Abstract
Rationale
Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT2A/2C/1A agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses.
Objectives
To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization.
Methods
In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration.
Results
DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose.
Conclusions
Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aloyo VJ, Dave KD, Rahman T, Harvey JA (2001) Selective and divergent regulation of cortical 5-HT2A receptors in rabbit. J Pharmacol Exp Ther 299:1066–1072
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (4th ed., text rev.). APA, Washington DC
Anderson IM, Deakin JF, Miller HE (1996) The effect of chronic fluvoxamine on hormonal and psychological responses to buspirone in normal volunteers. Psychopharmacology (Berl) 128:74–82
Assié MB, Lomenech H, Ravailhe V, Faucillon V, Newman-Tancredi A (2006) Rapid desensitization of somatodendritic 5-HT1A receptors by chronic administration of the high-efficacy 5-HT1A agonist, F13714: a microdialysis study in the rat. Br J Pharmacol 149:170–178
Bellido M, Rubiol E, Ubeda J, Estivill C, López O, Manteiga R, Nomdedéu JF (1998) Rapid and simple immunophenotypic characterization of lymphocytes using a new test. Haematologica 83:681–685
Buckholtz NS, Boggan WO (1977) Inhibition by β-carbolines of monoamine uptake into a synaptosomal preparation: structure-activity relationships. Life Sci 20:2093–2099
Callaway JC, McKenna DJ, Grob CS, Brito GS, Raymon LP, Poland RE, Andrade EN, Andrade EO, Mash DC (1999) Pharmacokinetics of Hoasca alkaloids in healthy humans. J Ethnopharmacol 65:243–256
Cole JM, Pieper WA (1973) The effects of N,N-dimethyltryptamine on operant behavior in squirrel monkeys. Psychopharmacologia 29:107–112
Dougherty JP, Aloyo VJ (2011) Pharmacological and behavioral characterization of the 5-HT2A receptor in C57BL/6 N mice. Psychopharmacology (Berl) 215:581–593
First MB, Spitzer RL, Gibbon M, Williams JB (1999) Entrevista Clínica Estructurada para los Trastornos del Eje I del DSM-IV: Versión Clínica (SCID-VC). Masson, Barcelona
Ghaziuddin N, Welch K, Greden J (2003) Central serotonergic effects of m-chlorophenylpiperazine (mCPP) among normal control adolescents. Neuropsychopharmacology 28:133–139
Gillin JC, Cannon E, Magyar R, Schwartz M, Wyatt RJ (1973) Failure of N,N-dimethyltryptamine to evoke tolerance in cats. Biol Psychiatry 7:213–220
Gillin JC, Kaplan J, Stillman R, Wyatt RJ (1976) The psychedelic model of schizophrenia: the case of N,N-dimethyltryptamine. Am J Psychiatry 133:203–208
Gresch PJ, Smith RL, Barrett RJ, Sanders-Bush E (2005) Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex. Neuropsychopharmacology 30:1693–1702
Isbell H, Belleville RE, Fraser WA, Logan CR (1956) Studies on lysergic acid diethylamide (LSD-25). I. Effects in former morphine addicts and development of tolerance during chronic intoxication. Arch Neurol Psychiatry 76:468–478
Koudas V, Nikolaou A, Hourdaki E, Giakoumaki SG, Roussos P, Bitsios P (2009) Comparison of ketanserin, buspirone and propranolol on arousal, pupil size and autonomic function in healthy volunteers. Psychopharmacology (Berl) 205:1–9
Kovacic B, Domino EF (1976) Tolerance and limited cross-tolerance to the effects of N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) on food-rewarded bar pressing in the rat. J Pharmacol Exp Ther 197:495–502
Lamas X, Farré M, Llorente M, Camí J (1994) Spanish version of the 49-item short form of the Addiction Research Center Inventory. Drug Alcohol Depend 35:203–209
Lerer B, Gelfin Y, Gorfine M, Allolio B, Lesch KP, Newman ME (1999) 5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge. Neuropsychopharmacology 20:628–639
Martin WR, Sloan JW, Sapira JD, Jasinski DR (1971) Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 12:245–258
McKenna DJ, Towers GHN, Abbott F (1984) Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and β-carboline constituents of ayahuasca. J Ethnopharmacol 10:195–223
Pitchot W, Wauthy J, Hansenne M, Pinto E, Fuchs S, Reggers J, Legros JJ, Ansseau M (2002) Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers. Psychopharmacology (Berl) 164:27–32
Riad M, Watkins KC, Doucet E, Hamon M, Descarries L (2001) Agonist-induced internalization of serotonin-1A receptors in the dorsal raphe nucleus (autoreceptors) but not hippocampus (heteroreceptors). J Neurosci 21:8378–8386
Riba J (2003) Human pharmacology of ayahuasca. Doctoral dissertation, Universitat Autònoma de Barcelona. Available at http://www.tdx.cesca.es/TDX-0701104-165104
Riba J, Rodriguez-Fornells A, Urbano G, Morte A, Antonijoan R, Monteiro M, Callaway JC, Barbanoj MJ (2001a) Subjective effects and tolerability of the South American psychoactive beverage ayahuasca in healthy volunteers. Psychopharmacology (Berl) 154:85–95
Riba J, Rodriguez-Fornells A, Strassman RJ, Barbanoj MJ (2001b) Psychometric assessment of the Hallucinogen Rating Scale. Drug Alcohol Depend 62:215–223
Riba J, Anderer P, Morte A, Urbano G, Jane F, Saletu B, Barbanoj MJ (2002) Topographic pharmaco-EEG mapping of the effects of the South American beverage ayahuasca in healthy volunteers. Br J Clin Pharmacol 53:613–628
Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ (2003) Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther 306:73–83
Romano AG, Quinn JL, Li L, Dave KD, Schindler EA, Aloyo VJ, Harvey JA (2010) Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit. Psychopharmacology (Berl) 212:441–448
Rosenberg DE, Isbell H, Miner EJ (1963) Comparison of a placebo, N-dimethyltryptamine and 6-hydroxy-N-dimethyltryptamine in man. Psychopharmacologia 4:39–42
Rosenberg DE, Isbell H, Miner EJ, Logan CR (1964) The effect of N, N-dimethyltryptamine in human subjects tolerant to lysergic acid diethylamide. Psychopharmacologia 5:217–227
Roth BL, Palvimaki EP, Berry S, Khan N, Sachs N, Uluer A, Choudhary MS (1995) 5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation. J Pharmacol Exp Ther 275:1638–1646
Santos RG, Valle M, Bouso JC, Nomdedéu JF, Rodríguez-Espinosa J, McIlhenny EH, Barker SA, Barbanoj MJ, Riba J (in press) Autonomic, neuroendocrine and immunological effects of ayahuasca. A comparative study with d-amphetamine
Sargent P, Williamson DJ, Pearson G, Odontiadis J, Cowen PJ (1997) Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity. Psychopharmacology (Berl) 132:296–302
Seletti B, Benkelfat C, Blier P, Annable L, Gilbert F, de Montigny C (1995) Serotonin1A receptor activation by flesinoxan in humans. Body temperature and neuroendocrine responses. Neuropsychopharmacology 13:93–104
Smith RL, Canton H, Barret RJ, Sanders-Bush E (1998) Agonist properties of N,N-dimethyltryptamine at 5-HT2A and 5-HT2C serotonin receptors. Pharmacol Biochem Behav 61:323–330
Smith RL, Barrett RJ, Sanders-Bush E (1999) Mechanism of tolerance development to 2,5-dimethoxy-4-iodoamphetamine in rats: down-regulation of the 5-HT2A, but not 5-HT2C, receptor. Psychopharmacology (Berl) 144:248–254
Strassman RJ, Qualls CR (1994) Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic and cardiovascular effects. Arch Gen Psychiatry 51:85–97
Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R (1994) Dose−response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry 51:98–108
Strassman RJ, Qualls CR, Berg LM (1996) Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans. Biol Psychiatry 39:784–795
Tupper KW (2008) The globalization of ayahuasca: harm reduction or benefit maximization? Int J Drug Policy 19:297–303
Yritia M, Riba J, Ortuno J, Ramirez A, Castillo A, Alfaro Y, De la Torre R, Barbanoj MJ (2002) Determination of N,N-dimethyltryptamine and β-carboline alkaloids in human plasma following oral administration of ayahuasca. J Chromatogr B 779:271–281
Acknowledgments
We wish to thank Antoni Pastor and Rafael de la Torre (IMIM-Parc de Salut Mar) for the determination of DMT concentrations in plasma. This work was supported by grant SAF 2002–02746 from the Spanish Ministry of Education and Science and a private donation by Richard Wolfe. MV is supported by FIS through grant CP04/00121 from the Spanish Ministry of Health in collaboration with the Institut de Recerca de l’Hospital de Sant Pau.
Conflicts of interest and source of funding
This work was supported by grant SAF 2002–02746 from the Spanish Ministry of Education and Science and a private donation by Richard Wolfe. The authors declare no conflict of interest. MV is supported by FIS through grant CP04/00121 from the Spanish Ministry of Health in collaboration with the Institut de Recerca de l’Hospital de Sant Pau.
Author information
Authors and Affiliations
Corresponding author
Additional information
Manel J. Barbanoj is deceased.
Rights and permissions
About this article
Cite this article
dos Santos, R.G., Grasa, E., Valle, M. et al. Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology 219, 1039–1053 (2012). https://doi.org/10.1007/s00213-011-2434-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-011-2434-x