Salvia divinorum

[1] [2] [3]

Propagation

Germination

Vegetative

Two or three node cuttings are sufficient to root.[4]

Stems of wild divinorum often break in high winds or even under their own weight and root directly in the rocky soil and water of their native habitat. Decumbent stems similarly root directly when exposed to moist soil.[1]

In-Vitro

Disinfection Protocol

• excise 4-6 mm nodal segments
• wash with 70% ethanol for 40 sec
• rinse with sterile water for 60 sec
• wash with 0.6% sodium hypochlorite + 0.1% Tween-20 for 10 min
• rinse 5× with sterile DDI water
• remove larger leaves
• place in media
• maintain at 400 µmol/m2/s, 14-hr photoperiod, 22-23°C[5]

Kutrezeba et al. developed an in vitro multiplation protocol for divinorum using 6-BAP during the investigation of the biosynthesis of salvinorin A.[5] The authors modified the work of Arikat et al. for their micropropagation protocol.[6]

Cultivation

Divinorum is a perennial herb.[1]

Harvest

Yield

Seed set is approximately 3% after manual cross-pollinations.[1]

Soilless

Divinorum can be cultivated (at least temporarily) using Hoagland’s medium.[7]

Rooted stem cuttings have been grown in typical potting mix consisting of topsoil, peatmoss, vermiculite, and perlite (4:2:1:1).[4]

Soil

Fertilization

Weekly irrigation with water-soluble fertilizer (Miracle Grow) has been used for divinorum cultivation in containers.[4]

Temperature

Divinorum cultivation is possible in temperatures 10-30°C without any reported negative effects.[4]

Lighting

Divinorum is a short-day photoperiod plant, with a critical period of about 12 hours. Tapered lighting is not necessary. Less than a week of exposure to long days will abort flowers and revert the plant to vegetative growth. Plant height is not a major factor in flowering.[4]

Pests

Ecology

Divinorum is endemic to the Sierra Mazateca, Oaxaca, Mexico at and elevation of 300-1800 m. It is often found along rocky stream banks in primary and secondary cloud forests and in evergreen tropical forests.[1]

Reported Locations

Morphology

[1]

Roots

Stem

Like other members of the Salvia genus, divinorum has quadrangular, hollow stems.[1]

Leaves

Opposite, elliptic to ovate, with irregularly serrate or crenate-serrate.[1]

Inflorescence

Divinorum has a violet calyx, not a blue one as originally described in the 1962 species identification.[12][4] This is likely due to miscommunication between Wasson and Epling, and that Epling did not at a flowering specimen at the time of identification.[1]

The corolla dries, turns brown, and falls off the flower approximately 72 hours after opening.[4][1]

Seeds

Phytochemistry

[13] [14] [15] [16] hanson_natural_2010 selvaraj_phytochemical_2023

Infraspecific Variation

Due to the low genetic diverity (or none), there is unlikely to be any substantial infraspecific variation in divinorum (except from zygosity in seed-grown accessions) either in circulation or the wild.[17][2]

Biosynthesis

[5] [18] [19] [20] mitchell_identification_2012 kutrzeba_salvinorin_2008 kutrzeba_13c-_2008

Distribution

Timecourse

Improvement

Identification

Diploid species n=11.[1]

The locals around Cerro Rabón were familiar with the propagation of divinorum by seed. It is possible that collections by Valdes et al. in the region were seed-grown.[4]

[21]

Named Clones

Seed propagated accessions

Bunnell
Also known as Wasson and Hofmann variety.

Hofmann and Wasson Wasson and Hofmann collected the first specimen to be returned to the US in 1962 in the Sierra Mazateca. A cutting was delivered to Epling which was used for identification of the species and was later grown in the UCLA and UC Berkely herbaria.[4][8][9]

Valdés

Blosser
Bret Blosser retrieved two divinorum specimens from Municipio de San José Tenango region in 1991. Synonymous with “Palatable” derived from the supposedly less bitter taste of this germplasm.[2] They are thought to be lost. Later comparisons between the “Palatable” and Wasson clones show no difference in taste or potency when grown in similar conditions, leading the authors to speculate they are from the same germplasm.[8]

Inheritance

Methods

Acetone is the most common solvent used to produce extracts of divinorum out of ethanol, isopropanol, and methanol. It is the least likely to cause DNA degradation, thus it should be possible to recover DNA for PCR analysis directly from commercial extracts.[2]

A more targeted method is “cotton swab extraction.” Since salvinorin A is found predominantly in the glandular trichomes of the abaxial side of the mature leaf, rubbing the leaf underside with a chloroform-soaked cotton swab can remove about 50% of the total salvinorin A in a sample.[18]

[24]

History & Society

[19] [15] [25] [26] [3] [21] line_total_2016

Work Log

19 Feb 2025

Requested the first half of Systematic Studies in Salvia Reisfield 1987, since only that part is restricted for some reason. https://minds.wisconsin.edu/handle/1793/11724

29 Dec 2023

Report of seed set when divinorum is crossed with S. concolor. Another possibility is S. venulosa.

The Salvia divinorum Research and Information Center created and maintained by Daniel Siebert went dead between May 5th and May 10th of 2022.

Bibliography

1. REISFIELD, AARON S., The Botany of Salvia Divinorum (Labiatae), SIDA, Contributions to Botany, vol. 15, no. 3, pp. 349--366, 1993. url: https://www.jstor.org/stable/41967014. Abstract
   Salvia divinorum, ceremoniously employed by the Mazatec Indians of Oaxaca, is endemic to the sierra inhabited by the Mazatec, its distribution anthropogenic. Plants spread vegetatively, flourishing in shaded, humid sites, flowering sporadically from October until June. Flower nectar and corolla dimensions suggest ornithophily, and the only pollination event observed involved a single hummingbird, but other factors suggest that visits by birds to the flowers in their present range are opportunistic, and not a product of plant-pollinator coevolution. The species is diploid with n= 11, pollen fertility is reduced, there is no active pollen tube inhibition within the style, but some event or process after the pollen tube reaches the ovary is aberrant, as no fully developed nutlet has ever been collected from a Mexican plant, and greenhouse cross-pollinations led to only 3\% seed set. Hybridity is suggested, although intermediacy between two known species has not been recognized. Salvia divinorum, que fue usada en las ceremonias por los Indios Mazatecas de Oaxaca, es una planta endémica de la sierra habitada por los Mazatecas y su distribución antropogénica. Se reproduce vegetativamente, prosperando en lugares húmedos y sombríos, y ocasionalmente florece de octubre a junio. Las dimensiones de la corola y la presencia de néctar sugieren ornitofilia y la única polinización observada fue realizada por un colibrí, pero hay otros factores que sugieren que las visitas de los pájaros a las flores son oportunistas y no el producto de una coevolución plantpolinizador. La especie es dipolide, n = 11, la fertilidad del polen reducida, no hay inhibición estilar activa del tubo polínico, pero algunos procesos posteriores a la llegada del tubo polínico al ovario son aberrantes, por lo que nunca se ha recolectado ninguna nuclua perfectamente desarrollada en plantas mexicanas, y las polinizaciones cruzadas realizadas en invernadero producen sólo un 3\% de semillas. Se ha sugerido hibridación, aunque no se ha reconocido que sea intermedia entre dos especies concocidas.
2. Casselman, Ivan, Genetics and Phytochemistry of Salvia Divinorum, 2016. url: https://researchportal.scu.edu.au/view/delivery/61SCU_INST/1267239090002368/1367454090002368. Abstract
   Salvia divinorum Epling \& Játiva (S. divinorum) is endemic to the Sierra Mazateca cloud forests of Oaxaca, Mexico. It has been used as a traditional medicine and in ceremonies by the Mazatec, the indigenous people of Oaxaca, for many centuries. In more recent times Salvia divinorum has become globally recognized, both for its potent psychoactive effects, as well as its potential use as a phyto-medicine. Previous research by the author demonstrated that S. divinorum use is a growing, global phenomenon, particularly for recreational use. Despite this, published, peer reviewed research on this plant species is limited in comparison to other medicinal plants. The purpose of this research was to explore the genetic and phytochemical variation of S. divinorum. One study has examined intraspecifc variation of this species but only in a small number of Oaxacan samples. Since its global dispersal from Mexico, propagation has been primarily by clonal methods, therefore, genetic variation of this species outside Mexico may be limited. Before to commencing investigation of intraspecifc variation, it was necessary to assess the quality of DNA which could be extracted from fortifed Saliva divinorum material. It was confrmed that DNA of suffcient quality could be obtained from fortifed extracts for further intraspecifc analysis. Regions of the chloroplast genome shown to be variable within other plant species were amplifed with universal primers to assess genetic variation in S. divinorum. In particular, regions containing chloroplast simple sequence repeats (cpSSR's) were targeted as these have been widely used for the detection of intraspecifc variation and phylogeography in plants. Chloroplast sequence data, approximately 2.4 kilobases in length, including the intergenetic spacers trnS-trnG, rps16-trnK, trnL-trnF and the trnL intron, were examined for variation among S. divinorum samples from Europe, North America and Australia. Sequenced alignments contained cpSSR repeat regions, however, no genetic variation was detected in more than 40 globally-distributed plant samples and fortifed commercial products used in the study. The majority of phytochemical research, to date, has focused on salvinorin A, the main psychoactive diterpene in S. divinorum, and little is known of other chemical compounds or chemical variation in S. divinorum. Numerous compounds have been identifed across the Salvia genus and many of these may also be present but not identifed in S. divinorum. HPLC and LC/MS data generated from the collected samples was used to perform two principal component analyses (PCA) to elucidate patterning in the chemical make up of S. divinorum. This analysis revealed two similar sets of groupings in both PCAs. HPLC and LC/MS analysis confrmed the presence of rosmarinic acid in S. divinorum. This compound is commonly identifed in the Salvia genus and it is surprising that it has not been confrmed in S. divinorum previously, as the UV peak is very prominent on the chromatogram. A high variation in the concentration of rosmarinic acid was also observed across the 37 samples tested. Not all salvinorin A fortifed products had higher salvinorin A concentrations than unfortifed samples. The variation in the phytochemical make up and the lack of genetic variation in S. divinorum are interesting results and the combined genetic phytochemical approach offers novel insights. The lack of genetic variation found, adds evidence to the proposition that all plants outside Mexico have a common source. While there are several other factors which may affect phytochemical variation it may be that chemical variation in S. divinorum is determined phenotypically. Growing conditions may be the primary consideration to achieve optimal levels of active constituents as this species is further developed as a phyto-medicine.
3. {Hernández-Alvarado}, R. Bruno and {Madariaga-Mazón}, Abraham and Ortega, Alfredo and {Martinez-Mayorga}, Karina, DARK Classics in Chemical Neuroscience: Salvinorin A, ACS Chemical Neuroscience, vol. 11, no. 23, pp. 3979--3992, December 2020. doi: 10.1021/acschemneuro.0c00608. Abstract
   Salvinorin A is the main bioactive compound in Salvia divinorum, an endemic plant with ancestral use by the inhabitants of the Mazateca mountain range (Sierra Mazateca) in Oaxaca, México. The main use of la pastora, as locally known, is in spiritual rites due to its extraordinary hallucinogenic effects. Being the first known nonalkaloidal opioid-mediated psychotropic molecule, salvinorin A set new research areas in neuroscience. The absence of a protonated amine group, common to all previously known opioids, results in a fast metabolism with the concomitant fast elimination and swift loss of activity. The worldwide spread and psychotropic effects of salvinorin A account for its misuse and classification as a drug of abuse. Consequently, salvinorin A and Salvia divinorum are now banned in many countries. Several synthetic efforts have been focused on the improvement of physicochemical and biological properties of salvinorin A: from total synthesis to hundreds of analogues. In this Review, we discuss the impact of salvinorin A in chemistry and neuroscience covering the historical relevance, isolation from natural sources, synthetic efforts, and pharmacological and safety profiles. Altogether, the chemistry behind and the taboo that encloses salvinorin A makes it one of the most exquisite naturally occurring drugs.
4. ValdÉs, L. J. and Hatheld, G. M. and Koreeda, M. and Paul, A. G., Studies of Salvia Divinorum (Lamiaceae), an Hallucinogenic Mint from the Sierra Mazateca in Oaxaca, Central Mexico, Economic Botany, vol. 41, no. 2, pp. 283--291, April 1987. doi: 10.1007/BF02858975. Abstract
   Salvia divinorum Epling \& Mtiva-M. is one of the vision-inducing plants used in ritual curing by the Mazatec Indians of central Mexico. The present status of research is summarized. Experiments with material collected at different Oaxacan sites confirmed that the mint has white (rather than blue) flowers with a purple calyx and that flowering is induced by short day length.
5. Kutrzeba, Lukasz and Dayan, Franck E. and Howell, J’Lynn and Feng, Ju and Giner, José-Luis and Zjawiony, Jordan K., Biosynthesis of Salvinorin A Proceeds via the Deoxyxylulose Phosphate Pathway, Phytochemistry, vol. 68, no. 14, pp. 1872--1881, July 2007. doi: 10.1016/j.phytochem.2007.04.034. Abstract
   Salvinorin A, a neoclerodane diterpenoid, isolated from the Mexican hallucinogenic plant Salvia divinorum, is a potent kappa-opioid receptor agonist. Its biosynthetic route was studied by NMR and HR-ESI-MS analysis of the products of the incorporation of [1-13C]-glucose, [Me-13C]-methionine, and [1-13C;3,4-2H2]-1-deoxy-d-xylulose into its structure. While the use of cuttings and direct-stem injection were unsuccessful, incorporation of 13C into salvinorin A was achieved using in vitro sterile culture of microshoots. NMR spectroscopic analysis of salvinorin A (2.7mg) isolated from 200 microshoots grown in the presence of [1-13C]-glucose established that this pharmacologically important diterpene is biosynthesized via the 1-deoxy-d-xylulose-5-phosphate pathway, instead of the classic mevalonic acid pathway. This was confirmed further in plants grown in the presence of [1-13C;3,4-2H2]-1-deoxy-d-xylulose. In addition, analysis of salvinorin A produced by plants grown in the presence of [Me-13C]-methionine indicates that methylation of the C-4 carboxyl group is catalyzed by a type III S-adenosyl-l-methionine-dependent O-methyltransferase.
6. Arikat, Naser A. and Jawad, Fawzia M. and Karam, Nabila S. and Shibli, Rida A., Micropropagation and Accumulation of Essential Oils in Wild Sage ({\emph{Salvia Fruticosa}} Mill.), Scientia Horticulturae, vol. 100, no. 1, pp. 193--202, March 2004. doi: 10.1016/j.scienta.2003.07.006. Abstract
   A protocol for in vitro propagation of the wild three-lobed sage (Salvia fruticosa Mill.) (Synonym, Salvia triloba L.) was developed. Shoot tips were excised from in vitro seedlings and established on MS, Nitch and Nitch (NN), or B5 medium. For shoot proliferation, in vitro nodal and apical explants were cultured on MS medium containing 0.25–2μM 6-benzylaminopurine (BA), 6-furfurylaminopurine (kinetin), or thidiazuron (TDZ). Proliferated microshoots were rooted on MS medium supplemented with 2.7–11.4μM indole-3-butyric acid (IBA), indole-3-acetic acid (IAA), or α-naphthaleneacetic acid (NAA). Results indicated that shoots established at 100\% regardless of media type, however, shoot height, nodes per shoot, and leaf number were highest for explants established on MS medium compared to NN or B5. Number and height of proliferated shoots, nodes per shoot, and leaf number were highest for nodal explants cultured on a medium containing 0.75μM BA. Microshoots cultured on a medium supplemented with 2.7μM IBA exhibited the highest rooting percentage compared to those cultured with IAA or NAA. Essential oil composition in microshoots and shoots of greenhouse-grown plants was determined by gas chromatography/mass spectrometry. The major essential oils detected in both plant materials were α-pinene, 1,8-cineole, camphor, and borneol. No α-thujone or β-thujone was detected. The content of essential oils, camphor, and borneol were higher in the microshoots than in shoots of greenhouse-grown plants.
7. Arikat, Naser A. and Jawad, Fawzia M. and Karam, Nabila S. and Shibli, Rida A., Micropropagation and Accumulation of Essential Oils in Wild Sage ({\emph{Salvia Fruticosa}} Mill.), Scientia Horticulturae, vol. 100, no. 1, pp. 193--202, March 2004. doi: 10.1016/j.scienta.2003.07.006. Abstract
   A protocol for in vitro propagation of the wild three-lobed sage (Salvia fruticosa Mill.) (Synonym, Salvia triloba L.) was developed. Shoot tips were excised from in vitro seedlings and established on MS, Nitch and Nitch (NN), or B5 medium. For shoot proliferation, in vitro nodal and apical explants were cultured on MS medium containing 0.25–2μM 6-benzylaminopurine (BA), 6-furfurylaminopurine (kinetin), or thidiazuron (TDZ). Proliferated microshoots were rooted on MS medium supplemented with 2.7–11.4μM indole-3-butyric acid (IBA), indole-3-acetic acid (IAA), or α-naphthaleneacetic acid (NAA). Results indicated that shoots established at 100\% regardless of media type, however, shoot height, nodes per shoot, and leaf number were highest for explants established on MS medium compared to NN or B5. Number and height of proliferated shoots, nodes per shoot, and leaf number were highest for nodal explants cultured on a medium containing 0.75μM BA. Microshoots cultured on a medium supplemented with 2.7μM IBA exhibited the highest rooting percentage compared to those cultured with IAA or NAA. Essential oil composition in microshoots and shoots of greenhouse-grown plants was determined by gas chromatography/mass spectrometry. The major essential oils detected in both plant materials were α-pinene, 1,8-cineole, camphor, and borneol. No α-thujone or β-thujone was detected. The content of essential oils, camphor, and borneol were higher in the microshoots than in shoots of greenhouse-grown plants.
8. del Misterio, Sociedad para la Preservatiòn de las Plantas, The Salvia Divinorum Grower's Guide, 1998. url: https://www.iamshaman.com/cultivation.htm. Abstract
   Salvia divinorum (aka “diviner’s sage”) is an extremely rare plant used by the Mazatec Indians in medico-magico-divinatory ceremonies. This comprehensive guide explains how anyone can cultivate this most mysterious of power plants.
9. Wasson, R Gordon, A New Mexican Psychotropic Drug from the Mint Family, Botanical Museum leaflets, Harvard University, vol. 20, no. 3, pp. 77--84, December 1962. doi: 10.5962/p.168538.
10. Takitos13, Ever Wondered What Salvia Looks like in the Wild?, r/Salvia, November 2024. url: www.reddit.com/r/Salvia/comments/1ghxrvg/ever_wondered_what_salvia_looks_like_in_the_wild/.
11. Takitos13, I Think I Found Wild Salvia Seeds, r/Salvia, November 2024. url: www.reddit.com/r/Salvia/comments/1gtpnpw/i_think_i_found_wild_salvia_seeds/.
12. Epling, Carl and {Jativa-M.}, Carlos D, A New Species of Salvia from Mexico, Botanical Museum leaflets, Harvard University, vol. 20, no. 3, pp. 75--76, December 1962. doi: 10.5962/p.168537.
13. Díaz, José Luis, Ethnopharmacology and Taxonomy of Mexican Psychodysleptic Plants, Journal of Psychedelic Drugs, vol. 11, no. 1-2, pp. 71--101, January 1979. doi: 10.1080/02791072.1979.10472094.
14. Hatipoglu, Seda Damla and Yalcinkaya, Burhanettin and Akgoz, Muslum and Ozturk, Turan and Goren, Ahmet C. and Topcu, Gulacti, Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species, Phytochemical Analysis, vol. 28, no. 6, pp. 541--549, 2017. doi: 10.1002/pca.2703. Abstract
    Introduction Salvia, an important and widely available member of Lamiaceae family. Although comparative analysis on secondary metabolites in several Salvia species from Turkey has been reported, their hallucinogenic chemicals have not been screened thoroughly. Objective This study provides LC–MS/MS analysis of 40 Salvia species for screening their psychoactive constituents of salvinorin A and salvinorin B. 5S–rRNA gene non-coding region of Salvia plants was sequenced, aligned and compared with that sequence of Salvia divinorum plant. Methodology Targeted molecules of salvinorin A and salvinorin B were quantified, using LC–MS/MS, from all aerial parts of 40 Salvia species, collected from different parts of Turkey. Regions of 5S–rRNA gene from different species were amplified by polymerase chain reaction and DNA sequences were aligned with Salvia divinorum DNA sequences. Results Very few of the Salvia species (S. recognita, S. cryptantha and S. glutinosa) contained relatively high levels of salvinorin A (212.86 ± 20.46 μg/g, 51.50 ± 4.95 μg/g and 38.92 ± 3.74 μg/g, respectively). Salvinorin B was also found in Salvia species of S. potentillifolia, S. adenocaulon and S. cryptantha as 2351.99 ± 232.22 μg/g, 768.78 ± 75.90 μg/g and 402.24 ± 39.71 μg/g, respectively. The sequences of 5S–rRNA gene of 40 different Salvia species were presented and it was found that none of the Salvia species in Turkey had similar DNA sequence to Salvia divinorum plant. Conclusion This is the first report of screening 40 Salvia species in Turkey according to their psychoactive constituents, salvinorin A and salvinorin B and their genomic structures. It is possible that some of these Salvia species may exhibit some psycho activity. Thus, they need to be screened further. Copyright © 2017 John Wiley \& Sons, Ltd.
15. {Hernández-Bello}, Rafael and {García-Rodríguez}, Rosa Virginia and {García-Sosa}, Karlina and {Peña-Rodríguez}, Luis Manuel and {Vázquez-Hernández}, Maribel and {Ramos-Morales}, Fernando Rafael and Corcoran, Olivia and {Sánchez-Medina}, Alberto, Salvinorin A Content in Legal High Products of {\emph{Salvia Divinorum}} Sold in Mexico, Forensic Science International, vol. 249, pp. 197--201, April 2015. doi: 10.1016/j.forsciint.2015.01.038. Abstract
    Salvia divinorum (Lamiaceae) is a herb native to Mexico where it is used by Mazatec shamans for spiritual and divination purposes. S. divinorum products are easily available to consumers and are used worldwide as legal highs because of the hallucinogenic effects caused mainly by salvinorin A. Highly popular videos and websites on the internet depicting the use of S. divinorum products have contributed to an increase in their consumption. Recent reports have highlighted the potential of these products to induce psychosis in consumers. In Mexico, dried leaf extracts of S. divinorum are sold in different strengths, claiming to correlate with increasing amounts of salvinorin A. In order to determine the variability of salvinorin A content between brands and to investigate possible correlation between brand strengths, this study sought to quantify salvinorin A in commercial products available in Mexico using an HPLC method. The HPLC analytical method showed a correlation coefficient R2{$>$}0.99, with LOD of 0.44μg/mL and LOQ of 1.34μg/mL. The retention time for salvinorin A was 23.09±0.95min and the measured concentrations ranged between 8.32±0.65 and 56.52±3.77mg/g dried leaf. The results for brand c did not show an agreement between the declared and the calculated amount of salvinorin A. Additionally, the emergence in Mexico of high strength salvia products (100×), the lack of regulation and the observed variability of salvinorin A content between brands of commercial legal highs products of S. divinorum could result in a health problem for consumers.
16. Tsujikawa, Kenji and Kuwayama, Kenji and Miyaguchi, Hajime and Kanamori, Tatsuyuki and Iwata, Yuko T. and Yoshida, Takemi and Inoue, Hiroyuki, Determination of Salvinorin A and Salvinorin B in Salvia Divinorum-Related Products Circulated in Japan, Forensic Science International, vol. 180, no. 2, pp. 105--109, September 2008. doi: 10.1016/j.forsciint.2008.07.008. Abstract
    Two major salvinorins, salvinorin A (SalA) and salvinorin B (SalB), in three Salvia divinorum dried leaf products and nine of its “concentrated extract” products circulated in Japan were determined. These ingredients were extracted twice with acetonitrile and decolored with graphite carbon powder. SalA and SalB were confirmed by liquid chromatography–tandem mass spectrometry in product ion scan mode, and quantified by high-performance liquid chromatography with UV detection (for SalA) and by mass spectrometry in single ion monitoring mode (for SalB). The SalA/SalB contents (μg/mg) were in the range of 3.2–5.0/0.10–0.17 in the dried leaf products and 4.1–38.9/0.26–2.42 in the “concentrated extract” products. These findings would be useful for analysis of S. divinorum-related products circulated in the drug market.
17. Jenks, Aaron A. and Walker, Jay B. and Kim, Seung-Chul, Evolution and Origins of the Mazatec Hallucinogenic Sage, Salvia Divinorum (Lamiaceae): A Molecular Phylogenetic Approach, Journal of Plant Research, vol. 124, no. 5, pp. 593--600, September 2011. doi: 10.1007/s10265-010-0394-6. Abstract
    Salvia divinorum Epl. \& Játiva-M. (Lamiaceae) is a potent hallucinogenic plant that is classified within Salvia subgenus Calosphace, section Dusenostachys, and hypothesized to be an interspecific hybrid. It is of ethnobotanical significance due to its employment in traditional healing ceremonies by the Mazatecs of Oaxaca, Mexico, and due to its unique pharmacology—a highly selective, non-nitrogenous, κ-opioid receptor agonist. In order to test its phylogenetic position and putative hybridity, we sequenced multiple DNA regions (ITS, trnL-trnF, and psbA-trnH) of 52 species—representing the major lineages of subgenus Calosphace—and six accessions of S. divinorum. Our molecular phylogenetic results suggest that S. divinorum should not be classified within Dusenostachys and that it is not a hybrid. Additionally, we determine that the closest known relative of this psychoactive Mexican sage is S. venulosa, a rare endemic of Colombia.
18. Pelot, Kyle A. and Mitchell, Rod and Kwon, Moonhyuk and Hagelthorn, Lynne M. and Wardman, Jacob F. and Chiang, Angela and Bohlmann, Jörg and Ro, Dae-Kyun and Zerbe, Philipp, Biosynthesis of the Psychotropic Plant Diterpene Salvinorin A: Discovery and Characterization of the Salvia Divinorum Clerodienyl Diphosphate Synthase, The Plant Journal, vol. 89, no. 5, pp. 885--897, 2017. doi: 10.1111/tpj.13427. Abstract
    Salvia divinorum commonly known as diviner's sage, is an ethnomedicinal plant of the mint family (Lamiaceae). Salvia divinorum is rich in clerodane-type diterpenoids, which accumulate predominantly in leaf glandular trichomes. The main bioactive metabolite, salvinorin A, is the first non-nitrogenous natural compound known to function as an opioid-receptor agonist, and is undergoing clinical trials for potential use in treating neuropsychiatric diseases and drug addictions. We report here the discovery and functional characterization of two S. divinorum diterpene synthases (diTPSs), the ent-copalyl diphosphate (ent-CPP) synthase SdCPS1, and the clerodienyl diphosphate (CLPP) synthase SdCPS2. Mining of leaf- and trichome-specific transcriptomes revealed five diTPSs, two of which are class II diTPSs (SdCPS1-2) and three are class I enzymes (SdKSL1-3). Of the class II diTPSs, transient expression in Nicotiana benthamiana identified SdCPS1 as an ent-CPP synthase, which is prevalent in roots and, together with SdKSL1, exhibits a possible dual role in general and specialized metabolism. In vivo co-expression and in vitro assays combined with nuclear magnetic resonance (NMR) analysis identified SdCPS2 as a CLPP synthase. A role of SdCPS2 in catalyzing the committed step in salvinorin A biosynthesis is supported by its biochemical function, trichome-specific expression and absence of additional class II diTPSs in S. divinorum. Structure-guided mutagenesis revealed four catalytic residues that enabled the re-programming of SdCPS2 activity to afford four distinct products, thus advancing our understanding of how neo-functionalization events have shaped the array of different class II diTPS functions in plants, and may promote synthetic biology platforms for a broader spectrum of diterpenoid bioproducts.
19. Nozawa, Masato and Suka, Yuhki and Hoshi, Takashi and Suzuki, Toshio and Hagiwara, Hisahiro, Total Synthesis of the Hallucinogenic Neoclerodane Diterpenoid Salvinorin A, Organic Letters, vol. 10, no. 7, pp. 1365--1368, April 2008. doi: 10.1021/ol800101v. Abstract
    Total synthesis of salvinorin A (1), a neoclerodane diterpenoid having the most potent hallucinogenic activity and a selective κ-opioid agonist, was completed in 20 steps starting from enantiomerically pure hydroxy-Wieland−Miescher ketone 5.
20. Kwon, Moonhyuk and Utomo, Joseph C. and Park, Keunwan and Pascoe, Cameron A. and Chiorean, Sorina and Ngo, Iris and Pelot, Kyle A. and Pan, Cheol-Ho and Kim, Seon-Won and Zerbe, Philipp and Vederas, John C. and Ro, Dae-Kyun, Cytochrome P450-Catalyzed Biosynthesis of a Dihydrofuran Neoclerodane in Magic Mint (Salvia Divinorum), ACS Catalysis, vol. 12, no. 1, pp. 777--782, January 2022. doi: 10.1021/acscatal.1c03691. Abstract
    The hallucinogenic plant, Salvia divinorum, synthesizes neoclerodane diterpenes, such as salvinorins, salvidivins, and salvinicins, which are agonistic or antagonistic to μ- or κ-opioid receptors. From S. divinorum trichomes, crotonolide G synthase (SdCS; CYP76AH39) was identified. It catalyzes the conversion of kolavenol to a dihydrofuran neoclerodane, crotonolide G. 18O2-feeding studies confirmed that SdCS incorporates an aerobic oxygen into crotonolide G, rather than forming a cation at C16 that is trapped by the alcohol at C15. Structural modeling of SdCS accompanied by site-directed mutagenesis established the importance of V367 and F479 residues in substrate-binding. The dihydrofuran neoclerodane can serve as a unique lead structure for drug development.
21. Reisfield, Aaron Shai, Systematic Studies in Salvia L. (Lamiaceae) with Special Emphasis on Subgenus Calosphace (Benth.) Benth. Section Dusenostachys Epl., 1987. url: https://minds.wisconsin.edu/handle/1793/11724. Abstract
    xvi, 423 leaves : ill. ; 29 cm.
22. {Arkham's Botanical}, List of Salvia Divinorum Clones, November 2020. url: https://web.archive.org/web/20201107235519/https://www.arkhamsbotanical.com/info/list-of-salvia-divinorum-clones/.
23. 101yeoz, Salvia from Seed January 2023 Update NEW CLONE NAME X2, r/GrowinSalviaDivinorum, May 2024. url: www.reddit.com/r/GrowinSalviaDivinorum/comments/1ckz2ij/salvia_from_seed_january_2023_update_new_clone/.
24. Mead, Rebecca and Chom, Elise and Rankin, J Graham, Development of a Field Method for the Identification of the Hallucinogenic Herb Salvia Divinorum Using ATR-FTIR, 2012. url: https://www.marshall.edu/forensics/files/2012/09/MeadR-Poster-Final-2-9-12.pdf. Abstract
    Salvia divinorum is a hallucinogenic plant that is increasing in popularity as a ‘legal’ alternative to marijuana. In response, however, thirty states have legislation concerning either S. divinorum or its psychoactive component, salvinorin A. Salvinorin A is unique to S. divinorum. Current analytical methods, including gas chromatography/mass spectrometry and thin layer chromatography, require the extraction of salvinorin A, and use it’s presence to identify S. divinorum rather than identifying the plant. No presumptive or field tests exist to analyze S. divinorum. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) has been shown to be able to distinguish between species of plant genera, and so is being explored as a possible field test for S. divinorum that would not require sample preparation.
25. {Brito-da-Costa}, Andreia Machado and {Dias-da-Silva}, Diana and Gomes, Nelson G. M. and {Dinis-Oliveira}, Ricardo Jorge and {Madureira-Carvalho}, Áurea, Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia Divinorum: Clinical and Forensic Aspects, Pharmaceuticals, vol. 14, no. 2, pp. 116, February 2021. doi: 10.3390/ph14020116. Abstract
    Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the κ-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles.
26. Hooker, Jacob M. and Xu, Youwen and Schiffer, Wynne and Shea, Colleen and Carter, Pauline and Fowler, Joanna S., Pharmacokinetics of the Potent Hallucinogen, Salvinorin A in Primates Parallels the Rapid Onset and Short Duration of Effects in Humans, NeuroImage, vol. 41, no. 3, pp. 1044--1050, July 2008. doi: 10.1016/j.neuroimage.2008.03.003. Abstract
    Salvia divinorum, a mint plant originally used by the Mazatecs of Oaxaca, Mexico in spiritual rituals has gained popularity, in smoked form, as a legal hallucinogen in the United States and Europe. Abuse results in rapid onset and short-lasting effects that include visual hallucinations and motor-function impairment. Salvinorin A, the psychoactive component of S. divinorum, is a uniquely potent agonist at κ-opioid receptors, targets for new therapeutic drugs. We labeled salvinorin A with C-11 by acylation of salvinorin B with [11C]-acetyl chloride to study whether its kinetic behavior in the brain parallels its uniquely fast, yet brief physiological effects. Positron emission tomography (PET) studies performed in 6 adult female baboons indicated extremely rapid brain uptake reaching a peak accounting for 3.3\% of the total administered dose in 40~s and clearing with a half-life of 8~min. [11C]-salvinorin A was distributed throughout the brain with the highest concentration in the cerebellum and a notable concentration in the visual cortex, perhaps accounting for its physiological effects when smoked. Naloxone administration did not reduce the overall concentration of [11C]-salvinorin A significantly nor did it change its regional distribution. Peripheral organ kinetics suggested at least two modes of metabolism and excretion occur: through the renal and biliary systems. Our findings have revealed that the exceptionally rapid uptake and brief duration of salvinorin A in the brain match the time-course of visual hallucinations for S. divinorum when smoked. The effects of salvinorin A may occur at {$<$}10~μg in the human brain, emphasizing its remarkable potency.