Dennis J. McKenna

Human Psychopharmacology of Hoasca, A Plant Hallucinogen Used in Ritual Context in Brazil

A multinational, collaborative, biomedical investigation of the effects of hoasca (ayahuasca), a potent concoction of plant hallucinogens, was conducted in the Brazilian Amazon during the summer of 1993. This report describes the psychological assessment of 15 long-term members of a syncretic church that utilizes hoasca as a legal, psychoactive sacrament as well as 15 matched controls with no prior history of hoasca ingestion. Measures administered to both groups included structured psychiatric diagnostic interviews, personality testing, and neuropsychological evaluation. Phenomenological assessment of the altered state experience as well as semistructured and open-ended life story interviews were conducted with the long-term use hoasca group, but not the hoasca-naive control group. Salient findings included the remission of psychopathology following the initiation of hoasca use along with no evidence of personality or cognitive deterioration. Overall assessment revealed high functional status. Implications of this unusual phenomenon and need for further investigation are discussed.

Platelet serotonin uptake sites increased in drinkers of ayahuasca

The binding of [3H]citalopram to the platelet 5-hydroxytryptamine (5-HT) transporter was measured in a group of healthy male drinkers ofayahuasca, a psychoactive sacrament indigenous to Amazonia, and a group healthy male controls. An increased number of binding sites (Bmax) in the platelets of ayahuasca drinkers was found, while the dissociation constant (Kd) remained the same for both groups. If indicative of neuronal 5-HT uptake activity, these results would suggest a decreased concentration of extracellular 5-HT, or a response to increased production and release of 5-HT. Such changes in 5-HT synaptic activity, in this case, should not be misinterpreted as an indication of developing neurological or psychiatric illness.

Common receptors for hallucinogens in rat brain: a comparative autoradiographic study using [125I]LSD and [125I]DOI, a new psychotomimetic radioligand.

The S and R enantiomers of the psychotomimetic 5HT2 agonist DOI (2,5-dimethoxy-4-iodophenylisopropylamine) were labeled with 125I at high-specific activity. The regional distribution of binding sites for each of the enantiomers was investigated using in vitro quantitative autoradiography and compared to the regional distribution of [125I]LSD in the rat brain. Saturable, specific binding of the radioligands was determined in cortical membrane homogenates. All radioligands exhibited specific binding in localized regions throughout the rat brain. Binding of [125I]DOI enantiomers was completely displaced (greater than 90%) by 1 microM of the corresponding unlabeled enantiomer; [125I]LSD was completely displaced by 1 microM LSD. The choroid plexus showed the highest-density binding. Other regions showing high-density binding included the frontoparietal cortex (motor and somatosensory areas), anterior cingulate gyrus, lateral olfactory tubercle, nucleus accumbens, caudate nuclei, claustrum, nucleus of the lateral olfactory tract, dentate gyrus, mamillary nuclei, and motor trigeminal nuclei. In most regions, [125I]S-DOI, the less active enantiomer, exhibited 25-40% of the amount of total binding as [125I]R-DOI. In some regions, [125I]R-DOI and [125I]LSD had similar binding densities; in others, marked differences were apparent. The regional distribution of specific [125I]R-DOI binding sites correlated with the distribution of 5HT2 receptors reported in previous studies. DOI and its analogs may have potential clinical applications for in vivo localization of 5HT2-receptors using positron emission tomography (PET) and similar techniques.

Morphological, phytochemical, and genetic variation in hawaiian cultivars of ’Awa (Kava,Piper methysticum, piperaceae)

Standardized morphological descriptions, quantitative phytochemical analyses (HPLC) of major kavalactones and DNA fingerprinting (AFLP) were utilized to define the extent of variation existing between Hawaiian cultivars of Piper methysticum. For each cultivar, morphotypes and chemotypes were compared to their respective genotypes. Overall, 63 samples were analyzed for their kavalactone content and composition (44 root samples, 6 stump, 5 basal stem, 7 leaves and 1 peelings). Results obtained from different cultivars planted in an homogeneous environment (soil and climate) are quite variable for the kavalactone content of their roots. Total kavalactone content decreases when shade increases over the plants. Total kavalactone content markedly increases with fertility, irrigation and in a cultivated type of habitat. However, kavalactone content appears to be independent of the age of the plant. For all cultivars analyzed, total kavalactone content decreases from the roots to the stump; the basal stems and the leaves exhibit the lower concentration. It is also observed that there is a correlation between the total kavalactone content and the size of the roots: smaller roots tend to have a higher kavalactone content. Peelings of the bark had a higher kavalactone content than the stump and represent a very interesting by-product for the extraction industry. Chemotypes are similar in the roots and the stump, while they differ in the aerial parts where the concentrations in dihydrokavain and dihydromethysticin increase. DNA samples were extracted from fresh leaves collected on 22 accessions. Most accessions, representing all Hawaiian morphotypes were monomorphs for the 21 pairs of primers assayed. Kava in Hawai’i is a species with an extremely narrow genetic base. Morphological and phytochemical variation is obviously controlled by very few genes. Most cultivars representing different morphotypes are most likely somatic mutants from a common clonal source introduced by Polynesians during early settlements.RésuméHo ’opa’a ’ia ka laulā o ka ’oko’a i waena o nā ’ano ’awa kanu (Piper methysticum) o ka Hawai’i ma nā wehewehe kino maekanu ma’amau ke kālailai heluna kemikala no nā “kavalactone” a me ke “kapāla māka manumana lima” ōewe DNA (kaila AFLKP). No kēlā me kēia ’ano ’awa ho’ohālikelike ’ia ke ’ano o ke kino, nā kemikala o Ioko a me nā ōewe. He 63 hāpana i kālailai ’ia no ka nui o nā kavalactone a me nā kemikala o Ioko (he 44 hāpana a’a, 6 kumu, 5 ku’ina hā, 7 lau me ka 1 ihina ’ili kumu.) I loko o ke kanu ’ia o nā ’ano ’awa ’oko’a ma loko o ke kaipuni like o ka lepo me ke ainau he ’oko’a pono nō ma nâ kavalactone o nā a’a. He emi mai ka heluna kavalactone ke pi’i ka malu o luna o nā meakanu. He pi’i na’e ka heluna kavalactone e like me ka momona o ka lepo, ka ho’okahe ’ia o ka wai, a me ka mahi ’ia o kahi kanu. Me he mea a la ’a’ohe pili o ka heluna kavalactone i ke o’o o ka meakanu. No nā ’ano ’awa a pau i kālailai ’ia, ’oi aku nā kavalactone o nā a’a ma mua o nā kumu a emi loa ma nā ku ’ina hā me nā lau. ’Ike pū ’ia he pili ka heluna kavalactone i ke ana o ke a’a: ’oi aku nā kavalactione o nā a’a li’ili’i. ’O nā ihina ’ili kumu, he ’oi pū aku ka heluna kavalactone ma mua o ko ke kumu a he mea waiwai paha ia no nā pā’oihana ’awa. ’Ano like nā kemikala o nā a’a me nā kumu. ’oiai na’e he ’oko’a ko nā māhele ulu i ka lewa, kahi nona ho’i ka ’oi ’o nā k “dihydrokavain” me ka “dihydromethysticin.” ’Uī ’ia ka DNA mail loko o nā lau hou loa i ’ohi ’ia ma nā ’ako ’ana he 22. ’O ka nui o nā ’ako ’ana no loko nō ho’i o nā ’ano 1awa kanu a pau. ua like nō ka hopena i ’ike ’ia ma ke kilo ’ana i ke ’ano o nā oewe ma na ’oki ōwewe ’oko’a ’ana he 21 i ka DNA. He meakanu ka ’awa o ka Hawai’i i hāiki loa kona kahua ōewe. ’O ka ’oko’a o nā kino meakanu a me nā kemikala o loko he ahuwale kona pili i nā ōewe kāka ’ikahi loa nō. ’O ka nui o nā ’awa kanu i ’oko’a ke kino, ua kupa huli mai nô paha mai loko mai o kekahi molekumu ’ano’ano ’ole ho’okahi i ho’opae ’ia mai e nā Polensia ma nā hō’ea mua ’ana o lākou i Hawai’i.

Plant hallucinogens: springboards for psychotherapeutic drug discovery

Medicinal chemists have traditionally looked to the biosynthetic diversity found in nature to provide structural templates for the development of novel therapeutic agents, and the field of hallucinogen chemistry is similar to other fields in this respect. Even LSD, for many psychopharmacologists the prototype hallucinogen, is not itself a natural compound but rather is a semisynthetic analogue of alkaloids found in plants and fungi. A similar statement could be made about the other major structural classes of hallucinogenic agents: the phenylethylamine derivatives, the tryptamine derivatives, and the beta-carboline derivatives. In each case, compounds occurring naturally in some plant, usually associated with a long tradition of ethnomedical or ceremonial use, have been the starting point for the synthesis of numerous analogues. Some of these, such as the methoxylated amphetamine derivatives, display a pharmacological profile that differs in important respects from their natural product templates. In some instances the analogues have proven to be useful tools in the hands of neurobiologists characterizing the structure and function of brain neurotransmitter systems; in other cases, they have led to the development of new psychopharmacological agents with realized or potential clinical utility. This paper gives a brief historical overview of the role of natural products in the history and development of medicinal chemistry and experimental pharmacology, particularly with respect to the development of psychopharmacology and the discovery of CNS-active agents. It discusses the potential for the discovery of new medications with psychotherapeutic and/or research applications though the investigation of plants and natural compounds with serotonergic activities. Finally, consideration is given to some lesser known plant hallucinogens which may provide further useful leads for psychotherapeutic drug discovery.

A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity.

N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded as an endogenous trace amine transmitter. The vast majority of research on DMT has targeted its psychotropic/psychedelic properties with less focus on its effects beyond the nervous system. The recent discovery that DMT is an endogenous ligand of the sigma-1 receptor may shed light on yet undiscovered physiological mechanisms of DMT activity and reveal some of its putative biological functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. In this paper, we overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics, the role of serotonin, and serotoninergic analogues in immunoregulation and the data regarding gene expression of the DMT synthesizing enzyme indolethylamine-N-methyltransferase in carcinogenesis. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.

New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca

New World indigenous peoples are noted for their sophisticated use of psychedelic plants in shamanic and ethnomedical practices. The use of psychedelic plant preparations among New World tribes is far more prevalent than in the Old World. Yet, although these preparations are botanically diverse, almost all are chemically similar in that their active principles are tryptamine derivatives, either DMT or related constituents. Part 1 of this paper provides an ethnopharmacological overview of the major tryptamine-containing New WorldNew World hallucinogensHallucinogens .

Receptor screening technologies in the evaluation of Amazonian ethnomedicines with potential applications to cognitive deficits

ETHNOPHARMACOLOGICAL RELEVANCE Amazonian peoples utilize a variety of psychoactive plants that may contain novel biologically active compounds. Efforts to investigate such remedies in terms of neuropharmacology have been limited. AIM OF THIS STUDY This study identified Amazonian ethnomedicines with potential for the treatment of cognitive deficits in schizophrenia and dementias, and characterized their interactions with CNS neurotransmitter receptors in vitro. MATERIALS AND METHODS Approximately 300 Amazonian species with folk uses or constituents indicative of central nervous system activity were incorporated into a database constructed from literature searches, herbarium surveys, and interviews with traditional practitioners. Approximately 130 of these targeted species were collected in Loreto province, Peru, and 228 fractions derived from them were screened in 31 radioreceptor assays via the resources of the NIMH Psychoactive Drug Screening Program. A subset was also screened in functional assays at selected serotonin, muscarinic, and adrenergic receptors. RESULTS Ninety-one samples displayed ≥60% inhibition of radioligand binding activity in receptor assays; 135 samples displayed agonist or antagonist activity (or both) in functional assays. CONCLUSIONS Potential CNS activity was detected in about 40% of the samples screened, with some correlations to both folk uses and phytochemical constituents. These results may point to novel and potentially therapeutic CNS active compounds.

Autoradiographic localization of 5HT2 receptors in rat brain using [125I]-DOI, a selective psychotomimetic radioligand.

1. Binding sites for the R and S enantiomers of the 5HT2 agonist DOI (2,5-dimethoxy-4-iodophenylisopropylamine) were identified in rat brain using quantitative in-vitro autoradiography and compared with [125I]-LSD binding. 2. In most regions of the brain, binding density of the less active isomer [125I]S-DOI was 15 to 85% of that exhibited by the active [125I]R-DOI isomer. 3. Cortical membrane preparations exhibited two binding sites, of the enantiomers with high (KdH) and low (KdL) affinity constants of 1.2 +/- 0.02 nM and 29 +/- 7 nM for the [125I]R-DOI and 2.1 +/- 0.2 nM and 18 +/- 4 nM for [125I]S-DOI respectively. The respective high (BmaxH) and low (BmaxL) binding densities were 92 +/- 10 and 536 +/- 164 fmol/mg protein for the [125I]R-DOI and 67 +/- 19 and 245 +/- 60 fmol/mg protein for [125I]S-DOI. 4. Our results correlate with regional distribution of 5HT2 receptors reported in previous studies and indicate that DOI and its congeners have potential clinical applications for the in-vivo localization of 5HT2 receptors.

Statement on ayahuasca

Sixty years ago, the esteemed academic journal Science pubished a “Statement on Peyote” (La Barre, McAllester, Slotkin, tewart, & Tax, 1951), in which a handful of leading researchers, ismayed by the misinformed and demonising drug politics of he time, defended the right of the Native American Church to onsume a psychedelic plant in its religious rites. Today, we feel imilarly compelled to speak out on behalf of an analogous, nonndigenous religious tradition—the Brazilian ayahuasca religions, ncluding the Santo Daime, the União do Vegetal, and other related roups (Dawson, 2007; Labate & MacRae, 2010). We have studied arious ritual uses of ayahuasca, participated in ceremonies and onsumed the sacramental brew. As the Brazilian ayahuasca religions have spread from South merica to North America, Europe and Asia over the past few ecades, their members have suffered arrests, criminal prosecuion, and stigmatization as “drug users.” Currently, Santo Daime embers in the UK, Ireland, Spain, and Portugal are facing criminal harges, and the protection of religious freedom for Santo Daime embers in Canada remains tentative and unresolved (Tupper, 011). Meanwhile, in the US, Oregon-based Santo Daime memers are in negotiations with the Department of Justice (Church . Holder, 2012), and in a highly politicized case, the União do Vegtal was recently denied a permit for building a temple in New exico (Haywood, 2011). We contend that such barriers to the reedom of religious practice are both legally and ethically untenble; moreover, as with oppression of the Native American Church Calabrese, 2004; Halpern, Sherwood, Hudson, Yurgelun-Todd, & ope, 2005), intolerance of the Brazilian ayahuasca religions is ot based on rational risk/benefit evaluations of consequences, ither for individual practitioners or for public safety. Instead, ersecution of the Brazilian ayahuasca religions has been mostly ased on misinformed prejudice against the use of psychedelic ubstances in what are reasonably safe and socially controlled rital contexts, and which constitute authentic cultural traditions nd expressions that must be respected as such. Here we discuss he scientific evidence available on these practices, and we argue hat the data justify modelling future regulation of these religions n Brazil’s largely self-enforced policies, which treat ayahuasca ore like a religious sacrament than a controlled psychotropic ubstance (Labate & Feeney, 2012). Such policies have proven uccessful in Brazil over the past several decades and they have llowed the Brazilian ayahuasca religions to develop the intriguing ocial, health and research implications that they present us with oday. Ayahuasca is a psychedelic decoction made from plants ative to the Amazon Basin—most often Banisteriopsis caapi and