doi.org/10.1093/cercor/bhy064] [PMID: 29917056]

[43]

Ly, C.; Greb, A.C.; Cameron, L.P.; Wong, J.M.; Barragan, E.V.; Wilson, P.C.; Burbach, K.F.; Soltanzadeh Zarandi, S.; Sood, A.; Paddy, M.R.; Duim, W.C.; Dennis, M.Y.; McAllister, A.K.; Ori-McKenney, K.M.; Gray, J.A.; Olson, D.E. Olson, D.E. Psychedelics promote structural and functional neural plasticity. Cell Rep. , 2018, 23(11), 3170-3182.
[http://dx.doi.org/10.1016/j.celrep.2018.05.022] [PMID: 29898390]

[44]

Bouso, J.C.; Palhano-Fontes, F.; Rodríguez-Fornells, A.; Ribeiro, S.; Sanches, R.; Crippa, J.A.; Hallak, J.E.C.; de Araujo, D.B.; Riba, J. Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. Eur. Neuropsychopharmacol. , 2015, 25(4), 483-492.
[http://dx.doi.org/10.1016/j.euroneuro.2015.01.008] [PMID: 25637267]

[47]

Schindler, E.A.D.; Wallace, R.M.; Sloshower, J.A.; D’Souza, D.C. Neuroendocrine associations underlying the persistent therapeutic effects of classic serotonergic psychedelics. Front. Pharmacol. , 2018, 9, 177.
[http://dx.doi.org/10.3389/fphar.2018.00177] [PMID: 29545753]

[48]

Chu, M.; Chen, X.; Wang, J.; Guo, L.; Wang, Q.; Gao, Z.; Kang, J.; Zhang, M.; Feng, J.; Guo, Q.; Li, B.; Zhang, C.; Guo, X.; Chu, Z.; Wang, Y. Polypharmacology of berberine based on multi-target binding motifs. Front. Pharmacol. , 2018, 9, 801.
[http://dx.doi.org/10.3389/fphar.2018.00801] [PMID: 30087614]

[54]

Esatbeyoglu, T.; Huebbe, P.; Ernst, I.M.; Chin, D.; Wagner, A.E.; Rimbach, G. Curcumin--from molecule to biological function. Angew. Chem. Int. Ed. Engl. , 2012, 51(22), 5308-5332.
[http://dx.doi.org/10.1002/anie.201107724] [PMID: 22566109]

[57]

Deng, Y.H.; Wang, N.N.; Zou, Z.X.; Zhang, L.; Xu, K.P.; Chen, A.F.; Cao, D.S.; Tan, G.S. Multi-target screening and experimental validation of natural products from Selaginella plants against Alzheimer’s disease. Front. Pharmacol. , 2017, 8, 539.
[http://dx.doi.org/10.3389/fphar.2017.00539] [PMID: 28890698]

[59]

Shan, C.S.; Zhang, H.F.; Xu, Q.Q.; Shi, Y.H.; Wang, Y.; Li, Y.; Lin, Y.; Zheng, G.Q. Herbal medicine formulas for Parkinson’s disease: a systematic review and meta-analysis of randomized double-blind placebo-controlled clinical trials. Front. Aging Neurosci. , 2018, 10, 349.
[http://dx.doi.org/10.3389/fnagi.2018.00349] [PMID: 30467472]

[61]

Singh, B.N.; Shankar, S.; Srivastava, R.K. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem. Pharmacol. , 2011, 82(12), 1807-1821.
[http://dx.doi.org/10.1016/j.bcp.2011.07.093] [PMID: 21827739]

[62]

Domínguez-Clavé, E.; Soler, J.; Elices, M.; Pascual, J.C.; Álvarez, E.; de la Fuente Revenga, M.; Friedlander, P.; Feilding, A.; Riba, J. Ayahuasca: Pharmacology, neuroscience and therapeutic potential. Brain Res. Bull. , 2016, 126(Pt 1), 89-101.
[http://dx.doi.org/10.1016/j.brainresbull.2016.03.002] [PMID: 26976063]

[64]

Santos, M.C.; Navickiene, S.; Gaujac, A. Determination of tryptamines and β-carbolines in ayahuasca beverage consumed during Brazilian religious ceremonies. J. AOAC Int. , 2017, 100(3), 820-824.
[http://dx.doi.org/10.5740/jaoacint.16-0337] [PMID: 28105971]

[66]

Herraiz, T.; González, D.; Ancín-Azpilicueta, C.; Arán, V.J.; Guillén, H. beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem. Toxicol. , 2010, 48(3), 839-845.
[http://dx.doi.org/10.1016/j.fct.2009.12.019] [PMID: 20036304]

[68]

Moura, D.J.; Richter, M.F.; Boeira, J.M.; Pêgas Henriques, J.A.; Saffi, J. Antioxidant properties of beta-carboline alkaloids are related to their antimutagenic and antigenotoxic activities. Mutagenesis , 2007, 22(4), 293-302.
[http://dx.doi.org/10.1093/mutage/gem016] [PMID: 17545209]

[69]

Riba, J.; Valle, M.; Urbano, G.; Yritia, M.; Morte, A.; Barbanoj, M.J. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J. Pharmacol. Exp. Ther. , 2003, 306(1), 73-83.
[http://dx.doi.org/10.1124/jpet.103.049882]] [PMID: 12660312]

[70]

Nasehi, M.; Piri, M.; Nouri, M.; Farzin, D.; Nayer-Nouri, T.; Zarrindast, M.R. Involvement of dopamine D1/D2 receptors on harmane-induced amnesia in the step-down passive avoidance test. Eur. J. Pharmacol. , 2010, 634(1-3), 77-83.
[http://dx.doi.org/10.1016/j.ejphar.2010.02.027] [PMID: 20188725]

[71]

Glennon, R.A.; Dukat, M.; Grella, B.; Hong, S.; Costantino, L.; Teitler, M.; Smith, C.; Egan, C.; Davis, K.; Mattson, M.V. Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors. Drug Alcohol Depend. , 2000, 60(2), 121-132.
[http://dx.doi.org/10.1016/S0376-8716(99)00148-9] [PMID: 10940539]

[72]

Husbands, S.M.; Glennon, R.A.; Gorgerat, S.; Gough, R.; Tyacke, R.; Crosby, J.; Nutt, D.J.; Lewis, J.W.; Hudson, A.L. beta-carboline binding to imidazoline receptors. Drug Alcohol Depend. , 2001, 64(2), 203-208.
[http://dx.doi.org/10.1016/S0376-8716(01)00123-5] [PMID: 11543990]

[73]

Farouk, L.; Laroubi, A.; Aboufatima, R.; Benharref, A.; Chait, A. Evaluation of the analgesic effect of alkaloid extract of Peganum harmala L.: possible mechanisms involved. J. Ethnopharmacol. , 2008, 115(3), 449-454.
[http://dx.doi.org/10.1016/j.jep.2007.10.014] [PMID: 18054186]

[74]

Akhtar, M.S.; Iqbal, Z.; Khan, M.N.; Lateef, M. Anthelmintic activity of medicinal plants with particular reference to their use in animals in the Indo-Pakistan subcontinent. Small Rumin. Res. , 2010, 38(2), 99-107.
[http://dx.doi.org/10.1016/S0921-4488(00)00163-2]

[75]

Moloudizargari, M.; Mikaili, P.; Aghajanshakeri, S.; Asghari, M.H.; Shayegh, J. Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. Pharmacogn. Rev. , 2013, 7(14), 199-212.
[http://dx.doi.org/10.4103/0973-7847.120524] [PMID: 24347928]

[76]

Beringer, K. Ueber ein neues, auf das extrapyramidalmotorische System wirkendes Alkaloid (Banisterin). Nervenarzt , 1928, 1, 265-275.

[77]

Lewin, L. Sur une substance enivrante, la banistérine, extraite de Banisteria Caapi. C. R. Hebd. Seances Acad. Sci. , 1928, 186, 469-471.

[78]

Djamshidian, A.; Bernschneider-Reif, S.; Poewe, W.; Lees, A.J. Banisteriopsis caapi, a forgotten potential therapy for Parkinson’s disease? Mov. Disord. Clin. Pract. (Hoboken) , 2015, 3(1), 19-26.
[http://dx.doi.org/10.1002/mdc3.12242] [PMID: 30713897]

[79]

Fisher, R.; Lincoln, L.; Jackson, M.J.; Abbate, V.; Jenner, P.; Hider, R.; Lees, A.; Rose, S. The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP-treated common marmoset model of Parkinson’s disease. Phytother. Res. , 2018, 32(4), 678-687.
[http://dx.doi.org/10.1002/ptr.6017] [PMID: 29368409]

[80]

Morales-García, J.A.; de la Fuente Revenga, M.; Alonso-Gil, S.; Rodríguez-Franco, M.I.; Feilding, A.; Perez-Castillo, A.; Riba, J. The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro. Sci. Rep. , 2017, 7(1), 5309.
[http://dx.doi.org/10.1038/s41598-017-05407-9] [PMID: 28706205]

[82]

Keiser, M.J.; Setola, V.; Irwin, J.J.; Laggner, C.; Abbas, A.I.; Hufeisen, S.J.; Jensen, N.H.; Kuijer, M.B.; Matos, R.C.; Tran, T.B.; Whaley, R.; Glennon, R.A.; Hert, J.; Thomas, K.L.; Edwards, D.D.; Shoichet, B.K.; Roth, B.L. Predicting new molecular targets for known drugs. Nature , 2009, 462(7270), 175-181.
[http://dx.doi.org/10.1038/nature08506] [PMID: 19881490]

[85]

Fontanilla, D.; Johannessen, M.; Hajipour, A.R.; Cozzi, N.V.; Jackson, M.B.; Ruoho, A.E. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science , 2009, 323(5916), 934-937.
[http://dx.doi.org/10.1126/science.1166127] [PMID: 19213917]

[87]

Revel, F.G.; Moreau, J.L.; Gainetdinov, R.R.; Ferragud, A.; Velázquez-Sánchez, C.; Sotnikova, T.D.; Morairty, S.R.; Harmeier, A.; Groebke Zbinden, K.; Norcross, R.D.; Bradaia, A.; Kilduff, T.S.; Biemans, B.; Pouzet, B.; Caron, M.G.; Canales, J.J.; Wallace, T.L.; Wettstein, J.G.; Hoener, M.C. Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol. Psychiatry , 2012, 72(11), 934-942.
[http://dx.doi.org/10.1016/j.biopsych.2012.05.014] [PMID: 22705041]

[89]

Riba, J.; Barbanoj, M.J. Ayahuasca.Tratado SET de trastornos adictivos; Peris, J.C.; Zurián, J.C.; Martínez, G.C; Valladolid, G.R.Ed. Médica Panamericana; Madrid, 2006, pp. 321-324.

[90]

Palhano-Fontes, F.; Barreto, D.; Onias, H.; Andrade, K.C.; Novaes, M.M.; Pessoa, J.A.; Mota-Rolim, S.A.; Osório, F.L.; Sanches, R.; Dos Santos, R.G.; Tófoli, L.F.; de Oliveira Silveira, G.; Yonamine, M.; Riba, J.; Santos, F.R.; Silva-Junior, A.A.; Alchieri, J.C.; Galvão-Coelho, N.L.; Lobão-Soares, B.; Hallak, J.E.C.; Arcoverde, E.; Maia-de-Oliveira, J.P.; Araújo, D.B. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol. Med. , 2019, 49(4), 655-663.
[http://dx.doi.org/10.1017/S0033291718001356] [PMID: 29903051]

[91]

Osório. Fde.L.; Sanches, R.F.; Macedo, L.R.; Santos, R.G.; Maia-de-Oliveira, J.P.; Wichert-Ana, L.; Araujo, D.B.; Riba, J.; Crippa, J.A.; Hallak, J.E.C. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Br. J. Psychiatry , 2015, 37(1), 13-20.
[http://dx.doi.org/10.1590/1516-4446-2014-1496] [PMID: 25806551]

[92]

Sanches, R.F.; de Lima Osório, F.; Dos Santos, R.G.; Macedo, L.R.; Maia-de-Oliveira, J.P.; Wichert-Ana, L.; de Araujo, D.B.; Riba, J.; Crippa, J.A.; Hallak, J.E.C. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J. Clin. Psychopharmacol. , 2016, 36(1), 77-81.
[http://dx.doi.org/10.1097/JCP.0000000000000436] [PMID: 26650973]

[93]

Franquesa, A.; Sainz-Cort, A.; Gandy, S.; Soler, J.; Alcázar-Córcoles, M.Á.; Bouso, J.C. Psychological variables implied in the therapeutic effect of ayahuasca: a contextual approach. Psychiatry Res. , 2018, 264, 334-339.
[http://dx.doi.org/10.1016/j.psychres.2018.04.012] [PMID: 29674223]

[94]

Soler, J.; Elices, M.; Franquesa, A.; Barker, S.; Friedlander, P.; Feilding, A.; Pascual, J.C.; Riba, J. Exploring the therapeutic potential of Ayahuasca: acute intake increases mindfulness-related capacities. Psychopharmacology (Berl.) , 2016, 233(5), 823-829.
[http://dx.doi.org/10.1007/s00213-015-4162-0] [PMID: 26612618]

[95]

Barbosa, P.C.; Cazorla, I.M.; Giglio, J.S.; Strassman, R. A six-month prospective evaluation of personality traits, psychiatric symptoms and quality of life in ayahuasca-naïve subjects. J. Psychoactive Drugs , 2009, 41(3), 205-212.
[http://dx.doi.org/10.1080/02791072.2009.10400530] [PMID: 19999673]

[98]

Lima, F.A.S.; Tófoli, L.F. An epidemiological surveillance system by the UDV: mental health recommendations concerning the religious use of hoasca. The internationalization of ayahuasca; Labate, B.C; Jungaberle, H., Ed.; , 2011, pp. 185-200.

[100]

Gouzoulis-Mayfrank, E.; Heekeren, K.; Neukirch, A.; Stoll, M.; Stock, C.; Obradovic, M.; Kovar, K.A. Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry , 2005, 38(6), 301-311.
[http://dx.doi.org/10.1055/s-2005-916185] [PMID: 16342002]

[102]

Riba, J.; Rodríguez-Fornells, A.; Urbano, G.; Morte, A.; Antonijoan, R.; Montero, M.; Callaway, J.C.; Barbanoj, M.J. Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers. Psychopharmacology (Berl.) , 2001, 154(1), 85-95.
[http://dx.doi.org/10.1007/s002130000606] [PMID: 11292011]

[103]

Barbosa, P.C.; Strassman, R.J.; da Silveira, D.X.; Areco, K.; Hoy, R.; Pommy, J.; Thoma, R.; Bogenschutz, M. Psychological and neuropsychological assessment of regular hoasca users. Compr. Psychiatry , 2016, 71, 95-105.
[http://dx.doi.org/10.1016/j.comppsych.2016.09.003] [PMID: 27653781]

[104]

Bouso, J.C.; González, D.; Fondevila, S.; Cutchet, M.; Fernández, X.; Ribeiro Barbosa, P.C.; Alcázar-Córcoles, M.Á.; Araújo, W.S.; Barbanoj, M.J.; Fábregas, J.M. Riba, J. Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One , 2012, 7(8)e42421
[http://dx.doi.org/10.1371/journal.pone.0042421] [PMID: 22905130]

[105]

Grob, C.S.; McKenna, D.J.; Callaway, J.C.; Brito, G.S.; Neves, E.S.; Oberlaender, G.; Saide, O.L.; Labigalini, E.; Tacla, C.; Miranda, C.T.; Strassman, R.J.; Boone, K.B. Human psychopharmacology of hoasca, a plant hallucinogen used in ritual context in Brazil. J. Nerv. Ment. Dis. , 1996, 184(2), 86-94.
[http://dx.doi.org/10.1097/00005053-199602000-00004] [PMID: 8596116]

[106]

Halpern, J.H.; Sherwood, A.R.; Passie, T.; Blackwell, K.C.; Ruttenber, A.J. Evidence of health and safety in American members of a religion who use a hallucinogenic sacrament. Med. Sci. Monit. , 2008, 14(8), SR15-SR22.
[PMID: 18668010]

[112]

Hindocha, C.; Freeman, T.P.; Schafer, G.; Gardener, C.; Das, R.K.; Morgan, C.J.; Curran, H.V. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur. Neuropsychopharmacol. , 2015, 25(3), 325-334.
[http://dx.doi.org/10.1016/j.euroneuro.2014.11.014] [PMID: 25534187]

[113]

Ben-Shabat, S.; Fride, E.; Sheskin, T.; Tamiri, T.; Rhee, M.H.; Vogel, Z.; Bisogno, T.; De Petrocellis, L.; Di Marzo, V.; Mechoulam, R. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. , 1998, 353(1), 23-31.
[http://dx.doi.org/10.1016/S0014-2999(98)00392-6] [PMID: 9721036]

[114]

Benbadis, S.R.; Sanchez-Ramos, J.; Bozorg, A.; Giarratano, M.; Kalidas, K.; Katzin, L.; Robertson, D.; Vu, T.; Smith, A.; Zesiewicz, T. Medical marijuana in neurology. Expert Rev. Neurother. , 2014, 14(12), 1453-1465.
[http://dx.doi.org/10.1586/14737175.2014.985209] [PMID: 25427150]

[115]

Blasco-Benito, S.; Seijo-Vila, M.; Caro-Villalobos, M.; Tundidor, I.; Andradas, C.; García-Taboada, E.; Wade, J.; Smith, S.; Guzmán, M.; Pérez-Gómez, E.; Gordon, M.; Sánchez, C. Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem. Pharmacol. , 2018, 157, 285-293.
[http://dx.doi.org/10.1016/j.bcp.2018.06.025] [PMID: 29940172]

[116]

Pamplona, F.A.; da Silva, L.R.; Coan, A.C. Potential clinical benefits of CBD-rich cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis. Front. Neurol. , 2018, 9, 759.
[http://dx.doi.org/10.3389/fneur.2018.00759] [PMID: 30258398]

[117]

Vigil, J.M.; Stith, S.S.; Diviant, J.P.; Brockelman, F.; Keeling, K.; Hall, B. Effectiveness of raw, natural medical cannabis flower for treating insomnia under naturalistic conditions. Medicines (Basel) , 2018, 5(3)E75
[http://dx.doi.org/10.3390/medicines5030075] [PMID: 29997343]

[120]

Maccarrone, M.; Bab, I.; Bíró, T.; Cabral, G.A.; Dey, S.K.; Di Marzo, V.; Konje, J.C.; Kunos, G.; Mechoulam, R.; Pacher, P.; Sharkey, K.A.; Zimmer, A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. , 2015, 36(5), 277-296.
[http://dx.doi.org/10.1016/j.tips.2015.02.008] [PMID: 25796370]

[121]

Piscitelli, F.; Di Marzo, V. “Redundancy” of endocannabinoid inactivation: new challenges and opportunities for pain control. ACS Chem. Neurosci. , 2012, 3(5), 356-363.
[http://dx.doi.org/10.1021/cn300015x] [PMID: 22860203]

[123]

Morrison, P.D.; Zois, V.; McKeown, D.A.; Lee, T.D.; Holt, D.W.; Powell, J.F.; Kapur, S.; Murray, R.M. The acute effects of synthetic intravenous Delta9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychol. Med. , 2009, 39(10), 1607-1616.
[http://dx.doi.org/10.1017/S0033291709005522] [PMID: 19335936]

[127]

Fischer, B.; Russell, C.; Sabioni, P.; van den Brink, W.; Le Foll, B.; Hall, W.; Rehm, J.; Room, R. Lower-risk cannabis use guidelines: a comprehensive update of evidence and recommendations. Am. J. Public Health , 2017, 107(8), e1-e12.
[http://dx.doi.org/10.2105/AJPH.2017.303818] [PMID: 28644037]

[129]

Mechoulam, R.; Ben-Shabat, S. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat. Prod. Rep. , 1999, 16(2), 131-143.
[http://dx.doi.org/10.1039/a703973e] [PMID: 10331283]

[130]

Elfawal, M.A.; Towler, M.J.; Reich, N.G.; Weathers, P.J.; Rich, S.M. Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. Proc. Natl. Acad. Sci. USA , 2015, 112(3), 821-826.
[http://dx.doi.org/10.1073/pnas.1413127112] [PMID: 25561559]

[131]

Gasser, P.; Holstein, D.; Michel, Y.; Doblin, R.; Yazar-Klosinski, B.; Passie, T.; Brenneisen, R. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J. Nerv. Ment. Dis. , 2014, 202(7), 513-520.
[http://dx.doi.org/10.1097/NMD.0000000000000113] [PMID: 24594678]

[133]

Studerus, E.; Kometer, M.; Hasler, F.; Vollenweider, F.X. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J. Psychopharmacol. , 2011, 25(11), 1434-1452.
[http://dx.doi.org/10.1177/0269881110382466] [PMID: 20855349]

[134]

Gallily, R.; Yekhtin, Z.; Hanuš, L.O. Overcoming the Bell-shaped dose-response of cannabidiol by using cannabis extract enriched in cannabidiol. Pharmacol. Pharm. , 2015, 6, 75-85.
[http://dx.doi.org/10.4236/pp.2015.62010]