ayahuasca: problems and prospects for clinical study dennis j. mckenna, ph.d. senior lecturer...
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Ayahuasca: Problems and Prospects for Clinical Study
Dennis J. McKenna, Ph.D.
Senior Lecturer
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 medicineImage of an
ayahuasca “spirit” from the NW Amazon
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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
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 leavesof either Psychotria viridis orDiplopterys 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
NHNH
CH3OCH3
NHNH
CH3OCH3
NH2NH
CH3OCH3
TETRAHYDROHARMINE
HARMALINE
HARMINE
N
NH
CH3
CH3
N,N-dimethyltryptamine (DMT)
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
Yanomamo Snuffing Virola powderOne 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)
NH2NH
CH3O
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 substanceß-carbolines are not classified as controlled substancesThe 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 abuseTreatment of behavioral/personality disordersAnecdotal 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 StudyMultiple 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 drugsFDA 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
B
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
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.