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Developments in Harmine Pharmacology — Implications for Ayahuasca Use and Drug-Dependence Treatment

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Developments in Harmine Pharmacology — Implications for Ayahuasca Use and Drug-Dependence Treatment Progress in Neuro-Psychopharmacology & Biological Psychiatry 39 (2012) 263–272 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp Review article Developments in harmine pharmacology — Implications for ayahuasca use and drug-dependence treatment Daniel I. Brierley, Colin Davidson ⁎ Pharmacology & Cell Physiology, Division of Biomedical Science, St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom article info abstract Article history: Ayahuasca is a hallucinogenic botanical mixture originating in the Amazon area where it is used ritually, but Received 14 March 2012 is now being taken globally. The 2 main constituents of ayahuasca are N,N-dimethyltryptamine (DMT), a Received in revised form 16 May 2012 hallucinogen, and harmine, a monoamine oxidase inhibitor (MAOI) which attenuates the breakdown of Accepted 3 June 2012 DMT, which would otherwise be broken down very quickly after oral consumption. Recent developments Available online 9 June 2012 in ayahuasca use include the sale of these compounds on the internet and the substitution of related botanical (anahuasca) or synthetic (pharmahuasca) compounds to achieve the same desired hallucinogenic effects. Keywords: Ayahuasca One intriguing result of ayahuasca use appears to be improved mental health and a reduction in recidivism Harmine to alternate (alcohol, cocaine) drug use. In this review we discuss the pharmacology of ayahuasca, with a 5-HT2 focus on harmine, and suggest pharmacological mechanisms for the putative reduction in recidivism to alco- Imidazoline hol and cocaine misuse. These pharmacological mechanisms include MAOI, effects at 5-HT2A and imidazoline DYRK1A receptors and inhibition of dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A) and the Dopamine transporter dopamine transporter. We also speculate on the therapeutic potential of harmine in other CNS conditions. © 2012 Elsevier Inc. All rights reserved. Contents 1. Introduction .............................................................. 264 2. Pharmacology of DMT ......................................................... 264 3. Pharmacology of harmine ....................................................... 264 3.1. Pharmacokinetics of harmine in ayahuasca ............................................ 265 3.2. MAO-A inhibition ........................................................ 265 3.3. DYRK1A and DAT membrane trafficking ............................................. 265 3.4. 5-HT2A receptor effects ..................................................... 266 3.5. DAT inhibition ......................................................... 266 3.6. Imidazoline I2 receptors ..................................................... 266 4. Ayahuasca and drug dependence therapeutics .............................................. 266 4.1. MAO inhibition and drug-dependence .............................................. 267 4.2. DYRK1A, the dopamine transporter and drug-dependence ..................................... 267 4.3. 5-HT2A receptor and drug-dependence .............................................. 268 4.4. Imidazoline I2 receptor and drug-dependence ........................................... 268 5. Use of harmine in other CNS conditions ................................................. 268 6. Further pharmacokinetic considerations ................................................. 269 7. Unwanted side-effects of harmine and its analogues ........................................... 269 8. Conclusions .............................................................. 270 References ................................................................. 270 Abbreviations: 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindeolacetic acid; BDNF, brain derived neurotrophic factor; ACTH, adrenocorticotropic hormone; CYP2D6, cytochrome P450 2D6; DMT, N,N-dimethyltryptamine; DOPAC, dihydroxyphenylacetic acid; DYRK1A, dual specificity tyrosine phosphorylated and regulated kinase 1A; EGCG, Epigallocatechin gallate; FST, forced swim test; HVA, homovanillic acid; IC50, inhibitory concentration-50; I-BS, imidazoline binding site; MAOI, monoamine oxidase inhibitor; TAAR1, trace amine associated receptor 1; UDV, The Centro Espírita Beneficente União do Vegetal. ⁎ Corresponding author. Tel.: +44 208 266 6135. E-mail address: [email protected] (C. Davidson). 264 D.I. Brierley, C. Davidson / Progress in Neuro-Psychopharmacology & Biological Psychiatry 39 (2012) 263–272 1. Introduction been granted for sacramental consumption of ayahuasca in a number of countries, including the United States in 2006 (Bullis, 2008). These The number and type of drugs consumed for recreational purposes churches now have established congregations across the world, including have become increasingly diverse in recent years, likely due to the the USA, Canada, Japan, South Africa and throughout Europe and Latin decreased purity and/or availability of classic drugs of abuse and America (Labate and Feeney, 2012), with total memberships reportedly the increased availability of legal/quasi-legal substances and dissemina- numbering in the tens of thousands. The willingness of these churches tion of information via internet drug forums (Measham et al., 2010; to engage with the scientific community has resulted in several major Schifano et al., 2006; Schmidt et al., 2011). In addition to cocaine- and studies of the pharmacological, psychological and social effects of their amphetamine-like psychostimulants (e.g. desoxypipradrol and mephe- practices (Barbosa et al., 2009; Callaway et al., 1999; Grob et al., 1996; drone), these have included hallucinogenic compounds such as 2C-I/ Riba et al., 2003). Of particular interest have been the findings that cer- 2C-B, Bromo-dragonFLY, synthetic cannabinoids and Salvia divinorum. emonial ayahuasca consumption is not associated with the deleterious The internet has created a vast resource for recreational users of hallu- effects typical of chronic drug abuse, but appears to represent a pro- cinogenic compounds, detailing methods to obtain, synthesise, extract tective factor for risk of alcohol and substance abuse in adolescents, and ingest such substances, previously only accessible to a relatively and attenuates recidivism in previously drug dependent individuals small minority (Halpern and Pope, 2001). One such compound is aya- (Doering-Silveira et al., 2005; Fabregas et al., 2010; Gable, 2007; huasca, a potent botanical hallucinogenic “tea” consumed by indige- Halpern et al., 2008). nous peoples throughout the Amazon since prehistoric times (Grob et The contemporary evolution of ayahuasca from an esoteric prepa- al., 1996). Ayahuasca consumption has now become globalised ration used by Amazonian shamans to one consumed throughout the (Tupper, 2008), accompanied by the emergence of ayahuasca ana- world for recreational, spiritual and alternative medical purposes has logues — preparations which mimic the pharmacology of ayahuasca, prompted this review. We focus on recent research into harmine, one but utilising more readily available sources of the active compounds. of the principal active compounds and one which has been the sub- The traditional preparation of ayahuasca typically comprises an aque- ject of the majority of biomedical investigations. Particular attention ous decoction of the bark and stem of the Banisteriopsis caapi vine and is focused on emerging aspects of harmine pharmacology which leaves of an admixture plant, usually from the Psychotria viridis shrub. may contribute to the purported benefits of ayahuasca consumption The primary active compounds in B. caapi are the β-carboline alkaloids related to drug dependence. harmine, harmaline and tetrahydroharmine (Wang et al., 2010), while the admixture plants typically contain the hallucinogenic 2. Pharmacology of DMT indolealkylamine N,N-dimethyltryptamine (McKenna, 2004). N,N-di- methyltryptamine (DMT) is orally inactive due to first-pass metabolism DMT is a tryptamine metabolite which has been long established as by visceral monoamine oxidase A (MAO-A), however the β-carboline a trace amine compound with psychoactive properties (Szara et al., alkaloids are potent MAO-A inhibitors, facilitating the entry of DMT to 1957), endogenously formed in both rat and human brains (Saavedra the bloodstream and its subsequent psychoactive effects (McKenna et and Axelrod, 1972). Although classically considered to exert psychoactive al., 1984). All ayahuasca analogues are based on this principle of com- effects via the serotonergic 5-HT2A receptor, this has been questioned as bining a MAO-A inhibitor with a hallucinogenic tryptamine, however many behavioural and biochemical effects cannot be explained solely the sources of such compounds may be botanical in origin, such as by this mechanism (Su et al., 2009). The compound was subsequently Peganum harmala (Syrian Rue, rich in β-carbolines), Acacia and Virola shown to be a high affinity agonist of the trace amine associated recep- species (containing DMT) or synthetic β-carbolines and tor 1 (TAAR1), during pharmacological screening of this newly discov- indolealkylamines (Ott, 1999). Preparations utilising synthetic com- ered prototypic receptor (Bunzow et al., 2001), and suggested to be an pounds have been termed ‘pharmahuasca’, in contrast to those using endogenous ligand. More recently this compound has also been shown plant analogues containing similar active compounds which are
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