# Presentation: 149797

## Ayahuasca: Problems and Prospects for Clinical Study 

- Dennis J. McKenna, Ph.D.
- Senior Lecturer
- Mcken031@umn.edu

## 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**

## Left: preparation of ayahuasca by Mestizo shamans in Peruvian Amazon

**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 ayahuasca****vessel from the NW****Amazon**

## Botanical Sources of Ayahuasca

_**Banisteriopsis caapi**_
**“****ayahuasca”****(Malpighiaceae)**

_**Psychotria viridis**_
**“****chacruna”****(Rubiaceae)**

_**Diplopterys cabrerana**_**“chagro-ponga”****(Malpighiaceae)**

**Traditionally, ayahuasca is a ****decoction prepared from the ****stems of **_**B. caapi**_** and the leaves****of either **_**Psychotria viridis**_** or**_**Diplopterys cabrerana**_

## 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

## Chemistry  of Ayahuasca

**The vine **_**Banisteriopsis caapi**_**contains three ß-carbolines ****as major active constituents.**
**Harmine and harmaline are****potent, reversible, selective ****inhibitors of MAO-A.**
**Tetrahydroharmine is weaker****as an MAOI but relatively ****potent as a serotonin uptake****inhibitor. **

**The leaf admixtures, Psychotria**** viridis or Diplopterys cabrerana****contain the potent, short-acting****hallucinogen, DMT.**
_**DMT is orally inactive**_** unless taken in conjunction with an MAO inhibitor**

## 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

## 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)**

## 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”**

## 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

## 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.

## 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

## 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

## 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.

## 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?

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## Standardization of Ayahuasca 

**Using analytical methods such as HPLC and functional assays such as MAO inhibition, a****standardized, 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**

## 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.

## Slide 25