Ayahuasca: Problems and Prospects for Clinical Study

1. Ayahuasca: Problems and Prospects for Clinical Study Dennis J. McKenna, Ph.D. Senior Lecturer Mcken031@umn.edu

2. What is Ayahuasca? • Ayahausca is Quechua for “vine of the souls” • It is a hallucinogenic beverage that forms an important component of Amazonian shamanism and ethnomedicine • It is the legal “sacrament” for at least two syncretic religions in Brasil • It has a reputation (deserved or not) as a healing medicine Image of an ayahuasca “spirit” from the NW Amazon

3. Left: preparation of ayahuasca by Mestizo shamans in Peruvian Amazon Below: UDV “preparo” in Manuas, Brasil. The brew is prepared on an industrial scale, and it is not uncommon for several hundred parishioners to consume it in group ceremonies Ceremonial ayahuascavessel from the NWAmazon

4. Botanical Sources of Ayahuasca Psychotria viridis “chacruna”(Rubiaceae) Traditionally, ayahuasca is a decoction prepared from the stems of B. caapi and the leavesof either Psychotria viridis orDiplopterys cabrerana Diplopterys cabrerana“chagro-ponga”(Malpighiaceae) Banisteriopsis caapi “ayahuasca”(Malpighiaceae)

5. Ayahuasca has a Unique Pharmacology • Its psychoactivity depends on a synergy between two classes of active constituents: • The leaf admixtures, Psychotria or Diplopterys species, contain the potent hallucinogen, N,N-Dimethyltryptamine (DMT) • DMT alone is not orally active, due to inactivation by peripheral Monoamine Oxidase (MAO) in the gut and liver • DMT can be rendered orally active by co-administration with an MAO inhibitor • Banisteriopsis contains harmine and other ß-carboline alkaloids, which are potent, reversible MAO inhibitors

6. Chemistry of Ayahuasca The vine Banisteriopsis caapicontains three ß-carbolines as major active constituents. Harmine and harmaline arepotent, reversible, selective inhibitors of MAO-A. Tetrahydroharmine is weakeras an MAOI but relatively potent as a serotonin uptakeinhibitor. The leaf admixtures, Psychotria viridis or Diplopterys cabreranacontain the potent, short-actinghallucinogen, DMT. DMT is orally inactive unless taken in conjunction with an MAO inhibitor

7. Yanomamo Snuffing Virola powder One way to get around the conundrum of oral inactivity is to ingest DMT parenterally • Yanomamo Indians prepare a snuff from the sap of Virola species, another DMT-containing plant • Drug abusers in the U.S. smoke free base DMT in a glass pipe or sprinkled on a vegetable matrix

8. Ubiquity of DMT and ß-carbolines • Both DMT and ß-carbolines are structurally simple indole alkaloids, biosynthetically derived from tryptophan • DMT and related tryptamine derivatives, and ß-carbolines are quite widespread in plants • Dozens of species containing them have been identified • Many more remain unidentified • They are also widespread in animals, including humans, and fungi • DMT is normally present in the human brain, cerebrospinal fluid, and adrenal glands • The pineal hormone, pinoline, is a ß-carboline Pinoline, a pineal hormone (6-MeO-tetrahydro-ß-carboline)

9. Ayahuasca “Analogs” • Due to their wide-spread occurrence in plants, many species could be used to prepare ayahuasca-like brews • Many of them have been used in this manner • All that is needed is the right combination: a plant containing DMT combined with a plant containing ß-carbolines The desert shrub on the left, Peganum harmala, contains ß-carbolines in the seeds, and the grass on the right, Phalaris arundinacea, contains DMT. Combinations of these and many other plants have been used to prepare “ayahuasca analogs”

10. Legal Status of Ayahuasca • DMT is a schedule 1 controlled substance • ß-carbolines are not classified as controlled substances • The law is ambiguous concerning the legal status of plants containing DMT • While DMT itself is scheduled, none of the plants containing it have been scheduled • DMT and ß-carboline containing plants are freely bought and sold on the Internet and elsewhere • Even if desirable, it seems a practical impossibility to control all of the dozens or hundreds of plants containing DMT

11. Uniâo do Vegetal Study • The Uniâo do Vegetal (UDV) is a Brasilian syncretic religion legally permitted to consume ayahuasca in ceremonial settings • In 1993, we conducted a biomedical investigation on long-term members of the UDV in Manaus, Brasil • The study looked at acute and long-term physiological and psychological parameters in long-term members • C. S. Grob, D. J. McKenna, J. C. Callaway, et al. (1996) Human pharmacology of hoasca, a plant hallucinogen used in ritual context in Brasil: Journal of Nervous & Mental Disease. 184:86-94.

12. Key findings from the UDV study • No evidence of acute toxicity • No evidence of neurological, cognitive, or personality dysfunctions in long-term users • Most UDV subjects performed slightly better than matched controls on psychological measurements • Strong evidence of positive behavioral changes • Most members had histories of drug abuse, alcoholism and domestic violence before joining the UDV • Initial terrifying experiences with ayahuasca helped them to change lifestyle in a more positive direction • Effects of supportive context are hard to separate from effects of ayahuasca

13. Upregulaton of Serotonin Transporters • An unexpected finding was that long-term users had significantly elevated densities (Bmax) of serotonin transporters in platelets compared to matched controls • Receptor affinity (Ki) was not significantly different between groups • J. C. Callaway, M. M. Airaksinen, Dennis J. McKenna, Glacus S. Brito, & Charles S. Grob (1994) Platelet serotonin uptake sites increased in drinkers of ayahuasca. Psychopharmacology 116: 385-387

14. Deficits of brain 5HT transporters and other monoamine transporters Have been associated with: • Alcoholism • Early onset alcoholism & violent/homocidal behavior • Suicidal behaviors • Binge eating Mantere T, Tupala E, et al. Serotonin transporter distribution and density in the cerebral cortex of alcoholic and nonalcoholic comparison subjects: a whole-hemisphere autoradiography study. Am J Psychiatry. 2002 Apr;159(4):599-606. Hallikainen T, Saito T, Lachman HM, et al. Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. Mol Psychiatry. 1999 Jul;4(4):385-8.

15. Unanswered questions: Could long-term use of ayahuasca actually reverse these transporter deficits? Could it therefore be used in the treatment of alcoholism and other behavioral dysfunctions associated with reduced transporter expression?

16. Possible Therapeutic Uses of Ayahuasca • Treatment of alcoholism & substance abuse • Treatment of behavioral/personality disorders • Anecdotal reports exist: • Spontaneous remission of cancer • Accelerated healing of physical injuries • In Amazonian shamanism, ayahuasca is used for healing both physical disease and mental disease

17. Public Health & Safety Concerns • Increasing popularity of ayahuasca raises public health concerns • Increasing experimentation with ayahuasca and ayahuasca “analogs” by experimental ethnopharmacologists • Increasing popularity of ayahuasca “tourism” • The safety, or potential risks, of these practices are unknown • There exists a need to collect more and better data on the human pharmacology of ayahuasca

18. Religious/sacramental use of ayahuasca • Religious use of ayahuasca has been legally sanctioned in Brasil since the late 1980’s • It is taken regularly by 1000’s of people in Brasil on a weekly or bimonthly basis • At least three syncretic religions - UDV, Santo Daime, and Barquinha - are allowed to use it in religious practices • There is no evidence that it is a public health or drug abuse problem • There is evidence that within a ritual and religions context, ayahuasca is a spiritual practice that may benefit members of these churches

19. Religious/sacramental use of ayahuasca in the U.S. may be permitted • Background: DEA raided a UDV ceremony in New Mexico in 1999 and seized the “sacrament” • UDV sued the Justice Department for right to use ayahuasca as a sacrament under the Religious Freedom Restoration Act • Judge James Parker of the U.S. District Court of New Mexico ruled in favor of the UDV • Government could demonstrate no “compelling interest” to restrict religious use • Government could not demonstrate that its use poses health risks • Government could not demonstrate that there was a significant risk of diversion to illegitimate use • The UDV is enjoined from resuming their religious use of ayahuasca while the Justice Department is appealing the decision

20. Rationale for Clinical Study • Multiple reasons exist to conduct well-designed clinical studies with ayahuasca in human subjects: • Possible therapeutic applications • Alcoholism, substance abuse, mental illness, cancer, etc. • Possible safety concerns • Is experimental or religious use safe? • Possible public health concerns • Use is growing, along with the potential for adverse reactions • We need to study ayahuasca in order to better understand its use and misuse

21. Challenges for Clinical Research • Clinical research in the U.S. must be conducted under an IND protocol • Affiliation with a university or other research institution • Approval by an IRB • FDA approved IND for phase I (safety) and phase II (efficacy) • For ayahuasca, DEA approval for research with a controlled substance may be required

22. IND application for botanical drugs • FDA has issued guidelines defining criteria for approval of IND applications for botanical drugs not previously marketed, or that may have safety issues • Investigator must provide details of the source, composition, standardization, and dosage formulation of botanical drugs that fit this definition • FDA guidelines did not cover botanicals containing controlled substances • It is unclear what restrictions may apply to botanicals containing DMT • DMT is “controlled” but plants containing it are not

23. B Standardization of Ayahuasca • Using analytical methods such as HPLC and functional assays such as MAO inhibition, astandardized, replicable dosage form of ayahuasca could easily be made: • A reliable source of fresh plant material is needed • A lyophilized, encapsulated extract containing quantified amounts of key marker alkaloids • If DEA permits are required, the work must be done in a GMP lab with licensure for use of DMT reference standard

24. Safety of Ayahuasca in Clinical Use • Phase I IND is to establish that ayahuasca is safe to use in human subjects • Previous studies indicate that occasional use is probably safe • CONFEN findings in Brasil • “Hoasca study” with the UDV in Brasil • Riba, et al. studies in Spain: Riba J, Rodriguez-Fornells A, Urbano G, Morte A, Antonijoan R, Montero M, Callaway JC, Barbanoj MJ. Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers. Psychopharmacology (Berl). 2001 Feb;154(1):85-95. Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther. 2003 Jul;306(1):73-83.