Salvia divinorum

[1] [2] [3] [4]

Propagation

Divinorum does not produce viable seed under normal circumstances, therefore the majority of available germplasm is from cuttings.[5][6][7] Artificial pollination can produce a dismal number of seeds, few of which survive to maturity (0.2% of hand-pollinated flowers producing thriving plants).[6]

Germination

[7]

Vegetative

Two or three node cuttings are sufficient to root.[8]

Wild divinorum stems 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]

[9] [10] [11] [12]

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[13]

Kutrezeba et al. developed an in vitro multiplation protocol for divinorum using 6-BAP during the investigation of the biosynthesis of salvinorin A.[13] The authors modified the work of Arikat et al. for their micropropagation protocol.[14]

[15] [11]

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.[13]

Rooted stem cuttings have been grown in typical potting mix consisting of topsoil, peatmoss, vermiculite, and perlite (4:2:1:1).[8]

Soil

Fertilization

Weekly irrigation with water-soluble fertilizer (Miracle Grow) has been used for divinorum cultivation in containers.[8]

Temperature

Divinorum cultivation is possible in temperatures 10-30°C without any reported negative effects.[8]

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.[8] Divinorum is very sensitive to light during the night, having been known to revert to vegetative growth in greenhouses with minimal nighttime lighting. A short day photoperiod can be simulated by covering divinorum with a black cloth each afternoon.[1]

Unfiltered greenhouse light in the winter at 43°N (University of Wiscondin-Madison) is sufficient to induce prolific flowering.[1] Divinorum grown in environmental chambers using incandescent and cool white fluorescent bulbs (2800-3300 ft-c) grew well enough for photoperiod flowering studies.[8]

Plant height is not directly a major factor in flowering. Tall plants are most likely to reach light, which is associated with heavier flowering.[1] Furthermore, divinorum has been noted to elongate shortly before flowering.[8]

Pests

Cultivators have had to cull their entire stock due to a possible viral infection transmitted from new plants. It presented as deformation and stunting. The infection could have spread via aphids or via touch. It is unclear if the potential virus was transmitted to seeds.[6]

[16]

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]

Divinorum is mostly located in the undergrowth forest. Plants exposed to partial or full sunlight often exhibit symptoms of dehydration, including wilting leaves.[1]

Divinorum is likely evolved for pollination by hummingbirds, though ineffectively.[1] Photos and videos have been taken of hummingbirds visiting divinorum flowers in open patches.[17]

[18] [19] [20] [21]

Reported Locations

Morphology

[1] [18] [26] [27] [28]

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]

Upper leaves become strongly aromatic as flowering buds develop.[8]

Inflorescence

Divinorum has a violet calyx, not a blue one as originally described in the 1962 species identification.[29][8] 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.[8][1] Flower buds begin to form approximately 2 months after exposure to a short photoperiod. The flowers open approximately one month later.[1]

Flowers open asynchronously during the evening or night.[1]

S. divinorum and the closely related S. venulosa can be distinguised by the color of the corolla: divinorum has white to pink and venulosa has light red corollas.[30]

Some good photos [17]

[19]

Seeds

Natural stands of divinorum are almost entirely void of fruitlets and seed, therefore the only thorough descriptions of seeds comes from artificial pollination of cultivated plants.[1]

Phytochemistry

Salvinorin A is the main psychoactive compound present in divinorin.[32]

Drying does not diminish the concentration of salvinorin A in whole leaves.[4] Forty-year-old herbarium samples have substaintially similar salvinorin A concentraion to new dried leaves.[25]

Salvinorin binding screening panel[32]

Salvinorin A was not found by HPLC analysis in S. concolor, S. blepharophylla, S. chiapensis, S. gregii var. San Isidro, S. leucantha, S. membranacea, S. recurva, or in Coleus blumei.[31]

[33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [31] [25] [45] [18] [46] [47] [48] [49] [50] [51] [52] [32] [53] [54] [55] [56] [57] [58] [59] [60] [27] [61] [62] [63]

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.[30][2] Zygosity is unlikely to produce substantial variation considering the low levels of heterozygosity (0.192%) in divinorum and high repeat content (53%).[64]

Biosynthesis

The biosynthetic pathway of Salvinorin A is not well known illucidated, though there are proposed routes. Several key enzymes remain unknown/unverified.[64]

[13] [65] [66] [67] [68] [69] [70] [71] [72] [73] [64]

Distribution

Salvinorin A is almost exclusively located in glandular trichomes on the leaf surface, primarily abaxial. Smaller amounts are located in trichomes on the stem.[25]

[65] [47]

Timecourse

Salvinorin A is similar in concentration across the lifespan of leaves. In contrast, salvinorin C is more concentrated in older leaves.[25]

[11]

Improvement

Of the available genomes, S. divinorum is most closely related to S. splendens and S. hispanica, genetically. They diverged approximately 8 MYA.[64] An earlier analysis, which did not test S. splendens or S. hispanica, put the closest relative as S. venulosa.[30] These species are possible candidates for hybridization.

A lack of genetic diversity due to repeated clonal propagation is likely the cause of poor reproduction in divinorum.[30]

In natural stands, divinorum plants exposed to the most sunlight (including full sun) exhibit the greatest number of flowers despite evidence of dehydration.[1]

The primary barrier to seed set is not pollination. Pollen fertility is low—Only 53-56% of divinorum pollen grains are viable (4614 specimens; greenhouse and natural stand plants). Fewer still generate pollen tubes that reach the ovaries. Of the nutlets that form, many likely fail by post-zygotic embryo abortion or endosperm failure.[1]

Unsuccessfully fertilized flowers will die and fall off after a few days. Flowers with successfull fertilization will remain for several weeks. Seeds will dehisce when mature.[17]

Cross-pollination and self-pollination yield approximately equal nutlet formation (3%), though this may still be self-incompatibility given the lack of diversity in natural stands.[1]¹ Other attempts at seed production have about a 2% success rate for seed generation (6,000 flowers, 108 seeds). The reported germination fraction was 30% (27/91). A further fifteen plants were stunted or deformed and later discarded. Only 12 plants survived giving a final fraction of 0.2% (pollinated flowers:mature plants).[6]

Valdés reported a 28% seed set (14 flowers:4 set seed) which is considerably higher than other attempts. The plants used were “Epling’s original specimen” (i.e. “Wasson”) and “plants collected on Cerro Quemado.” The number of seeds was not given. Unfortunately, an overheating accident caused a total loss of all seedlings.[8]

Identification

Extraction and identification of Salvinorin A from plant material provides positive identification of divinorum.[64]

Diploid species n=11 of ~541 Mb (Pubmed BioProject:PRJNA1104206; RNA Sequence:SRX1875790).[1][64]

Divinorum is unlikely to be a recent hybrid.[30]

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.[8] However, the local people also practice vegetative propagation as well.[1]

[74] [64] [75] [76] [48] [77] [78] [20] [79] [26] [80] [21] [81]

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.[8][5][22]

Valdés
Valdés obtained two divinorum samples. One was from Cerro Rabon near the Mazatec village of Ayautla. The other was near the village of Cerro Quemado. Those two samples along with a clone from Berkley (likely a “Wasson” clone) were donated to the University of Wisconsin-Madison circa 1993.[1]

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.[5]

Reisfield Reisfield et al. traveled to Oaxaca, Mexico during the winter of 1984-85. About fifteen populations of divinorum were located in the region.[1]

Siebert

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.[65]

Salvinorins react with vanillin reagent³ to produce a pinkish-purple spot in TLC. It can also be used directly by dipping dried plant material in the reagent and briefly heating in an oven at 110°C.[25]

[25] [84] [40] [44] [85] [31] [86] [48] [49] [50] [51] [52] [59] [81] [28]

History & Society

Divinorum is traditionally taken via the oral route where pairs of leaves are nibbled on slowly and chewed. Smoking seems to have developed at a later time.[4]

Several alternative routes of administration were explored by Siebert in 1994. Methods that bypassed first-pass metabolism (oral spray, vaporizing, and smoking) proved effective, while others (swallowed capsules) were not.[32] This supports the traditional use of chewing the leaves as a method of absorption via oral mucosa.

[66] [35] [87] [88] [3] [74] [89] [90] [91] [92] [93] [94] [41] [95] [96] [97] [98] [99] [100] [101] [76] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [49] [50] [51] [52] [32] [115] [116] [117] [118] [119] [120] [121] [122] [54] [56] [123] [124] [125] [126] [127] [27] [62] [63] [128] [129] [130] [131] [132] [133]

Clones in Research

Work Log

07 Mar 2025

Survivor

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.[4]

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. Ott, Jonathan, Pharmacotheon: Entheogenic Drugs, Their Plant Sources and History, January 1996. url: http://archive.org/details/JonathanOttPharmacotheon. Abstract
   If you get only one book on the topic of psychoactive plants \& compounds, this is it, the most complete reference book, a dense 639 pages covering over 1000 species with the largest bibliography on the subject ever compiled. Everything you ever wanted to know, and much more. Accurate, definitive, and surprisingly entertaining
5. 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.
6. Michael, Salvia Divinorum Seed Project, Enchanted Plants Nursery, March 2023. url: https://enchantedplantsnursery.co.uk/salvia-divinorum-seed-project. Abstract
   Our Salvia divinorum seed project
7. Hanna, Jon, Growing Salvia Divinorum from Seed, The Entheogen Review, vol. 8, no. 3, pp. 110--124, 1999. url: https://aciddata.com/plants/salvia/salvia_cultivation4.pdf.
8. 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.
9. {RareShrub}, How to Take Salvia Divinorum Plant Cuttings, August 2022. url: https://www.youtube.com/watch?v=LwdDQ4tSYKs. Abstract
   Here is a video on how to take live Salvia Divinorum cuttings. Check out my reddit account u/zorg621 for more tips and tricks and advice. Live Salvia Divinorum plants are available here: https://rareshrub.com/product/salvia-... List of Products that I use in my grows: Small Azamax https://amzn.to/3Fkatl7 Large Azamax https://amzn.to/3SG8FGn Predatory Nematodes (For Soil pest treatment of fungus gnats, thrips, spider mites, etc): https://amzn.to/3DdHY5U Mosquito Bits (for soil pest treatment of fungus gnats only): https://amzn.to/3zm2aBz Humidity domes: Mondi Dome https://amzn.to/3swWwbR Trays: Supersprouter quad thick trays https://amzn.to/3TVy8gt Fans: https://amzn.to/3Fh0NrL Repeat cycle timer: https://amzn.to/3DcfDNB Light Timer: https://amzn.to/3N7V61c Lights I use and recommend (although they're pretty pricey on amazon, you can find comparable ones locally if you're crafty. I like these because they're linkable and good lights overall): https://amzn.to/3Fh2ghL Shelving (W/O wheels): https://amzn.to/3gKz5tg Shelving (With wheels): https://amzn.to/3gNvHhf Foxfarm Grow Big Fertilizer: https://amzn.to/3DB2leV Foxfarm Soil (The only soil I use): https://amzn.to/3ziRkwd Reverse Osmosis System I've upgraded to and recommend: https://amzn.to/3zj9Y78 6 pack crystal Geyser Mountain spring Water: https://amzn.to/3SznrhW Shop Stool I love: https://amzn.to/3FlWH1s Camera I use: https://amzn.to/3gKPhuz Strap kit for camera: https://amzn.to/3fdE84L Mount for Kit: https://amzn.to/3gKXL4N Air conditioner: https://amzn.to/3SJDdqu Medical Squeeze Bottle for watering: https://amzn.to/3NaALIw
10. {Mountain Gardens}, Making Cuttings from Salvia Divinorum, April 2015. url: https://www.youtube.com/watch?v=cA1pwjoX60Q. Abstract
    Joe Hollis of Mountain Gardens shows an alternative way of heating a greenhouse using a wood fired hot tub, and then demonstrates how to make cuttings of Salvia Divinorum. To learn more, visit http://www.mountaingardensherbs.com/
11. {[deleted]}, Micropropagation: Sally For The Masses!, r/GrowinSalviaDivinorum, October 2021. url: www.reddit.com/r/GrowinSalviaDivinorum/comments/qb1ag8/micropropagation_sally_for_the_masses/.
12. {Ranch of Plants}, Propagating Salvia Divinorum: PART 1, December 2023. url: https://www.youtube.com/watch?v=NTTQb5f5ypI. Abstract
    \#salvia \#salviadivinorum \#propagation \#plantcutting \#howto \#gardening \#garden \#greenhouse We'll try two methods of propagating Salvia divinorum. This is going to be a two part episode; here, in PART 1, we'll go step by step what to do first.
13. 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.
14. 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.
15. {Santos-Gomes}, Paula C. and Seabra, Rosa M. and Andrade, Paula B. and {Fernandes-Ferreira}, Manuel, Determination of Phenolic Antioxidant Compounds Produced by Calli and Cell Suspensions of Sage (Salvia officinalisL.), Journal of Plant Physiology, vol. 160, no. 9, pp. 1025--1032, January 2003. doi: 10.1078/0176-1617-00831. Abstract
    Sage (Salvia officinalis L.) calli were established by culturing internodal segments, excised from aseptic seedlings, on MS basal medium gellied with agar and supplemented with 0.05 mg/L dichlorophenoxyacetic acid (2,4-D) in presence of benzyladenine (BA) or zeatin (ZEA) or kinetin (KIN), at 1.5 mg/L. Suspended cells were established by transferring one callus to 50 mL of liquid MS basal medium devoid of agar and containing the same type of hormonal supplementation used in respective calli growth. The highest growth of calli and suspensions occurred with 1.5 mg/L ZEA. However, with this cytokinin supplementation, as well as with 1.5 mg/L KIN, both in presence of 0.05 mg/L 2,4-D, suspensions differentiated small root shaped structures. Well shaped, majority single cell suspensions were formed under the effect of 0.05 mg/L 2,4-D and 0.5 mg/L KIN. Calli grown with 0.05 mg/L 2,4-D and 1.5 mg/L BA and suspended cells grown with 0.05 mg/L 2,4-D and ZEA or KIN at 1.5 mg/L, or KIN at 0.5 mg/L, were searched for phenolics production. Twelve phenolic compounds were identified in calli: gallic acid, 3-O-caffeoylquinic acid, 5-O-caffeoylquinic acid, caffeic acid, rosmarinic acid, hesperetin, epirosmanol, hispidulin, genkwanin, carnosol, carnosic acid, and methyl carnosate. With the exception for genkwanin and epirosmanol all of these phenolic compounds were also produced by the sage suspension cultures grown in the presence of 1.5 or 0.5 mg/L KIN. Genkwanin was the only phenolic absent in the suspensions grown with 1.5 ZEA. Suspended cells, grown with 0.5 mg/L KIN, and calli cultures showed the highest specific accumulation of the total phenolics, with rosmarinic acid representing 94-97 percnt;.
16. Goh, C. J. and Hahn, Y., Identification of a Novel Member of the Family Betaflexiviridae from the Hallucinogenic Plant Salvia Divinorum, Acta virologica, vol. 63, no. 04, pp. 373--379, 2019. doi: 10.4149/av_2019_401. Abstract
    Betaflexiviridae is a family of plant-infecting RNA viruses with 11 recognized genera, of which genomes have diverse organization with three to six open reading frames (ORFs). A genome sequence of a novel Betaflexiviridae species, named Salvia divinorum RNA virus 1 (SdRV1), was identified in Salvia divinorum, herbal mint plant with hallucinogenic properties. The SdRV1 genome was predicted to have four ORFs encoding a replicase polyprotein (REP), a movement protein (MP), a coat protein (CP), and a putative nucleic acid-binding protein (NBP). Phylogenetic analyses based on the REP, MP, and CP sequences indicated that SdRV1 is most closely related to members of the genus Citrivirus. However, the genome organization of SdRV1 is the same as that of the genus Prunevirus. Moreover, the SdRV1 NBP had greatest sequence similarity with members of the genus Carlavirus. A complex evolutionary history involving ancestors of these three genera might have resulted in the unique phylogenetic position of SdRV1, which could be considered the founding member of a new genus in the family Betaflexiviridae. The genome sequence of SdRV1 might be useful for studies on the evolution of Betaflexiviridae.
17. Goh, C. J. and Hahn, Y., Identification of a Novel Member of the Family Betaflexiviridae from the Hallucinogenic Plant Salvia Divinorum, Acta virologica, vol. 63, no. 04, pp. 373--379, 2019. doi: 10.4149/av_2019_401. Abstract
    Betaflexiviridae is a family of plant-infecting RNA viruses with 11 recognized genera, of which genomes have diverse organization with three to six open reading frames (ORFs). A genome sequence of a novel Betaflexiviridae species, named Salvia divinorum RNA virus 1 (SdRV1), was identified in Salvia divinorum, herbal mint plant with hallucinogenic properties. The SdRV1 genome was predicted to have four ORFs encoding a replicase polyprotein (REP), a movement protein (MP), a coat protein (CP), and a putative nucleic acid-binding protein (NBP). Phylogenetic analyses based on the REP, MP, and CP sequences indicated that SdRV1 is most closely related to members of the genus Citrivirus. However, the genome organization of SdRV1 is the same as that of the genus Prunevirus. Moreover, the SdRV1 NBP had greatest sequence similarity with members of the genus Carlavirus. A complex evolutionary history involving ancestors of these three genera might have resulted in the unique phylogenetic position of SdRV1, which could be considered the founding member of a new genus in the family Betaflexiviridae. The genome sequence of SdRV1 might be useful for studies on the evolution of Betaflexiviridae.
18. Jenks, Aaron A. and Kim, Seung-Chul, Medicinal Plant Complexes of Salvia Subgenus Calosphace: An Ethnobotanical Study of New World Sages, Journal of Ethnopharmacology, vol. 146, no. 1, pp. 214--224, March 2013. doi: 10.1016/j.jep.2012.12.035. Abstract
    Ethnopharmacological relevance The species of Salvia subgenus Calosphace are used medicinally and ritually in numerous traditions of folk healing among indigenous cultures of North and South America with more than 500 species. These species contain numerous bioactive terpenes and terpenoids, some active at human opioid and GABA receptors, which may contribute to their effectiveness as folk medicines. Medicinal plant complexes contain species which share common names, morphological and/or aromatic properties, and medicinal uses; these complexes are found in traditional systems of medicine. Our research looks for complexes within Calosphace and the secondary metabolites they contain. Materials and methods Several studies have combined molecular phylogenetics and ethnopharmacology to successfully target active medicinal species. In this paper, we have selected a monophyletic clade, Salvia subgenus Calosphace, and performed a literature search to identify medicinal plant complexes within it. We created a database from over 200 references, found using keywords, and herbarium sheets. To identify medicinal plant complexes within the database, all species with shared vernacular names were first grouped. If the species sharing common names had similar medicinal uses and morphological similarity, they were concluded to be a complex. In order to determine the accuracy and validity of this approach, the chia complex was used as control, and we more species than reported by all of the published references combined. After identifying complexes and species within each, we searched the phytochemical literature to identify all reported secondary metabolites for each. Results We identify four previously unidentified complexes. Mirto (5 species) is used extensively in the treatment of the folk illness susto and other illnesses in Mexico, and is characterized by red flowers. Ñucchu (7 species) used as a symbolic element in religious processions and in the treatment of respiratory ailments in Peru and characterized by red flowers. Cantueso (2 species), with blue flowers, is used for respiratory ailments in Mexico, and Manga-paqui (3 species) is used for kidney and liver diseases in Ecuador. For the species of each complex we report all traditional preparations, other vernacular names, and known secondary metabolites. Among these complexes, Mirto and Ñucchu appear to have exceptional levels of cultural significance. Conclusions Our results support our hypothesis that species within Salvia subgenus Calosphace will assort into complexes of medicinal plants that share common names, appearances, and medicinal uses. We have identified four new complexes within this monophyletic lineage, mirto, ñucchu, cantueso, and manga-paqui.
19. Wester, Petra and {Claßen-Bockhoff}, Regine, Pollination Syndromes of New World Salvia Species with Special Reference to Bird Pollination1, Annals of the Missouri Botanical Garden, vol. 98, no. 1, pp. 101--155, April 2011. doi: 10.3417/2007035. Abstract
    The genus Salvia L. (Lamiaceae) encompasses about 1000 species, approximately two thirds of which are in the New World. Bees and birds are known as pollinators, but a more detailed analysis of the pollinator groups is lacking. This paper presents a complete list of all currently accepted New World Salvia species and their classification according to their pollination syndromes, focusing particularly on bird-pollinated species. The concept of pollination syndromes is used and complemented by field investigations, morphometric measurements, and experiments to reconstruct the process of pollen transfer and to confirm the fitting or exclusion of a given pollinator group. Within the 602 New World Salvia species, 58\% are identified to be melittophilous (bee pollinated) and 31\% to be ornithophilous (bird pollinated). Salvia whitehousei Alziar is assumed to be psychophilous (butterfly pollinated/long-tongued fly pollinated). About 11\% of the species show characters of two or more syndromes and eight species are not assignable to any group. Bird-pollinated Salvia species occur from North America southward to Chile and Argentina. They usually grow as shrubs or perennial herbs (97\%) and have red flowers (at least 49\%) of an average size of 34 mm (7–130 mm). With respect to their floral diversity and phylogeny, parallel evolution is evident.
20. {González-Gallegos}, Jesús Guadalupe and {Vega-Mares}, José Humberto and Fernández, Jesús A., Salvia Reginae and S. Spellenbergii (Lamiaceae), Two New Species from Chihuahua, Mexico, Willdenowia, vol. 49, no. 3, pp. 319--328, November 2019. doi: 10.3372/wi.49.49303. Abstract
    During botanical explorations in the highlands of NW Mexico, two new Salvia L. species were discovered in the state of Chihuahua: S. reginae J. G. González \& J. H. Vega and S. spellenbergii J. G. González. The first one is morphologically similar to S. concolor Lamb. ex Benth., from which it differs by having smaller floral bracts, a longer upper corolla lip, stamens parallel to the dorsal corolla line, longer filament and connective, the latter ornate with an antrorse tiny acute tooth, longer thecae, longer and exserted styles, and bigger mericarps. Salvia spellenbergii resembles S. fruticulosa Benth., S. goldmanii Fernald and S. pruinosa Fernald; however, it can be distinguished from these because of its shorter petioles, smaller leaf blades, usually fewer floral nodes, fewer flowers per floral node, and regularly shorter calyces. Both species are described and illustrated. Tables with morphological comparisons, illustrations, conservation assessment, and a distribution map are also presented.Citation: González-Gallegos J. G., Vega-Mares J. H. \& Fernández J. A. 2019: Salvia reginae and S. spellenbergii (Lamiaceae), two new species from Chihuahua, Mexico. – Willdenowia 49: 319 – 328. doi: https://doi.org/10.3372/wi.49.49303Version of record first published online on 26 November 2019 ahead of inclusion in December 2019 issue.
21. Wood, J. R. I. and Harley, R. M., The Genus Salvia (Labiatae) in Colombia, Kew Bulletin, vol. 44, no. 2, pp. 211--278, 1989. doi: 10.2307/4110799. Abstract
    A revision of the genus Salvia L. in Colombia is presented. A key to the 42 species recognized is given together with short descriptions, distribution notes and maps. Illustrations of new taxa are provided. Four new species, S. chicamochae, S. falcata, S. nubigena and S. uribei are described. In order to account for variation found in many species, subspecies are recognized for S. rubescens, S. melaleuca, S. amethystina, S. pauciserrata, S. sphaceloides, S. bogotensis and S. rufula. S. carnea is shown to be a very variable species distributed throughout much of tropical America and embracing eight names formerly recognized at specific rank. S. moschata is shown to be synonymous with the variable S. tortuosa and it is suggested that its relationships need reevaluation. A number of species hitherto recognized are shown to be synonymous with other taxa.
22. 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.
23. 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/.
24. 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/.
25. Siebert, D. J., Localization of Salvinorin A and Related Compounds in Glandular Trichomes of the Psychoactive Sage, Salvia Divinorum, Annals of Botany, vol. 93, no. 6, pp. 763--771, June 2004. doi: 10.1093/aob/mch089.
26. Jenks, Aaron Allon, Systematics and Ethnobotany of Salvia Subgenus Calosphace and Origins of the Hallucinogenic Sage, Salvia Divinorum, 2008. url: https://escholarship.org/uc/item/3f24n5mp. Abstract
    Salvia subgenus Calosphace (Lamiaceae), the largest of 5 subgenera with some 500 species and strongly supported as monophyletic, has received no comprehensive systematic research since the initial establishment of 91 taxonomic sections. Representative taxa of 73 sections of Calosphace were sampled to investigate the phylogenetic relationships and identify major lineages using chloroplast (intergenic spacer, psbA-trnH) and nuclear DNA (ribosomal spacer region, ITS). Phylogenetic analysis of the combined data set established the monophyly of nine sections (Blakea, Corrugatae, Dusenostachys, Erythrostachys, Hastatae, Incarnatae, Microsphace, Nobiles, and Sigmoideae) and four major lineages (S. axillaris, “Hastatae clade”, “Uliginosae clade”, and “Core Calosphace”) corresponding with the four major stamen types identified within the subgenus. Disjunct sections spanning two or more centers of diversity are not supported by the results; no more than seven dispersal events to South America are required to account for the current disjunct distributions. One member of the subgenus, Salvia divinorum is hallucinogenic and used in traditional healing ceremonies by the Mazatec of Mexico. It was classified within section Dusenostachys and hypothesized to be an interspecific hybrid. 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 were sequenced to test its phylogenetic position and putative hybridity. Salvia divinorum should not be classified within Dusenostachys nor is it a hybrid according to the results; its closest relative is S. venulosa, a Colombian endemic. In addition to S. divinorum, there are many other Calosphace species that are used medicinally in North and South America. Ethnobotanical data was gathered for 150 species; those sharing the common names, medicinal uses, appearances, and similar compounds associated into medicinal plant complexes. Five new, previously undocumented complexes were identified: Mirto (5 spp. used extensively in the treatment of susto and other illnesses in Mexico), Ñucchu (7 spp. used as a symbolic element in religious prossessions and in the treatment of respiratory ailments in Peru), Lí'l++ (3 spp. used for food and medicine by the Chianantec), Cantueso (2 spp. used for respiratory ailments in Mexico), and Manga-paqui (3 spp. used for kidney and liver problems in Ecuador).
27. Marushia, Robin, The Botany, Ethnobotany, Biochemistry and Future of a Mexican Mint, pp. 62, June 2002. url: http://www.rexresearch.com/salviadivinorum/Salvia%20divinorum%20BotanythnobotanyBiochemistry.pdf. Abstract
    Salvia divinorum (Labiatae) is an entheogen used by the Mazatec Indians of the Sierra Mazateca in Oaxaca, Mexico. S. divinorum was introduced to the scientific community in the 1950's, and has since become the subject of ethnobotanical, botanical, and biochemical research. Plant biologists are interested in S. divinorum due to its anthropogenic distribution and limited sexual reproduction, while biochemists have found that S. divinorum contains one of the most potent natural hallucinogens known: salvinorin A. Ethnobotanically, the Mazatec shamans used the plant for healing, divination, and shamanic training, and the spiritual qualities of S. divinorum may now contribute to its growing popularity among the general public, as experimental users seeking to “expand consciousness” order S. divinorum over the internet. The many applications and mysteries of Salvia divinorum have led to numerous research opportunities, and the plant may become more important both pharmacologically and socially worldwide.
28. Kowalczuk, Anna P. and Raman, Vijayasankar and Galal, Ahmed M. and Khan, Ikhlas A. and Siebert, Daniel J. and Zjawiony, Jordan K., Vegetative Anatomy and Micromorphology of Salvia Divinorum (Lamiaceae) from Mexico, Combined with Chromatographic Analysis of Salvinorin A, Journal of Natural Medicines, vol. 68, no. 1, pp. 63--73, January 2014. doi: 10.1007/s11418-013-0769-9. Abstract
    Salvia divinorum—a species traditionally cultivated in Oaxaca, Mexico—possesses hallucinogenic properties. It is legally recognized as a controlled substance and prohibited in many countries. The proper identification of the plant, both in fresh and dried forms, is an important issue in crime-prevention campaigns. This paper provides a thorough anatomical description of leaves, petioles, and stems of S. divinorum. Detailed investigation of foliar trichomes was performed and illustrated. In addition, chromatographic analyses, including TLC and HPLC, were applied to fresh and dried plant material, together with the standard reference salvinorin A. A comprehensive identification method for S. divinorum based on a thorough anatomical examination is proposed, combined with chemical analysis for proper plant recognition.
29. 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.
30. 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.
31. Gruber, John W. and Siebert, Daniel J. and Marderosian, Ara H. Der and Hock, Rick S., High Performance Liquid Chromatographic Quantification of Salvinorin a from Tissues of Salvia Divinorum Epling \& Játiva-m, Phytochemical Analysis, vol. 10, no. 1, pp. 22--25, 1999. doi: 10.1002/(SICI)1099-1565(199901/02)10:1<22::AID-PCA428>3.0.CO;2-0. Abstract
    A reversed-phase high performance liquid chromatographic method for the determination of salvinorin A, a psychotropic diterpene isolated from the Mexican sage Salvia divinorum, has been developed. Extracts from several plant collections were examined on a C-18 column with UV detection and isocratic elution with acetonitrile: water (45:55). This assay allowed quantification of salvinorin A in extracts of leaves and stems of S. divinorum and has also been applied to the screening of related species for the production of salvinorin A. Levels of salvinorin A in leaves range from 0.89 to 3.70 mg/g dry weight. Copyright © 1999 John Wiley \& Sons, Ltd.
32. Siebert, Daniel J., Salvia Divinorum and Salvinorin A: New Pharmacologic Findings, Journal of Ethnopharmacology, vol. 43, no. 1, pp. 53--56, June 1994. doi: 10.1016/0378-8741(94)90116-3. Abstract
    The diterpene salvinorin A from Salvia divinorum (Epling and Jativa-M), in doses of 200–500 μg produces effects which are subjectively identical to those experienced when the whole herb is ingsted. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity. Traditionally the herb is consumed either by chewing the fresh leaves or by drinking the juices of freshly crushed leaves. The effects of the herb when consumed this way depend on absorption of salvinorin A through the oral mucosa before the herb is swallowed.
33. 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.
34. 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.
35. {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.
36. 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.
37. Hanson, James R., Natural Products from the Hallucinogenic Sage, Science Progress, vol. 93, no. 2, pp. 171--180, June 2010. doi: 10.3184/003685010X12626983776947. Abstract
    The isolation, structures and biological activity of the neoclerodane and other natural products obtained from the Mexican hallucinogenic sage, Salvia divinorum are reviewed.
38. Selvaraj, Chinnadurai Immanuel and Hadkar, Vrushali Manoj and Anjum, Gadwal Shaik Nishat, Phytochemical and Pharmacological Profile of Diviner's Sage (Salvia Divinorum Epling a Jativa.), 2023. Abstract
    Salvia divinorum, or the ‘diviner’s sage’, is a member of the Lamiaceae family. it is a perennial shrub-like herb and grows to a height of 0.5–1.5 metres. S. divinorum is native to the Sierra Mazateca in Oaxaca, Mexico where the Mazatec people consume the plant's fresh leaves or leaf preparations for medicinal, therapeutic, and divinatory rites. The plant is a rich source of diterpenes and terpenoids. Divinatorins, salvinicins, salvidivins, neoclerodane diterpene and salvinorins are the predominant diterpenes isolated from the plant. The terpenoids such as divinorin A and divinorin B found in S. divinorum have psychotropic effect. Traditionally the plant is used to cure diarrhoea, anemia, headaches, rheumatism, and a semi-magical disease known as panzón de borrego, or a swollen belly, hemialgia and bursitis. The plant is believed to possess hallucinogenic effect which is due to the presence of Salvinorin A. The plant extracts have been studied to 196evaluate its antinociceptive effects, anti-inflammatory effect, neuroprotective activity, psychoactive properties, antidepressant and anxiolytic activity. Salvinorin A can be used as a remedy for treatment of gastrointestinal dysfunction such as inflammatory bowel disease and diarrhoea. This chapter helps in understanding the phytochemistry and pharmacological aspect of S. divinorum and provides information about the potential pharmaceutical and psychotropic properties of the plant.
39. Hao, Da Cheng and Gu, Xiao-Jie and Xiao, Pei Gen, 14 - Phytochemical and Biological Research of Salvia Medicinal Resources, pp. 587--639, January 2015. doi: 10.1016/B978-0-08-100085-4.00014-1. Abstract
    Sage (Salvia) species have been used in traditional medicine for the relief of pain, protecting the body against oxidative stress, free radical damages, angiogenesis, inflammation, bacterial and virus infection, etc. Various terpenoids and phenolic compounds of Salvia plants are found to be useful in industry and health care. Many studies suggest that sage species can be considered for drug development because of their reported pharmacology and therapeutic activities in many countries of Asia and Middle East. Transcriptome data provide useful information on transcript profiles, gene discovery, transcriptional regulation, tissue biogenesis, and marker-assisted selections. Omics platform will greatly contribute to the improvement of Salvia medicinal plants, for the purpose of ensuring adequate drug resources. This chapter covers the latest advances in phytochemical, pharmacological, phylogenetic, and omics studies of Salvia plants. More Salvia plants, besides the well-known S. miltiorrhiza, S. sclarea, and S. officinalis, have application potential in pharmaceutical industry and clinical therapy.
40. Jermain, John D. and Evans, Hiram K., Analyzing Salvia Divinorum and Its Active Ingredient Salvinorin A Utilizing Thin Layer Chromatography and Gas Chromatography/Mass Spectrometry, Journal of Forensic Sciences, vol. 54, no. 3, pp. 612--616, 2009. doi: 10.1111/j.1556-4029.2009.00999.x. Abstract
    Abstract: In recent years, Salvia divinorum has become a major focus by state legislatures throughout the United States looking to prohibit the sale of the psychoactive plant. After researching testing procedures presented in the literature and those employed by crime laboratories throughout the country, it was decided that thin layer chromatography (TLC) and gas chromatography/mass spectrometry (GC/MS) were the methods to use to analyze plant material for salvinorin A. With TLC, salvinorin A was detected from extracted plant material and was easily distinguishable from 13 other Salvia species as well as Cannabis sativa L. (marijuana). When using GC/MS, salvinorin A was best extracted from plant material with chloroform at ambient temperature when using a nonpolar solvent and acetone at ambient temperature when using a polar solvent. By utilizing these techniques, criminalists are now able to confirm the presence of salvinorin A in a submitted plant material suspected to be Salvia divinorum.
41. Keasling, Adam W. and Zjawiony, Jordan K., Chapter 51 - The Plant Salvia Divinorum (Lamiaceae)—Chemistry and Pharmacology, pp. 551--560, January 2016. doi: 10.1016/B978-0-12-800212-4.00051-0. Abstract
    The plant Salvia divinorum (Epling \& Játiva-M.) is a member of the mint family (Lamiaceae) endemic to the Sierra Mazateca region of the Sierra Madre de Oaxaca of southern Mexico. It has a history of known ethnobotanical use by the Mazatec Indians extending several centuries both in medicinal and spiritual practices. Reports of the perceptiotropic effects that accompanied use of this material led to phytochemical investigations which yielded a novel neoclerodane diterpenoid, salvinorin A. This compound was found to possess extremely high affinity and selectivity for the kappa opioid receptors and was determined to bind in a unique manner different from classic opioids. While S. divinorum and salvinorin A both produce pronounced perceptotropic effects (i.e., mixed hallucinogenic and dissociative effects) they have also been shown to attenuate drug-seeking behavior. Furthermore, salvinorin A has been repeatedly shown to possess an extremely low potential for physiological toxicity. Salvia divinorum represents a novel source of bioactive molecules some of which have been shown to have utility as antiaddiction therapeutics.
42. Bigham, Andrea K. and Munro, Thomas A. and Rizzacasa, Mark A. and {Robins-Browne}, Roy M., Divinatorins A−C, New Neoclerodane Diterpenoids from the Controlled Sage Salvia Divinorum, Journal of Natural Products, vol. 66, no. 9, pp. 1242--1244, September 2003. doi: 10.1021/np030313i. Abstract
    Three new neoclerodane diterpenoids, divinatorins A−C (7−9), have been isolated from the leaves of Salvia divinorum. The compounds were identified by spectroscopic methods as derivatives of the antibiotic (−)-hardwickiic acid (10), which was also isolated, along with four other known terpenoids. Neither the crude extract nor 7−9 displayed antimicrobial activity.
43. Valdes, Leander J. III and Butler, William M. and Hatfield, George M. and Paul, Ara G. and Koreeda, Masato, Divinorin A, a Psychotropic Terpenoid, and Divinorin B from the Hallucinogenic Mexican Mint, Salvia Divinorum, The Journal of Organic Chemistry, vol. 49, no. 24, pp. 4716--4720, November 1984. doi: 10.1021/jo00198a026.
44. Pentea, Marius and Butu, Marian and Samfira, Ionel and Cristina, Romeo and BUTNARIU, Monica, Extraction and Analytical Study of Salvinorin a from Leaves of Salvia Divinorum, Digest Journal of Nanomaterials and Biostructures, vol. 10, pp. 291--297, March 2015. Abstract
    Brain-imaging studies in animals provided evidence that salvinorin A biostructure, in addition to hallucinations and impairment of motor function in humans, could become a popular drug. Salvia divinorum samples were analyzed by gas chromatography, after being dried at 40C. For extraction was used analytical grade purity acetone and recrystallisation was achieved with methanol of chromatographic purity. Preliminary processing of crude extract allowed enriching the final solution composition in salvinorin A. The large number of signals showed that under ionization an advanced fragmentation of the molecule occurred. By the advanced fragmentation of S. divinorum it was obtained a sample image, with the mass spectrometer, which may constitute a specific footprint of the component salvinorin A.
45. Valdes, Leander J. III., Loliolide from Salvia Divinorum, Journal of Natural Products, vol. 49, no. 1, pp. 171--171, January 1986. doi: 10.1021/np50043a031.
46. Shirota, Osamu and Nagamatsu, Kumi and Sekita, Setsuko, Neo-Clerodane Diterpenes from the Hallucinogenic Sage Salvia Divinorum, Journal of Natural Products, vol. 69, no. 12, pp. 1782--1786, December 2006. doi: 10.1021/np060456f. Abstract
    Seven new neo-clerodane diterpenes, salvidivins A (2), B, (3), C (4), and D (5), salvinorins H (6) and I (7), and divinorin F (8), along with eight known neo-clerodane diterpenes, salvinorins A (1)−F, divinatorins A and B, and seven other constituents, were isolated from the hallucinogenic sage Salvia divinorum. The structures of 1−7 were elucidated on the basis of 2D NMR spectroscopic studies.
47. Lee, David Y. W. and Ma, Zhongze and {Liu-Chen}, Lee-Yuan and Wang, Yulin and Chen, Yong and Carlezon, William A. and Cohen, Bruce, New Neoclerodane Diterpenoids Isolated from the Leaves of Salvia Divinorum and Their Binding Affinities for Human κ Opioid Receptors, Bioorganic \& Medicinal Chemistry, vol. 13, no. 19, pp. 5635--5639, October 2005. doi: 10.1016/j.bmc.2005.05.054. Abstract
    Bioactivity-guided fractionation of the leaves of Salvia divinorum has resulted in the isolation of three new neoclerodane diterpenoids: divinatorin D (1), divinatorin E (2), and salvinorin G (3), together with 10 known terpenoids, divinatorin C (4), hardwickiic acid (5), salvinorin-A (6), -B (7), -C (8), -D (9), -E (10), and -F (11), presqualene alcohol (12), and (E)-phytol (13). The structures of these three new compounds were characterized by spectroscopic methods. All these compounds were evaluated for their binding affinities to the human κ opioid receptors. In comparison with divinatorin D (1), divinatorin E (2), and salvinorin G (3), salvinorin A (6) is still the most potent κ agonist.
48. Bertea, Cinzia M. and Luciano, Pino and Bossi, Simone and Leoni, Francesca and Baiocchi, Claudio and Medana, Claudio and Azzolin, Chiara M. M. and Temporale, Giovanni and Lombardozzi, Maria Antonietta and Maffei, Massimo E., PCR and PCR–RFLP of the 5S-rRNA-NTS Region and Salvinorin A Analyses for the Rapid and Unequivocal Determination of Salvia Divinorum, Phytochemistry, vol. 67, no. 4, pp. 371--378, February 2006. doi: 10.1016/j.phytochem.2005.12.006. Abstract
    Salvia divinorum Epling \& Játiva-M. is a perennial herb belonging to the Lamiaceae family; its active ingredient, the neoclerodane diterpene salvinorin A, is a psychotropic molecule that produces hallucinations. A comparative evaluation of S. divinorum fresh and dried leaves, S. officinalis fresh leaves, and dried powdered leaves claimed to be S. divinorum was done. HPLC–MS data confirmed the presence of salvinorin A in both S. divinorun leaf extracts and the powdered leaves, whereas no salvinorin A was found in S. officinalis. The non-transcribed spacer (NTS) in the 5S-rRNA gene of all leaf samples and the dried powdered leaves was amplified by PCR using a pair of primers located at the 3′ and 5′ ends of the coding sequence of 5S-rRNA gene. The resulting PCR products (about 500bp for S. divinorum and 300bp for S. officinalis) were gel purified, subcloned into pGEM®-T Easy vector and sequenced. By aligning the isolated nucleotide sequences, great diversities were found in the spacer region of the two species. Specific S. divinorum primers were designed on the sequence of the 5S-rRNA gene spacer region. In addition, a PCR–restriction fragment length polymorphism (PCR–RFLP) method was applied using NdeI and TaqI restriction enzymes. An NdeI site, absent in S. officinalis, was found in S. divinorum NTS region at 428–433bp. For TaqI, multiple sites (161–164, 170–173, and 217–220bp) were found in S. officinalis, whereas a unique site was found in S. divinorum (235–238bp). The results of this work show that the combined use of analytical chemical (HPLC–MS) and molecular (DNA fingerprinting) methods lead to the precise and unequivocal identification of S. divinorum.
49. Pichini, Simona and Abanades, Sergio and Farré, Magí and Pellegrini, Manuela and Marchei, Emilia and Pacifici, Roberta and de la Torre, Rafael and Zuccaro, Piergiorgio, Quantification of the Plant-Derived Hallucinogen Salvinorin A in Conventional and Non-Conventional Biological Fluids by Gas Chromatography/Mass Spectrometry after Salvia Divinorum Smoking, Rapid Communications in Mass Spectrometry, vol. 19, no. 12, pp. 1649--1656, 2005. doi: 10.1002/rcm.1970. Abstract
    A gas chromatography method with mass spectrometric detection is described for the determination of Salvinorin A, the main active ingredient of the hallucinogenic mint Salvia divinorum. The method was validated in plasma, urine, saliva and sweat using 17-α-methyltestosterone as internal standard. The analytes were extracted from biological matrices with chloroform/isopropanol (9:1, v/v). Chromatography was performed on a 5\% phenyl methyl silicone capillary column and analytes were determined in the selected ion monitoring mode. The method was validated over the concentration range 0.015–5 μg/mL plasma, urine and saliva and 0.01–5 μg/patch in the case of sweat. Mean recoveries ranged between 77.1 and 92.7\% for Salvinorin A in different biological matrices, with precision and accuracy always better than 15\%. The method was applied to the analysis of urine, saliva and sweat from two consumers after smoking 75 mg plant leaves to verify the presence of the active ingredient of S. divinorum in human biological fluids as a biomarker of plant consumption. Salvinorin A was detected in urine (2.4 and 10.9 ng/mL) and saliva (11.1 and 25.0 ng/mL), but not in sweat patches from consumers. Copyright © 2005 John Wiley \& Sons, Ltd.
50. Lin, Po-Xiang and Li, Jih-Heng and Chen, Su-Hwei and Chang, Hsien-Chang and McKetin, Rebecca, Quantitative Determination of Salvinorin A, a Natural Hallucinogen with Abuse Liability, in Internet-Available Salvia Divinorum and Endemic Species of Salvia in Taiwan, Journal of Food and Drug Analysis, vol. 22, no. 3, pp. 370, 2014. doi: 10.1016/j.jfda.2014.01.017. Abstract
    In recent years, recreational use of Salvia divinorum (Lamiaceae), a herbal drug that contains a hallucinogenic ingredient, salvinorin A, has become a new phenomenon among young drug users. In Taiwan, as in many other countries, dry leaves of S. divinorum ...
51. Chambers, MeganI. and {Giffen-Lemieux}, Justine E. and Musah, Rabi A., Rapid Detection and Quantification of Hallucinogenic Salvinorin A in Commercial Salvia Divinorum Products by DART-HRMS, ACS Omega, vol. 8, no. 1, pp. 761--770, December 2022. doi: 10.1021/acsomega.2c06106. Abstract
    , In recent years, national laboratories have identified several plant-derived materials as concerns to public health because of their psychoactive effects, potential for abuse, and the lack of federal regulation of their use. One of these is Salvia divinorum (aka Salvia), which has received focused attention due to its increasing recreational use and the ease by which it can be acquired. Traditional chromatographic approaches for the detection of the major psychoactive component of Salvia (i.e., salvinorin A) typically require time-consuming sample pretreatment prior to identifying the presence of salvinorin A in plant material unknowns. In this study, direct analysis in real time–high-resolution mass spectrometry (DART-HRMS) was used to rapidly screen for Salvia plant material. This approach facilitated the analysis of bulk material in its native form, thereby bypassing sample pretreatment steps. In addition, a validated DART-HRMS method was developed for the quantification of salvinorin A in commercial Salvia products (e.g., raw plant materials, enhanced leaf extracts). In this regard, cholesterol was found to be a suitable internal standard. The average salvinorin A content in raw Salvia leaves was determined to be 1.54 mg/g, while the salvinorin A quantified in enhanced Salvia leaf extracts was between 13.0 and 53.2 mg/g.
52. Grundmann, Oliver and Phipps, Stephen M. and Zadezensky, Immo and Butterweck, Veronika, Salvia Divinorum and Salvinorin A: An Update on Pharmacology and Analytical Methodology, Planta Medica, vol. 73, no. 10, pp. 1039--1046, August 2007. doi: 10.1055/s-2007-981566. Abstract
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53. Harding, Wayne W. and Tidgewell, Kevin and Schmidt, Matthew and Shah, Kushal and Dersch, Christina M. and Snyder, John and Parrish, Damon and Deschamps, Jeffrey R. and Rothman, Richard B. and Prisinzano, Thomas E., Salvinicins A and B, New Neoclerodane Diterpenes from Salvia Divinorum, Organic Letters, vol. 7, no. 14, pp. 3017--3020, July 2005. doi: 10.1021/ol0510522. Abstract
    Two new neoclerodane diterpenes, salvinicins A (4) and B (5), were isolated from the dried leaves of Salvia divinorum. The structures of these compounds were elucidated by spectroscopic techniques, including 1H and 13C NMR, NOESY, HMQC, and HMBC. The absolute stereochemistry of these compounds was assigned on the basis of single-crystal X-ray crystallographic analysis of salvinicin A (4) and a 3,4-dichlorobenzoate derivative of salvinorin B.
54. Chavkin, Charles and Sud, Sumit and Jin, Wenzhen and Stewart, Jeremy and Zjawiony, Jordan K. and Siebert, Daniel J. and Toth, Beth Ann and Hufeisen, Sandra J. and Roth, Bryan L., Salvinorin A, an Active Component of the Hallucinogenic Sage Salvia Divinorum Is a Highly Efficacious κ-Opioid Receptor Agonist: Structural and Functional Considerations, Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 3, pp. 1197--1203, March 2004. doi: 10.1124/jpet.103.059394. Abstract
    The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective κ-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human κ-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. Additional studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective κ-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for κ-opioid receptor binding and activation. Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K+ channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593) (two standard κ-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for κ-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at κ-opioid receptors.
55. {Soto-Restrepo}, Valentina and {Taborda-Ocampo}, Gonzalo and {Garzon-Mendez}, William, Salvinorin A: A hallucinogenic terpene present in Salvia divinorum Epling \& Jativa/Salvinorina A: terpeno alucinogeno presente en Salvia divinorum Epling \& Jativa/Salvinorina A: terpeno alucinogeno presente na Salvia divinorum Epling \& Jativa, Colombia Forense, vol. 4, no. 1, pp. 41--55, April 2017. url: https://go.gale.com/ps/i.do?p=IFME&sw=w&issn=21450684&v=2.1&it=r&id=GALE%7CA585087319&sid=googleScholar&linkaccess=abs. Abstract
    {$<$}em{$>$}Gale{$<$}/em{$>$} OneFile includes Salvinorin A: A hallucinogenic terpene present in Salvi by Valentina Soto-Restrepo, Gonzalo Tabord. Click to explore.
56. Vortherms, Timothy A. and Roth, Bryan L., Salvinorin A: From Natural Product to Human Therapeutics, Molecular Interventions, vol. 6, no. 5, pp. 257--265, October 2006. doi: 10.1124/mi.6.5.7. Abstract
    The hallucinogenic plant Salvia divinorum (i.e., "magic mint") is a member of the Sage family that has been used for divination and shamanism by the Mazatecs. Over the past decade or so, S. divinorum has been increasingly used recreationally. The neoclerodane diterpene salvinorin A is the active component of S. divinorum, and recently, the kappa opioid receptor (KOR) has been identified, in vitro and in vivo, as its molecular target. The discovery of KOR as the molecular target of salvinorin A has opened up many opportunities for drug discovery and drug development for a number of psychiatric and non-psychiatric disorders.
57. Valdés, Leander J. and Chang, Hui-Ming and Visger, Daniel C. and Koreeda, Masato, Salvinorin C, a New Neoclerodane Diterpene from a Bioactive Fraction of the Hallucinogenic Mexican Mint Salvia Divinorum, Organic Letters, vol. 3, no. 24, pp. 3935--3937, November 2001. doi: 10.1021/ol016820d.
58. Ortega, Alfredo and Blount, John F. and Manchand, Percy S., Salvinorin, a New Trans-Neoclerodane Diterpene from Salvia Divinorum(Labiatae), Journal of the Chemical Society, Perkin Transactions 1, no. INVALID\_SCITE\_VALUE, pp. 2505--2508, January 1982. doi: 10.1039/P19820002505. Abstract
    Salvinorin, isolated from Salvia divinorum, has been shown by spectroscopic and X-ray-crystallographic methods to be a trans-neoclerodane diterpene of structure (1). Crystals of compound (1) are orthorhombic, space group P212121 with a= 6.368(2), b= 11.338(3), c= 30.710(6)Å, and Z= 4. The structure was refined by leastsquares to R 0.052 and R′ 0.056.
59. Munro, Thomas A. and Rizzacasa, Mark A., Salvinorins D−F, New Neoclerodane Diterpenoids from Salvia Divinorum, and an Improved Method for the Isolation of Salvinorin A, Journal of Natural Products, vol. 66, no. 5, pp. 703--705, May 2003. doi: 10.1021/np0205699. Abstract
    Three new neoclerodane diterpenoids, salvinorins D−F (4−6), have been isolated from the leaves of Salvia divinorum. The structures were elucidated by chemical and spectroscopic methods, particularly 1D and 2D NMR. A simplified isolation method using chromatography on activated carbon also gave improved yields of the controlled substance salvinorin A (1) and of salvinorin C (3).
60. Kutrzeba, Lukasz M. and Ferreira, Daneel and Zjawiony, Jordan K., Salvinorins J from Salvia Divinorum: Mutarotation in the Neoclerodane System, Journal of Natural Products, vol. 72, no. 7, pp. 1361--1363, July 2009. doi: 10.1021/np900181q. Abstract
    A search for biosynthetic precursors of salvinorin A (1) led to the isolation of a new neoclerodane diterpenoid hemiacetal mixture, salvinorins J (2), from the chloroform extract of Salvia divinorum. A leaf surface extraction method was used on S. divinorum, affording a chlorophyll-free extract containing predominantly neoclerodane diterpenoids, including the new salvinorins J (2) and 14 known analogues. Salvinorins J (2) represent an example of a neoclerodane hemiacetal (lactol) susceptible to mutarotation with the formation of an equilibrium mixture of C-17 epimers.
61. Munro, Thomas, The Chemistry of Salvia Divinorum, April 2006. url: https://files.shroomery.org/attachments/7440909-Munro2006thesisSALVIADIVINORUM.pdf. Abstract
    Salvia divinorum is a hallucinogenic sage used to treat illness by the Mazatec Indians of Mexico. Salvinorin A (1a), a neoclerodane diterpenoid isolated from the plant, is a potent, selective agonist at the kappa opioid receptor (KOR), and is the first non-nitrogenous opioid. The plant is used recreationally as a hallucinogen, but is unpopular due to its dysphoric effects. 1a has been prohibited in Australia under an invalid systematic name. An early report of psychoactive alkaloids in S. divinorum proved to be irreproducible. Similarly, tests in mice suggesting the presence of psychoactive compounds other than 1a were confounded and therefore unreliable. In this work, an improved isolation method for 1a was developed, using filtration through activated carbon to decolourise the crude extract. Six new diterpenoids were isolated: salvinorins D–F (1d–1f) and divinatorins A–C (28a–28c). Five known terpenoids not previously reported from this species were also isolated. The structure–activity relationships of 1a were evaluated via selective modifications of each functional group. Useful synthetic methods are reviewed, including the first thorough review of furanolactone hydrogenations. Testing of the derivatives at the KOR suggests that the methyl ester and furan ring of 1a are required for activity, but that the lactone and ketone functionalities are not. Other compounds from S. divinorum did not bind to the KOR, suggesting that 1a is the plant’s active principle.
62. {Willmore-Fordham}, Catherine B. and Krall, Daniel M. and McCurdy, Christopher R. and Kinder, David H., The Hallucinogen Derived from Salvia Divinorum, Salvinorin A, Has Kappa-Opioid Agonist Discriminative Stimulus Effects in Rats, Neuropharmacology, vol. 53, no. 4, pp. 481--486, September 2007. doi: 10.1016/j.neuropharm.2007.06.008. Abstract
    Data from clinical and preclinical studies converge implicating the plant-derived hallucinogen salvinorin A as an important pharmacologic tool; this psychoactive compound may expand scientific understandings on mammalian kappa-opioid receptor systems. Human salvinorin A effects, consistent with kappa-opioid receptor agonism, include antinociception, sedation, dysphoria and distorted perceptions. The experiments reported here measured salvinorin A (1-3mg/kg, i.p.) discriminative stimulus properties in male Sprague-Dawley rats conditioned to recognize the discriminative stimulus cue generated by the well characterized kappa-opioid agonist U-69593 (0.56 mg/kg, i.p.). At three distinct active doses, salvinorin A fully substituted for U-69593 without altering response rates. The lever choice pattern in U-69593 trained animals reverted to vehicle lever responding when a kappa selective antagonist compound, nor-BNI (4.5 nM, i.c.v.) was administered 1h prior to salvinorin A, yet nor-BNI alone failed to impact the rate or pattern of subject responses. These findings confirm and extend results published after similar drug discrimination tests were performed in rhesus monkeys. The discussion section of this article highlights public concern over salvinorin A misuse and emphasizes several potential pharmacotherapeutic applications for salvinorin A or analogue compounds.
63. Capasso, R. and Borrelli, F. and Zjawiony, J. and Kutrzeba, L. and Aviello, G. and Sarnelli, G. and Capasso, F. and Izzo, A. A., The Hallucinogenic Herb Salvia Divinorum and Its Active Ingredient Salvinorin A Reduce Inflammation-Induced Hypermotility in Mice, Neurogastroenterology \& Motility, vol. 20, no. 2, pp. 142--148, 2008. doi: 10.1111/j.1365-2982.2007.00994.x. Abstract
    The hallucinogenic plant Salvia divinorum has been used for medical treatments of gastrointestinal disorders. Here, we evaluated the effect of a standardized extract from the leaves of Salvia divinorum (SDE) and of its active ingredient salvinorin A on motility in vivo, both in physiological states and during croton oil-induced intestinal inflammation. SDE (1–100 mg kg−1) significantly inhibited motility only in inflamed, but not in control, mice. In control mice, salvinorin A (0.01–10 mg kg−1) significantly inhibited motility only at the highest doses tested (3 and 10 mg kg−1) and this effect was not counteracted by naloxone or by the κ-opioid receptor (KOR) antagonist nor-binaltorphimine. Inflammation significantly increased the potency of salvinorin A (but not of the KOR agonist U-50488) in reducing motility. The inhibitory effects of both salvinorin A and U-50488 in inflamed mice were counteracted by naloxone or by nor-binaltorphimine. We conclude that salvinorin A may reduce motility through activation of different targets. In physiological states, salvinorin A, at high doses, inhibited motility through a non-KOR mediated mechanism. Gut inflammation increased the potency of salvinorin A; this effect was mediated by KOR, but it was not shared by U-50488, thus suggesting that salvinorin A may have target(s) other than KOR in the inflamed gut.
64. Ford, Scott A. and Ness, Rob W. and Kwon, Moonhyuk and Ro, Dae-Kyun and Phillips, Michael A., A Chromosome Level Reference Genome of Diviner’s Sage (Salvia Divinorum) Provides Insight into Salvinorin A Biosynthesis, BMC Plant Biology, vol. 24, no. 1, pp. 914, October 2024. doi: 10.1186/s12870-024-05633-0. Abstract
    Diviner’s sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human Κ-opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date.
65. 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.
66. 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.
67. 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.
68. Mitchell, Rod, Identification and Characterization of Diterpene Synthases in the Salvinorin A Biosynthetic Pathway, August 2012. url: http://hdl.handle.net/11023/171. Abstract
    Salvia divinorum is a hallucinogenic plant that is used for divination and spiritual communion by the Mazatecs of Mexico. The active component of the plant is salvinorin A, a neoclerodane diterpenoid that selectively acts as a potent κ opioid receptor agonist. Salvinorin A's novel receptor binding profile makes derivatives of the compound potentially useful in the treatment of various psychiatric and mood disorders. In this work, next generation sequencing (Roche 454) was used to generate a S. divinorum transcript database. Five distinct putative diterpene synthase cDNAs (two type II and three type I) were identified in the database. We report here a recombinant type II diterpene synthase capable of catalyzing the rearrangement of GGPP into terpentedienyl diphosphate (a neoclerodane diphosphate), and a recombinant type I diterpene synthase that renders terpentedienyl diphosphate into kolavenol. These enzymatic products are potential intermediates in the salvinorin A biosynthetic pathway.
69. Kutrzeba, L. M. and Zjawiony, J. K. and Dayan, F. E., Salvinorin B as a Putative Biosynthetic Precursor of Salvinorin A. Study on O-Acetyltransferasein Glandular Trichomes Isolated from Salviadivinorium, Planta Medica, vol. 74, no. 3, pp. P-30, February 2008. doi: 10.1055/s-2008-1075226. Abstract
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70. Kutrzeba, L. M. and Dayan, F. E. and Giner, J. L. and Zjawiony, J. K., 13C- and 2H-Labeled Deoxyxylulose as a Tool in Study of Kinetics and Mechanism of Salvinorin A Biosynthesis, Planta Medica, vol. 74, no. 3, pp. P-29, February 2008. doi: 10.1055/s-2008-1075225. Abstract
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71. Chen, Xiaoyue and Berim, Anna and Dayan, Franck E. and Gang, David R., A (–)-Kolavenyl Diphosphate Synthase Catalyzes the First Step of Salvinorin A Biosynthesis in Salvia Divinorum, Journal of Experimental Botany, vol. 68, no. 5, pp. 1109--1122, February 2017. doi: 10.1093/jxb/erw493. Abstract
    Salvia divinorum (Lamiaceae) is an annual herb used by indigenous cultures of Mexico for medicinal and ritual purposes. The biosynthesis of salvinorin A, its major bioactive neo-clerodane diterpenoid, remains virtually unknown. This investigation aimed to identify the enzyme that catalyzes the first reaction of salvinorin A biosynthesis, the formation of (–)-kolavenyl diphosphate [(–)-KPP], which is subsequently dephosphorylated to afford (–)-kolavenol. Peltate glandular trichomes were identified as the major and perhaps exclusive site of salvinorin accumulation in S. divinorum. The trichome-specific transcriptome was used to identify candidate diterpene synthases (diTPSs). In vitro and in planta characterization of a class II diTPS designated as SdKPS confirmed its activity as (–)-KPP synthase and its involvement in salvinorin A biosynthesis. Mutation of a phenylalanine into histidine in the active site of SdKPS completely converts the product from (–)-KPP into ent-copalyl diphosphate. Structural elements were identified that mediate the natural formation of the neo-clerodane backbone by this enzyme and suggest how SdKPS and other diTPSs may have evolved from ent-copalyl diphosphate synthase.
72. Ngo, Iris and Kumar, Rahul and Li, Liang and Kim, Seon-Won and Kwon, Moonhyuk and Ro, Dae-Kyun, Identification of Clerodane Diterpene Modifying Cytochrome P450 (CYP728D26) in Salvia Divinorum - En Route to Psychotropic Salvinorin A Biosynthesis, Physiologia Plantarum, vol. 176, no. 5, pp. e14569, 2024. doi: 10.1111/ppl.14569. Abstract
    Salvia divinorum is a hallucinogenic plant native to the Oaxaca in Mexico. The active ingredient for psychotropic effects in this plant is salvinorin A, a potent and highly selective κ-opioid receptor agonist. Salvinorin A is distinct from other well-known opioids, such as morphine and codeine, in that it is a non-nitrogenous diterpenoid with no affinity for μ-opioid receptor, the prime receptor of alkaloidal opioids. A terpene opioid that selectively targets a new opioid receptor (κ-opioid receptor) can be instrumental in developing alternative analgesics. Elucidation of the salvinorin A biosynthetic pathway can help bio-manufacture diverse semi-synthetic derivatives of salvinorin A but, to date, only two enzymes in the Salvinorin A pathway have been identified. Here, we identify CYP728D26 that catalyzes a C18 oxygenation on crotonolide G, which bears a clerodane backbone. Biochemical identity of CYP728D26 was validated by in vivo reconstitution in yeast, 1H- and 13C-NMR analyses of the purified product, and kinetic analysis of CYP728D26 with a Km value of 13.9 μM. Beyond the single oxygenation on C18, collision-induced dissociation analysis suggested two additional oxygenations are catalyzed by CYP728D26 to form crotonoldie G acid, although this carboxylic acid form is a minor product. Its close homologue CYP728D25 exhibited a C1-hydroxylation on the clerodane backbone in a reconstituted yeast system. However, CYP728D25 showed no activity in in vitro assays. This result implies that catalytic activities observed from overexpression systems should be interpreted cautiously. This work identified a new CYP catalyst and advanced our knowledge of salvinorin A biosynthesis.
73. Ngo, Iris, Oxidative Decorations of the Salvinorin A Backbone: Characterization of Salvia Divinorum Cytochrome P450s, August 2019. url: http://hdl.handle.net/1880/110839. Abstract
    Salvia divinorum is an ethnomedicinal plant belonging to the Lamiaceae (mint) family. The main bioactive compound in S. divinorum is the psychotropic diterpenoid salvinorin A. Salvinorin A was the first naturally occurring, non-nitrogenous, human kappa opioid receptor agonist identified, it thus holds potential for the treatment of addiction and mental disorders. Heterologous production of salvinorin A is desirable as purification from S. divinorum or total synthesis remains arduous. However, only the first step in the biosynthesis of salvinorin A has been elucidated, the formation of (-)-kolavenyl diphosphate (KPP) from the universal diterpenoid precursor, geranylgeranylpyrophosphate by the class II diterpene synthase (diTPS) enzyme, SdCPS2. To date, no class I diTPS which acts upon KPP has been identified, but in Saccharomyces cerevisiae, KPP can be dephosphorylated by endogenous phosphatases to yield kolavenol (KOH), the predicted class I diTPS product. From KOH, a cytochrome P450 monooxygenase (P450) known as crotonolide G synthase (SdCS) can form crotonolide G. Additional oxidative decorations to the salvinorin A backbone are also likely catalyzed by P450s. We thus sought to identify P450s which can catalyze the decorative steps succeeding KPP/KOH and crotonolide G. Since salvinorin A accumulates in the peltate glandular trichomes of S. divinorum, we mined a trichome-specific transcriptome, identifying eight candidate P450s. Of the eight P450s tested, using S. cerevisiae as a platform for heterologous expression and compound production, two P450s, CYP728D25 and CYP728D26, utilized crotonolide G to generate distinctly oxidized compounds. The highest titre of the compounds identified was obtained by having the six pathway genes necessary to synthesize SA intermediates both integrated into the yeast genome using CRISPR-Cas9 and expressed in plasmids. These results advance diterpene biosynthesis knowledge and bring us closer to obtaining therapeutic SA through heterologous means.
74. 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.
75. Murphy, Terence M. and Bola, Gurpreet, DNA Identification of Salvia Divinorum Samples, Forensic Science International: Genetics, vol. 7, no. 1, pp. 189--193, January 2013. doi: 10.1016/j.fsigen.2012.04.004. Abstract
    Salvia divinorum (diviner's sage) is a plant in the mint family that produces an hallucinogenic compound, salvinorin A. The plant is used, often by chewing or smoking, as a “recreational” drug source and is regulated or banned in several states and countries. We describe a simple DNA technique, polymerase chain reaction of the ribulose bisphosphate carboxylase large subunit (rbcL) gene, that can distinguish S. divinorum leaf pieces from pieces of tobacco or cannabis. We have also found DNA sequences adjacent to the chloroplast leucine transfer RNA (trnL) gene that are specific to S. divinorum and distinguish it from other horticulturally popular Salvia species. We report some significant differences between the S. divinorum trnL sequences we determined and those now published in GenBank.
76. Willard, Melissa A. Bodnar and McGuffin, Victoria L. and Smith, Ruth Waddell, Forensic Analysis of Salvia Divinorum Using Multivariate Statistical Procedures. Part I: Discrimination from Related Salvia Species, Analytical and Bioanalytical Chemistry, vol. 402, no. 2, pp. 833--842, January 2012. doi: 10.1007/s00216-011-5479-0. Abstract
    Salvia divinorum is a hallucinogenic herb that is internationally regulated. In this study, salvinorin A, the active compound in S. divinorum, was extracted from S. divinorum plant leaves using a 5-min extraction with dichloromethane. Four additional Salvia species (Salvia officinalis, Salvia guaranitica, Salvia splendens, and Salvia nemorosa) were extracted using this procedure, and all extracts were analyzed by gas chromatography-mass spectrometry. Differentiation of S. divinorum from other Salvia species was successful based on visual assessment of the resulting chromatograms. To provide a more objective comparison, the total ion chromatograms (TICs) were subjected to principal components analysis (PCA). Prior to PCA, the TICs were subjected to a series of data pretreatment procedures to minimize non-chemical sources of variance in the data set. Successful discrimination of S. divinorum from the other four Salvia species was possible based on visual assessment of the PCA scores plot. To provide a numerical assessment of the discrimination, a series of statistical procedures such as Euclidean distance measurement, hierarchical cluster analysis, Student's t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores. The statistical procedures were then compared to determine the advantages and disadvantages for forensic applications.
77. Wagstaff, Steven J. and Hickerson, Laura and Spangler, Russ and Reeves, Patrick A. and Olmstead, Richard G., Phylogeny in Labiatae s. l., Inferred from cpDNA Sequences, Plant Systematics and Evolution, vol. 209, no. 3, pp. 265--274, September 1998. doi: 10.1007/BF00985232. Abstract
    Sequences ofrbcL andndhF were analysed independently and in combination to resolve phylogenetic relationships inLabiatae s. l. Monophyly ofLabiatae s. l was supported by all three analyses.Congea tomentosa (Symphoremataceae) is nested withinLabiatae s. l. in therbcL analysis, but emerges as the sister group ofLabiatae s. l. in thendhF and combined analyses. Four noteworthy clades ofLabiate s. l. also are supported by all analyses corresponding to subfamiliesNepetoideae, Lamioideae, Pogostemonoideae andScutellarioideae. Monophyly of subfamiliesChloanthoideae andViticoideae is not supported. A clade comprisingTeucrioideae plusAjuga is supported byndhF and the combined analysis.
78. Walker, Jay B. and Sytsma, Kenneth J. and Treutlein, Jens and Wink, Michael, {\emph{Salvia}} (Lamiaceae) Is Not Monophyletic: Implications for the Systematics, Radiation, and Ecological Specializations of {\emph{Salvia}} and Tribe Mentheae, American Journal of Botany, vol. 91, no. 7, pp. 1115--1125, July 2004. doi: 10.3732/ajb.91.7.1115. Abstract
    Salvia , with over 900 species from both the Old and New World, is the largest genus in the Lamiaceae. Unlike most members of the subfamily Nepetoideae to which it belongs, only two stamens are expressed in Salvia . Although the structure of these stamens is remarkably variable across the genus, generally each stamen has an elongate connective and divergent anther thecae, which form a lever mechanism important in pollination. In a preliminary investigation of infrageneric relationships within Salvia , the monophyly of the genus and its relationship to other members of the tribe Mentheae were investigated using the chloroplast DNA regions rbcL and trnL‐F. Significant conclusions drawn from the data include: Salvia is not monophyletic, Rosmarinus and Perovskia together are sister to an Old World clade of Salvia , the section Audibertia is sister to subgenus Calosphace or the monotypic Asian genus Dorystaechas , and the New World members of section Heterosphace are sister to section Salviastrum . Owing to the non‐monophyly of Salvia , relationships at the next clearly monophyletic level, tribe Mentheae, were investigated.
79. Walker, Jay B. and Sytsma, Kenneth J., Staminal Evolution in the Genus Salvia (Lamiaceae): Molecular Phylogenetic Evidence for Multiple Origins of the Staminal Lever, Annals of Botany, vol. 100, no. 2, pp. 375--391, August 2007. doi: 10.1093/aob/mcl176. Abstract
    Background and Aims The genus Salvia has traditionally included any member of the tribe Mentheae (Lamiaceae) with only two stamens and with each stamen expressing an elongate connective. The recent demonstration of the non-monophyly of the genus presents interesting implications for staminal evolution in the tribe Mentheae. In the context of a molecular phylogeny, the staminal morphology of the various lineages of Salvia and related genera is characterized and an evolutionary interpretation of staminal variation within the tribe Mentheae is presented. Methods Two molecular analyses are presented in order to investigate phylogenetic relationships in the tribe Mentheae and the genus Salvia. The first presents a tribal survey of the Mentheae and the second concentrates on Salvia and related genera. Schematic sketches are presented for the staminal morphology of each major lineage of Salvia and related genera. Key Results These analyses suggest an independent origin of the staminal elongate connective on at least three different occasions within the tribe Mentheae, each time with a distinct morphology. Each independent origin of the lever mechanism shows a similar progression of staminal change from slight elongation of the connective tissue separating two fertile thecae to abortion of the posterior thecae and fusion of adjacent posterior thecae. A monophyletic lineage within the Mentheae is characterized consisting of the genera Lepechinia, Melissa, Salvia, Dorystaechas, Meriandra, Zhumeria, Perovskia and Rosmarinus. Conclusions Based on these results the following are characterized: (1) the independent origin of the staminal lever mechanism on at least three different occasions in Salvia, (2) that Salvia is clearly polyphyletic, with five other genera intercalated within it, and (3) staminal evolution has proceeded in different ways in each of the three lineages of Salvia but has resulted in remarkably similar staminal morphologies.
80. Qian, Jun and Song, Jingyuan and Gao, Huanhuan and Zhu, Yingjie and Xu, Jiang and Pang, Xiaohui and Yao, Hui and Sun, Chao and Li, Xian’en and Li, Chuyuan and Liu, Juyan and Xu, Haibin and Chen, Shilin, The Complete Chloroplast Genome Sequence of the Medicinal Plant Salvia Miltiorrhiza, PLoS ONE, vol. 8, no. 2, pp. e57607, February 2013. doi: 10.1371/journal.pone.0057607. Abstract
    Salvia miltiorrhiza is an important medicinal plant with great economic and medicinal value. The complete chloroplast (cp) genome sequence of Salvia miltiorrhiza, the first sequenced member of the Lamiaceae family, is reported here. The genome is 151,328 bp in length and exhibits a typical quadripartite structure of the large (LSC, 82,695 bp) and small (SSC, 17,555 bp) single-copy regions, separated by a pair of inverted repeats (IRs, 25,539 bp). It contains 114 unique genes, including 80 protein-coding genes, 30 tRNAs and four rRNAs. The genome structure, gene order, GC content and codon usage are similar to the typical angiosperm cp genomes. Four forward, three inverted and seven tandem repeats were detected in the Salvia miltiorrhiza cp genome. Simple sequence repeat (SSR) analysis among the 30 asterid cp genomes revealed that most SSRs are AT-rich, which contribute to the overall AT richness of these cp genomes. Additionally, fewer SSRs are distributed in the protein-coding sequences compared to the non-coding regions, indicating an uneven distribution of SSRs within the cp genomes. Entire cp genome comparison of Salvia miltiorrhiza and three other Lamiales cp genomes showed a high degree of sequence similarity and a relatively high divergence of intergenic spacers. Sequence divergence analysis discovered the ten most divergent and ten most conserved genes as well as their length variation, which will be helpful for phylogenetic studies in asterids. Our analysis also supports that both regional and functional constraints affect gene sequence evolution. Further, phylogenetic analysis demonstrated a sister relationship between Salvia miltiorrhiza and Sesamum indicum. The complete cp genome sequence of Salvia miltiorrhiza reported in this paper will facilitate population, phylogenetic and cp genetic engineering studies of this medicinal plant.
81. Parveen, Iffat and Techen, Natascha and Handy, Sara M. and Li, Jing and Wu, Charles and Chittiboyina, Amar G. and Khan, Ikhlas A., The Low Copy Nuclear Gene Region, Granule Bound Starch Synthase (GBSS1), as a Novel Mini-DNA Barcode for the Identification of Different Sage (Salvia) Species, Planta Medica, September 2021. doi: 10.1055/a-1618-6496. Abstract
    Morphological similarity within species makes the identification and authentication of Salvia species challenging, especially in dietary supplements that contain processed root or leaf powder of different sage species. In the present study, the species discriminatory power of 2 potential DNA barcode regions from the nuclear genome was evaluated in 7 medicinally important Salvia species from the family Lamiaceae. The nuclear internal transcribed spacer 2 and the exon 9 – 14 region of low copy nuclear gene WAXY coding for granule-bound starch synthase 1 were tested for their species discrimination ability using distance, phylogenetic, and BLAST-based methods. A novel 2-step PCR method with 2 different annealing temperatures was developed to achieve maximum amplification from genomic DNA. The granule-bound starch synthase 1 region showed higher amplification and sequencing success rates, higher interspecific distances, and a perfect barcode gap for the tested species compared to the nuclear internal transcribed spacer 2. Hence, these novel mini-barcodes generated from low copy nuclear gene regions (granule-bound starch synthase) that were proven to be effective barcodes for identifying 7 Salvia species have potential for identification and authentication of other Salvia species.
82. {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/.
83. 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/.
84. 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.
85. Georgiev, Vasil and Pavlov, Atanas, Genetic Engineering and Manipulation of Metabolite Pathways in Salvia Spp., pp. 399--414, 2017. doi: 10.1007/978-3-319-73900-7_10. Abstract
    Plants from the genus Salvia have been recognized as medicinal herbs all over the world since earliest times. They are known to accumulate diverse range of bioactive phytochemicals, including polyphenols (rosmarinic and salvianolic acids), triterpenes (ursolic and oleanolic acids), diterpenes (tanshinones, carnosic acid), flavonoids and sterols, etc. Nowadays, the powerful methods of genetic and metabolic engineering, synthetic biology and combinatorial biosynthesis have been widely applied for improvement of commercial crops yields and for increasing their medicinal value by modulating the accumulation of biologically active phytochemicals. Over the past few years, these techniques have been applied in Salvia plants and in vitro systems, but the research still remains limited to few species. In this chapter, we summarized the recent achievements in genetic engineering of Salvia species, with special attention on metabolite engineering of phenolic biosynthesis and terpenoids biosynthesis pathways. Some aspects of the applications of functional genes, cloned by Salvia species, for the needs of synthetic biology and combinatorial biosynthesis are reviewed as well.
86. Peters, Frank T. and Meyer, Markus R., In Vitro Approaches to Studying the Metabolism of New Psychoactive Compounds, Drug Testing and Analysis, vol. 3, no. 7-8, pp. 483--495, 2011. doi: 10.1002/dta.295. Abstract
    In the last two decades, a large number of new drugs from several drug classes have appeared on the illicit drug market. While some of these compounds have meanwhile been scheduled as controlled substances, the majority of them are (still) sold as so-called ‘legal highs’, mostly via the Internet. At the time they appear on the market the metabolism of these drugs is generally unknown. Therefore, it must be studied in order to obtain data necessary for analytical method development as well as toxicological risk assessment. In vitro metabolism studies of new designer drugs can be performed for identification and structure elucidation of new designer drug metabolites or to assess the qualitative and quantitative involvement of certain enzymes in the metabolism of a particular drug. In this review, the value of the following enzyme preparations for in vitro metabolism studies of new designer drugs will be discussed: liver microsomes, recombinant cDNA-expressed enzymes, liver cytosol, S9 mix, and hepatocytes. This will cover the major metabolic enzymes: cytochrome P450 monooxygenases, flavin-monooxygenases, monoamine oxidases, UDP-glucuronyltransferases, sulfotransferases, and catechol-O-methyltransferases. Important analytical aspects such as the value of mass spectrometric techniques will also be covered. Copyright © 2011 John Wiley \& Sons, Ltd.
87. {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.
88. 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.
89. Line, Nathan, Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy, 2016. url: https://etd.ohiolink.edu/acprod/odb_etd/etd/r/1501/10?clear=10&p10_accession_num=osu1461161309.
90. Addy, Peter H., That Deep Internal Voice: Controlled Administration of Salvia Divinorum, June 2010. Abstract
    Basic scientific research was performed by administering the psychedelic plant Salvia divinorum to 30 human participants. A placebo-controlled, double-blind, randomized study design was used that incorporated quantitative and qualitative data collection and analysis to study the subjective experience of S. divinorum and consequences of use after 8 weeks. Participants were screened using the Structured Clinical Interview for DSM Disorders-I and semi-structured interviews for medical and psychological issues in order to minimize the chance of a negative reaction. An Emergency Medical Technician was present during administration of either 1000 mcg salvinorin A or placebo dose. Vital signs, observable behavior, and the Hallucinogen Rating Scale (HRS) were administered to all participants. Interviews were also audiotaped and transcribed to elicit themes based upon thematic analysis. Thirty participants had a mean age of 39, were experienced with psychedelics, and well-educated. Two 2-way ANOVAs were used to determine differences between groups based upon sex (women and men), dose (active and placebo), and time (before and after). Pulse rate dropped 5.3 bpm between time measurements. Participants talked, laughed, and moved more often on an active dose. All 6 HRS subscales were significantly elevated on an active dose. No sex differences were noted. Participant experiences displayed 10 common themes presented in depth through qualitative analysis, profiling the phenomenology of this state, including cognitive alteration, synesthesia, and immersion in another reality iv During an 8-week follow-up interview no participants met DSM criteria for substance abuse or dependence of S. divinorum. Positive aftereffects were noted more frequently than negative aftereffects. Use of this plant is increasing, and medical professionals should be aware of what an S. divinorum experience can look like and how to treat a user. This study serves as an introduction to the plant, its use as a psychedelic, physiological and phenomenological effects, and indications for future research.
91. Mowry, Mark and Mosher, Michael and Briner, Wayne, Acute Physiologic and Chronic Histologic Changes in Rats and Mice Exposed to the Unique Hallucinogen Salvinorin A, Journal of Psychoactive Drugs, vol. 35, no. 3, pp. 379--382, 2003. doi: 10.1080/02791072.2003.10400021. Abstract
    Salvinorin A is a unique hallucinogen that is seeing increased use in humans. It is not currently a controlled substance and is used as a legal alternative to controlled substances. Usually smoked or buccally absorbed by chewing, doses of approximately 200 mcg can produce profound hallucinogenic effects of short duration. The mechanism of action of salvinorin A is at the kappa-opioid receptor. Little data is available on the medical effects of this substance so animal studies were undertaken to explore the acute toxic effects of this substance in rats and the chronic effects in mice. Rats were anesthetized and administered salvinorin A at 1600 mcg/kg or vehicle. Recordings were made of galvanic skin response, EKG, temperature, and pulse pressure for 100 minutes. Mice were chronically exposed to vehicle or 400, 800, 1600, 3200, or 6400 mcg/kg of salvinorin A for two weeks. After exposure the animals were sacrificed and brain, heart, kidney, bone marrow, blood and spleen were removed, fixed, sectioned, stained and examined by light microscopy. No effects were seen on cardiac conduction, temperature, or galvanic skin response. A nonsignificant rise was seen in pulse pressure. Histologic studies of spleen, blood, brain, liver, kidney, and bone marrow did not find any significant histologic changes at any of the doses examined. These data suggests that the toxicity of salvinorin A is relatively low, even at doses many times greater than what humans are exposed to. However, further studies should be done on blood pressure effects. The psychological impact of this potent hallucinogen should also be investigated.
92. Harden, Mitchell T. and Smith, Staci E. and Niehoff, Jennifer A. and McCurdy, Christopher R. and Taylor, George T., Antidepressive Effects of the κ-Opioid Receptor Agonist Salvinorin A in a Rat Model of Anhedonia, Behavioural Pharmacology, vol. 23, no. 7, pp. 710, October 2012. doi: 10.1097/FBP.0b013e3283586189. Abstract
    Salvinorin A (SalvA), the hallucinogenic derivative of the plant Salvia divinorum, is a selective κ-opioid receptor agonist that may also have antidepressant properties. Chronic mild stress (CMS) was applied to male and female Long–Evans rats to model anhedonia common in depression. The progressive loss in preference for a sucrose solution over plain water, a measure of anhedonia, and locomotor activity were monitored for 7 weeks. Because antidepressant medications often modify reproductive functions, endocrine glands and hormone-sensitive tissues were assessed at necropsy after the conclusion of the behavioral protocol. Three weeks of CMS exposure led to a decrease in sucrose preference. CMS was continued for 3 additional weeks and animals were randomly assigned to treatment with 1 mg SalvA/kg body weight or to a vehicle control group. The results indicate that SalvA reversed anhedonia whereas control animals continued to show a suppressed preference for the sucrose solution. In addition, no change in sucrose preference was observed in nonstressed rats that were exposed to the same dosage of SalvA. The results indicate that SalvA is an effective antidepressant agent when administered chronically to rats showing symptoms of depression similar to those observed in humans.
93. Ansonoff, Michael A. and Zhang, Jiwen and Czyzyk, Traci and Rothman, Richard B. and Stewart, Jeremy and Xu, Heng and Zjwiony, Jordan and Siebert, Daniel J. and Yang, Feng and Roth, Bryan L. and Pintar, John E., Antinociceptive and Hypothermic Effects of Salvinorin A Are Abolished in a Novel Strain of κ-Opioid Receptor-1 Knockout Mice, Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 2, pp. 641--648, August 2006. doi: 10.1124/jpet.106.101998. Abstract
    Salvia divinorum is a natural occurring hallucinogen that is traditionally used by the Mazatec Indians of central Mexico. The diterpene salvinorin A was identified as an active component of S. divinorum over 20 years ago, but only recently has biochemical screening indicated that a molecular target of salvinorin A in vitro is the κ-opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as κ-opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1 to 30 μg of both salvinorin A and salvinorinyl-2-propionate produces antinociception in wild-type mice but not in a novel strain of κ-opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional κ-opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for κ1- but not κ2-opioid receptors, demonstrating selectivity for this receptor subclass. Finally, treatment over the same dose range with salvinorin B, which is inactive in vitro, produced neither antinociceptive nor hypothermic effects in wild-type mice. These data demonstrate that salvinorin A is the active component of S. divinorum, selective for κ1-opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the κ-opioid receptor.
94. McCurdy, Christopher R. and Sufka, Kenneth J. and Smith, Grant H. and Warnick, Jason E. and Nieto, Marcelo J., Antinociceptive Profile of Salvinorin A, a Structurally Unique Kappa Opioid Receptor Agonist, Pharmacology Biochemistry and Behavior, vol. 83, no. 1, pp. 109--113, January 2006. doi: 10.1016/j.pbb.2005.12.011. Abstract
    Salvinorin A, is a structurally unique, non-nitrogenous, kappa opioid receptor (KOP) agonist. Given the role of KOPs in analgesic processes, we set out to determine whether salvinorin A has antinociceptive activity in thermal and chemo-nociceptive assays. The tail-flick assay was employed to investigate 1) salvinorin A's (0.5, 1.0, 2.0, and 4.0 mg/kg) dose–response and time-course (10, 20, and 30 min) effects in a thermal nociceptive assay, and 2) the ability for the KOP antagonist norBNI (10.0 mg/kg) to prevent salvinorin A antinociception. The hotplate assay was utilized as a second thermal nociceptive measure to test salvinorin A's dose–response effects. The acetic acid abdominal constriction assay was used to study salvinorin A's dose–response and time-course (over 30 min) effects in a chemo-nociceptive assay. Together, these studies revealed that salvinorin A produces a dose-dependent antinociception that peaked at 10 min post-injection but rapidly returned to baseline. Additionally, pretreatment with the KOP antagonist norbinaltorphimine (norBNI) reversed salvinorin A-induced antinociception. These findings demonstrate that salvinorin A produces a KOP mediated antinociceptive effect with a short duration of action.
95. Addy, Peter H., Chapter 68 - Behavioral and Psychological Effects of Salvia Divinorum: A Focus on Self-Reported Subjective Acute Behavioral Effects and Laboratory Studies, pp. 733--738, January 2016. doi: 10.1016/B978-0-12-800212-4.00068-6. Abstract
    Salvia divinorum is a plant used as a recreational hallucinogen that is legally available in many states and countries. Salvia divinorum is not a popular substance of abuse, is rarely used frequently or regularly, and is used primarily out of curiosity, for interest in altered states of consciousness and for spiritual purposes. Smoking commercially available Salvia divinorum produces rapid onset and short duration of intense subjective effects (5–15min), with few effects lasting more than 24h after use. Preliminary evidence suggests that acute inhalation may lead to transient and reversible verbal learning memory deficits, but does not affect verbal working memory. Research subjects do not report euphoria or craving to use, and do not seek out Salvia divinorum, subsequent to experimental exposure. Large surveys have found little or no associations between Salvia divinorum use and adverse events, although Salvia divinorum use is correlated with use of other recreational substances, particularly hallucinogens and cannabis.
96. Gonzalez, Eduardo Jose, Chewing Gum Formula for Enhancing Psycho-Spirituality, no. US20110038915A1, February 2011. url: https://patents.google.com/patent/US20110038915A1/en?oq=+US+2011%2f0038915+A1. Abstract
    The present invention relates to a chewing gum formulation which serves as a means for awakening human consciousness and mindfulness to the sensorial subtleties, which in turn strengthens sovereignty such that overall psycho-spirituality is enhanced. More particularly, this invention relates to a dietary supplement consisting of the botanical plant Salvia divinorum as the source substance, including Salvinorin Alpha (A) as its primary active constituent, which is precisely extracted from S. divinorum to achieve a consistent dosing regimen predetermined for standardized efficacies.
97. Ranganathan, Mohini and Schnakenberg, Ashley and Skosnik, Patrick D. and Cohen, Bruce M. and Pittman, Brian and Sewell, R. Andrew and D'Souza, Deepak Cyril, Dose-Related Behavioral, Subjective, Endocrine, and Psychophysiological Effects of the κ Opioid Agonist Salvinorin A in Humans, Biological Psychiatry, vol. 72, no. 10, pp. 871--879, November 2012. doi: 10.1016/j.biopsych.2012.06.012.
98. MacLean, Katherine A. and Johnson, Matthew W. and Reissig, Chad J. and Prisinzano, Thomas E. and Griffiths, Roland R., Dose-Related Effects of Salvinorin A in Humans: Dissociative, Hallucinogenic, and Memory Effects, Psychopharmacology, vol. 226, no. 2, pp. 381--392, March 2013. doi: 10.1007/s00213-012-2912-9. Abstract
    Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum, which has increased in popularity as a recreational drug over the past decade. Few human studies have examined salvinorin A.
99. Gram, Harold, Ethnopharmacognosy and Human Pharmacology of Salvia Divinorum and Salvinorin A - Salvia Divinorum, Drug Times, December 2022. url: https://www.drugtimes.org/salvia-divinorum/ethnopharmacognosy-and-human-pharmacology-of-salvia-divinorum-and-salvinorin-a.html. Abstract
    Abstract After a thorough review of the limited ethnographic data on shamanic use of the entheogenic mint Salvia divinorum by the Mazatec Indians of the Sierra
100. Valdes, I. I. I. and Diaz, JoseLuis and Paul, Ara G., Ethnopharmacology of Ska Maria Pastora (Salvia Divinorum, Epling AND Jativa-M.), May 1983. url: http://deepblue.lib.umich.edu/handle/2027.42/25229. Abstract
     Salvia divinorum is a perennial labiate used for curing and divination by the Mazatec Indians of Oaxaca, Mexico. The psych otropic effects the plant produces are compared to those of the other hallucinogens employed by the Mazatecs, the morning glory, Riuea corymbosa L., Hallier f. and the psilocybin-containing mushrooms. A discussion of the role of ska Maria Pastora in the native "pharmacopeia" is based on previous reports and fieldwork by the authors, with a Mazatec shaman.
101. Teksin, Zeynep S. and Lee, Insong J. and Nemieboka, Noble N. and Othman, Ahmed A. and Upreti, Vijay V. and Hassan, Hazem E. and Syed, Shariq S. and Prisinzano, Thomas E. and Eddington, Natalie D., Evaluation of the Transport, in Vitro Metabolism and Pharmacokinetics of Salvinorin A, a Potent Hallucinogen, European Journal of Pharmaceutics and Biopharmaceutics, vol. 72, no. 2, pp. 471--477, June 2009. doi: 10.1016/j.ejpb.2009.01.002. Abstract
     Salvinorin A is an unregulated potent hallucinogen isolated from the leaves of Salvia divinorum. It is the only known non-nitrogenous kappa-opioid selective agonist, and rivals synthetic lysergic acid diethylamide (LSD) in potency. The objective of this study was to characterize the in vitro transport, in vitro metabolism, and pharmacokinetic properties of Salvinorin A. The transport characteristics of Salvinorin A were assessed using MDCK-MDR1 cell monolayers. The P-glycoprotein (P-gp) affinity status was assessed by the P-gp ATPase assay. In vitro metabolism studies were performed with various specific human CYP450 isoforms and UGT2B7 to assess the metabolic characteristics of Salvinorin A. Cohorts (n=3) of male Sprague Dawley rats were used to evaluate the pharmacokinetics and brain distribution of Salvinorin A (10mg/kg, intraperitoneal (i.p.) over a 240-min period. A validated UV-HPLC and LC/MS/MS method was used to quantify the hallucinogen concentrations obtained from the in vitro and in vivo studies, respectively. Salvinorin A displayed a high secretory transport in the MDCK-MDR1 cells (4.07±1.34×10−5cm/s). Salvinorin A also stimulated the P-gp ATPase activity in a concentration (5 and 10μM)-dependent manner, suggesting that it may be a substrate of (P-gp). A significant decrease in Salvinorin A concentration ranging from 14.7±0.80\% to 31.1±1.20\% was observed after incubation with CYP2D6, CYP1A1, CYP2C18, and CYP2E1, respectively. A significant decrease was also observed after incubation with UGT2B7. These results suggest that Salvinorin A maybe a substrate of UGT2B7, CYP2D6, CYP1A1, CYP2E1, and CYP2C18. The in vivo pharmacokinetic study showed a relatively fast elimination with a half-life (t1/2) of 75min and a clearance (Cl/F) of 26L/h/kg. The distribution was extensive (Vd of 47.1L/kg); however, the brain to plasma ratio was 0.050. Accordingly, the brain half-life was relatively short, 36min. Salvinorin A is rapidly eliminated after i.p. dosing, in accordance with its fast onset and short duration of action. Further, it appears to be a substrate for various oxidative enzymes and multi-drug resistant protein, P-gp.
102. Johnson, Matthew W. and MacLean, Katherine A. and Reissig, Chad J. and Prisinzano, Thomas E. and Griffiths, Roland R., Human Psychopharmacology and Dose-Effects of Salvinorin A, a Kappa Opioid Agonist Hallucinogen Present in the Plant Salvia Divinorum, Drug and Alcohol Dependence, vol. 115, no. 1, pp. 150--155, May 2011. doi: 10.1016/j.drugalcdep.2010.11.005. Abstract
     Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375μg/kg to 21μg/kg. Subject-rated drug strength was assessed every 2min for 60min after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2min (first time point) and definite subjective effects were no longer present at approximately 20min after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2A) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects.
103. Yan, Feng and Mosier, Philip D. and Westkaemper, Richard B. and Stewart, Jeremy and Zjawiony, Jordan K. and Vortherms, Timothy A. and Sheffler, Douglas J. and Roth, Bryan L., Identification of the Molecular Mechanisms by Which the Diterpenoid Salvinorin A Binds to κ-Opioid Receptors, Biochemistry, vol. 44, no. 24, pp. 8643--8651, June 2005. doi: 10.1021/bi050490d. Abstract
     Salvinorin A is a naturally occurring hallucinogenic diterpenoid from the plant Salvia divinorum that selectively and potently activates κ-opioid receptors (KORs). Salvinorin A is unique in that it is the only known lipid-like molecule that selectively and potently activates a G-protein coupled receptor (GPCR), which has as its endogenous agonist a peptide; salvinorin A is also the only known non-nitrogenous opioid receptor agonist. In this paper, we identify key residues in KORs responsible for the high binding affinity and agonist efficacy of salvinorin A. Surprisingly, we discovered that salvinorin A was stabilized in the binding pocket by interactions with tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119). Intriguingly, activation of KORs by salvinorin A required interactions with the helix 7 tyrosines Tyr312, Tyr313, and Tyr320 and with Tyr139 in helix 3. In contrast, the prototypical nitrogenous KOR agonist U69593 and the endogenous peptidergic agonist dynorphin A (1−13) showed differential requirements for these three residues for binding and activation. We also employed a novel approach, whereby we examined the effects of cysteine-substitution mutagenesis on the binding of salvinorin A and an analogue with a free sulfhydryl group, 2-thiosalvinorin B. We discovered that residues predicted to be in close proximity, especially Tyr313, to the free thiol of 2-thiosalvinorin B when mutated to Cys showed enhanced affinity for 2-thiosalvinorin B. When these findings are taken together, they imply that the diterpenoid salvinorin A utilizes unique residues within a commonly shared binding pocket to selectively activate KORs.
104. Tsujikawa, K. and Kuwayama, K. and Miyaguchi, H. and Kanamori, T. and Iwata, Y. T. and Inoue, H., In Vitro Stability and Metabolism of Salvinorin A in Rat Plasma, Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 39, no. 5, pp. 391--398, May 2009. doi: 10.1080/00498250902769967. Abstract
     Salvinorin A is the main active psychoactive ingredient in Salvia divinorum, a Mexican plant that has been widely available as a hallucinogen in recent years. The aims of this study were to investigate the stability of salvinorin A in rat plasma, esterases responsible for its degradation, and estimation of the degradation products. The apparent first-order rate constants of salvinorin A at 37 degrees C, 25 degrees C, and 4 degrees C were 3.8 x 10(-1), 1.1 x 10(-1), and {$<$} 6.0 x 10(-3) h(-1), respectively. Salvinorin A degradation was markedly inhibited by the addition of sodium fluoride, an esterase inhibitor. Moreover, phenylmethylsulfonyl fluoride (serine esterase inhibitor) and bis-p-nitrophenylphosphate (carboxylesterase inhibitor) also inhibited salvinorin A degradation. In contrast, little or no suppression of the degradation was seen with 5,5'-dithiobis-2-nitrobenzoic acid (arylesterase inhibitor),ethopropazine (butyrylcholinesterase inhibitor), and BW284c51 (acetylcholineseterase inhibitor). These findings indicated that carboxylesterase was mainly involved in the salvinorin A hydrolysis in rat plasma.4. The degradation products of salvinorin A estimated by liquid chromatography-mass spectrometry included the deacetylated form (salvinorin B) and the lactone-ring-open forms of salvinorin A and salvinorin B. This lactone-ring-opening reactions were involved in calcium-dependent lactonase.
105. Hoover, Valerie and Marlowe, Douglas B. and Patapis, Nicholas S. and Festinger, David S. and Forman, Robert F., Internet Access to Salvia Divinorum: Implications for Policy, Prevention, and Treatment, Journal of Substance Abuse Treatment, vol. 35, no. 1, pp. 22--27, July 2008. doi: 10.1016/j.jsat.2007.07.011. Abstract
     This study determined the degree to which Salvia divinorum, a potent hallucinogenic drug that is legal in most U.S. jurisdictions, is being proffered for sale over the Internet and how it is being characterized on popular Web sites. Search results revealed that between one half and two thirds (58\%) of the Web sites either offered to sell S. divinorum or linked to other Web sites offering to sell the drug and that more than three quarters (78\%) of the Web sites advocated for its use. Many of the statements issued on the Web sites were erroneous or falsely interpreted the absence of scientific data on the possible side effects of S. divinorum as evidence that no side effect exists. The portrayal and availability of S. divinorum on the Internet are similar to those of other illicit and prescription drugs of abuse. However, much less is known about the short- and long-term effects of this novel drug. Consequently, there is little basis to contradict the many Web sites that encourage its use. Implications for drug policy, prevention, and treatment are discussed.
106. Mendelson, John E. and Coyle, Jeremy R. and Lopez, Juan Carlos and Baggott, Matthew J. and Flower, Keith and Everhart, E. Thomas and Munro, Thomas A. and Galloway, Gantt P. and Cohen, Bruce M., Lack of Effect of Sublingual Salvinorin A, a Naturally Occurring Kappa Opioid, in Humans: A Placebo-Controlled Trial, Psychopharmacology, vol. 214, no. 4, pp. 933--939, 2011. doi: 10.1007/s00213-010-2103-5. Abstract
     Rationale Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. Objectives The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. Methods Sublingual SA doses up to 4~mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. Results No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported “typical” effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5~ng/mL). Conclusions Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.
107. Gibbons, Simon, ‘Legal Highs’ – Novel and Emerging Psychoactive Drugs: A Chemical Overview for the Toxicologist, Clinical Toxicology, vol. 50, no. 1, pp. 15--24, January 2012. doi: 10.3109/15563650.2011.645952. Abstract
     Introduction. ‘Legal highs’ are psychoactive chemicals which are sold from ‘head shops’, the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. Methods. A survey of the internet was used to identify websites that are marketing ‘legal highs’ in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl-tryptamine. Results. ‘Legal highs’ from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. Conclusions. ‘Legal highs’ are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with ‘legal highs’ is needed.
108. Kelly, Brian C., Legally Tripping: A Qualitative Profile of Salvia Divinorum Use among Young Adults, Journal of Psychoactive Drugs, vol. 43, no. 1, pp. 46--54, 2011. doi: 10.1080/02791072.2011.566500. Abstract
     During recent years, there has been increasing interest in "legal highs" among youth and young adults. Salvia divinorum is a legally available hallucinogenic plant, primarily utilized in smokable form, that produces a brief but intense hallucinogenic experience for the user. Data are presented from an ethnographic project to provide a qualitative profile of salvia use among young adults. Most users report primarily using in home settings such as apartments and houses, although a significant minority report use in environments such as parks, bars, and parties. The intense nature of the substance creates a differential subjective experience. Some describe the intensity of the hallucinogenic experience in positive ways. Others find the experience so intense that they would not continue to use the substance. With regard to the health effects of salvia, most young adults report no significant negative health effects from salvia use, although some report a mental cloudiness. Beyond their own experiences, users did not report any negative health events among peers. The lack of reports of negative effects may reinforce social norms favorable towards salvia use. Overall, young adults report a relatively low risk profile for salvia divinorum, which may be influenced, in part, by its legal status.
109. SaturnofElysium, The r/GrowinSalviaDivinorum Trust Vendor List, r/GrowinSalviaDivinorum, March 2021. url: www.reddit.com/r/GrowinSalviaDivinorum/comments/mb18sg/the_rgrowinsalviadivinorum_trust_vendor_list/.
110. Yan, F., Molecular Mechanisms by Which Salvinorin A Binds to and Activates the κ-Opioid Receptor, 2008. url: http://rave.ohiolink.edu/etdc/view?acc_num=case1207342013. Abstract
     Salvinorin A, the most potent naturally-occurring hallucinogen, has gained great attention since the κ-opioid receptor (KOR) was identified as its principal molecular target (1). However, the molecular mechanisms by which salvinorin A, a small-molecule agonist, binds to and activates KOR was unclear. To understand these mechanisms, three aims were proposed for my dissertation research; correspondingly, I will report our findings in three parts (Chapter 3, Chapter 4 and Chapter 5) in this dissertation. The primary goal (Chapter 3) is to identify the binding site of salvinorin A in KOR. A combination of site-directed mutagenesis and molecular modeling was applied to determine the structural features of KOR essential for the binding of Salvinorin A (2). Meanwhile, a series of naturally-occurring and synthetic salvinorin A derivatives was designed and assayed to compare their binding and functional properties (3-6). The subsequent goal (Chapter 4) is to investigate KOR's conformational change during the activation process. In this part of the dissertation research, over-expression of Gα16 and Gαi2 were used to increase the coupling ratio between KOR and the Gα subunits (7). The substituted cysteine accessibility method (SCAM), utilizing the specific reaction between the thiolate groups (-S-) and 2-aminoethylmethanethiosulfonate (MTSEA), was applied to detect the conformational changes of the receptor (7). Intriguingly, these G protein-dependent conformational changes significantly increased the binding affinity of salvinorin A. In PART III (Chapter 5), our goal is to further verify ligand-receptor interactions by designing a series of ligands capable of covalently binding to KOR. From our earlier work using the SCAM approach, we demonstrated that C3157.38 was both water accessible and highly reactive to methanethiosulfonate (MTS) reagents (7). Thus far, two compounds RB-48 and RB-64 (both with pM potency and extraordinary selectivity for KOR) have emerged as being suitable for affinity-labeling KOR. Our preliminary mass spectrometry data was consistent with C3157.38 as the labeling site. Collectively, this research project has revealed the molecular mechanisms by which a small-molecule agonist selectively binds to and activates a Class A GPCR.
111. Chakraborty, Soumen and Majumdar, Susruta, Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide, Biochemistry, vol. 60, no. 18, pp. 1381--1400, May 2021. doi: 10.1021/acs.biochem.0c00629. Abstract
     Pain remains a very pervasive problem throughout medicine. Classical pain management is achieved through the use of opiates belonging to the mu opioid receptor (MOR) class, which have significant side effects that hinder their utility. Pharmacologists have been trying to develop opioids devoid of side effects since the isolation of morphine from papaver somniferum, more commonly known as opium by Sertürner in 1804. The natural products salvinorin A, mitragynine, and collybolide represent three nonmorphinan natural product-based targets, which are potent selective agonists of opioid receptors, and emerging next-generation analgesics. In this work, we review the phytochemistry and medicinal chemistry efforts on these templates and their effects on affinity, selectivity, analgesic actions, and a myriad of other opioid-receptor-related behavioral effects.,
112. Casselman, Ivan and Heinrich, Michael, Novel Use Patterns of Salvia Divinorum: Unobtrusive Observation Using YouTube™, Journal of Ethnopharmacology, vol. 138, no. 3, pp. 662--667, December 2011. doi: 10.1016/j.jep.2011.07.065. Abstract
     Ethnopharmacological relevance and Aims The traditional use of the Hallucinogenic sage, Salvia divinorum has been of ethnopharmalogical interest for some time. This plant, endemic to Oaxaca Mexico and traditionally used by the Mazatec, is now utilized worldwide for its psychoactive effects. This use demonstrates a novel use pattern which is distinctly different from Mazatec use. This study offers a new methodology to study emerging global plant use and assesses the users’ experience with it. The aim of this research was to develop a new methodology to collect and analyze archived data on the World Wide Web, specifically videos which depict Salvia divinorum use. Methods The basis of the methodology for this project was unobtrusive observation which allows the researcher to observe without influencing the event which is being observed. Qualitative, ethnographic data was used in conjunction with quantitative meta data collected by a customized web crawler programed to archive YouTube™ data. Results Using this methodology enabled us to understand reported uses and the users’ experiences as expressed on the World Wide Web. The main result of this research was the documentation of a distinct, novel use pattern of Salvia divinorum which has developed outside of Oaxaca; a use pattern which differs in a number of ways from traditional, Mazatec use. The majority of the YouTube™ videos analyzed were found to present indications of a positive Salvia divinorum experience. This result highlighted the contradiction between ethnographic data and what is reported by the media. Finally the representation of Salvia divinorum on YouTube™ (and by inference the WWW as a whole) is a growing phenomena. Conclusions While anthropological and more specifically medico-anthropological research has, for many years, embraced the dynamics of cultures, until recently, ethnopharmalogical research has generally focused on ‘traditional’ plant use, failing to capture the dynamic elements of plant/human interaction and framing research in the past or as decontextualized largely descriptive reports. Global migration and urban environments formed a basis for looking at the interplay of continuity and change. Such cultural dynamics are exacerbated by the opportunities which the WWW offers.
113. Braida, Daniela and Capurro, Valeria and Zani, Alessia and Rubino, Tiziana and Viganò, Daniela and Parolaro, Daniela and Sala, Mariaelvina, Potential Anxiolytic- and Antidepressant-like Effects of Salvinorin A, the Main Active Ingredient of Salvia Divinorum, in Rodents, British Journal of Pharmacology, vol. 157, no. 5, pp. 844--853, 2009. doi: 10.1111/j.1476-5381.2009.00230.x. Abstract
     Background and purpose: Drugs targeting brain κ-opioid receptors produce profound alterations in mood. In the present study we investigated the possible anxiolytic- and antidepressant-like effects of the κ-opioid receptor agonist salvinorin A, the main active ingredient of Salvia divinorum, in rats and mice. Experimental approach: Experiments were performed on male Sprague-Dawley rats or male Albino Swiss mice. The anxiolytic-like effects were tested by using the elevated plus maze, in rats. The antidepressant-like effect was estimated through the forced swim (rats) and the tail suspension (mice) test. κ-Opioid receptor involvement was investigated pretreating animals with the κ-opioid receptor antagonist, nor-binaltorphimine (1 or 10 mg·kg−1), while direct or indirect activity at CB1 cannabinoid receptors was evaluated with the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl) -5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, 0.5 or 3 mg·kg−1), binding to striatal membranes of naïve rats and assay of fatty acid amide hydrolase in prefrontal cortex, hippocampus and amygdala. Key results: Salvinorin A, given s.c. (0.001–1000 µg·kg−1), exhibited both anxiolytic- and antidepressant-like effects that were prevented by nor-binaltorphimine or AM251 (0.5 or 3 mg·kg−1). Salvinorin A reduced fatty acid amide hydrolase activity in amygdala but had very weak affinity for cannabinoid CB1 receptors. Conclusions and implications: The anxiolytic- and antidepressant-like effects of Salvinorin A are mediated by both κ-opioid and endocannabinoid systems and may partly explain the subjective symptoms reported by recreational users of S. divinorum.
114. Prisinzano, Thomas E., Psychopharmacology of the Hallucinogenic Sage Salvia Divinorum, Life Sciences, vol. 78, no. 5, pp. 527--531, December 2005. doi: 10.1016/j.lfs.2005.09.008. Abstract
     At present, the Mexican mint Salvia divinorum is an unregulated hallucinogen. This has resulted in various on-line botanical companies advertising and selling S. divinorum as a legal alternative to other regulated plant hallucinogens. It is predictable that its misuse will increase rapidly. The active ingredient in S. divinorum is the neoclerodane diterpene, salvinorin A (1a), which has been shown to be a κ agonist both in vitro and in vivo. This review will cover the current state of research into the psychopharmacology of S. divinorum.
115. Díaz, José-Luis, Salvia Divinorum: A Psychopharmacological Riddle and a Mind-Body Prospect, Current Drug Abuse Reviews, vol. 6, no. 1, pp. 43--53, 2013. doi: 10.2174/18744737112059990004. Abstract
     The multidisciplinary research on Salvia divinorum and its chemical principles is analyzed concerning whether the ethnobotany, phytochemistry, mental effects, and neuropharmacology of this sacred psychoactive plant and main principle clarify its experienced effects and divinatory uses. The scientific pursuit spans from the traditional practices, continues with the botanical identification, isolation of active molecules, characterization of mental and neural effects, possible therapeutic applications, and impinges upon the mind-body problem. The departure point is ethnopharmacology and therefore the traditional beliefs, ritual uses, and mental effects of this Mazatec sacred mint recorded during a 1973- 1983 field research project are described. A water potion of crushed leaves produced short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and an increase visual and auditory imagery, but not actual hallucinations. Similar effects were described using questionnaires and are attributable to salvinorin A, but cannot be explained solely by its specific and potent brain kappa-opioid receptor agonist activity. Some requirements for a feasible classification and mechanism of action of consciousness-altering products are proposed and include the activation of neural networks comprising several neurochemical systems. Top-down analyses should be undertaken in order to characterize such neural networks and eventually allowing to explore the differential ethnic effects. As is the case for other consciousness-altering preparations, a careful and encompassing research on this plant and principle can be consequential to endeavors ranging from the mind-body problem, a better understanding of shamanic ecstasy, to the potential generation of analgesic, antidepressant, and drug-abuse attenuating products.
116. Giroud, C and Felber, F and Augsburger, M and Horisberger, B and Rivier, L and Mangin, P, Salvia Divinorum: An Hallucinogenic Mint Which Might Become a New Recreational Drug in Switzerland, Forensic Science International, vol. 112, no. 2, pp. 143--150, August 2000. doi: 10.1016/S0379-0738(00)00180-8. Abstract
     Salvia divinorum Epling \& Jativa is an hallucinogenic mint traditionally used for curing and divination by the Mazatec Indians of Oaxaca, Mexico. Young people from Mexican cities were reported to smoke dried leaves of S. divinorum as a marijuana substitute. Recently, two S. divinorum specimens were seized in a large-scale illicit in-door and out-door hemp plantation. Salvinorin A also called divinorin A, a trans-neoclerodane diterpene, was identified in several organic solvent extracts by gas chromatography–mass spectrometry. The botanical identity of the plant was confirmed by comparing it to an authentic herbarium specimen. More plants were then discovered in Swiss horticulturists greenhouses. All these data taken together suggest that many attempts exist in Switzerland to use S. divinorum as a recreational drug. This phenomenon may be enhanced because neither the magic mint, nor its active compound are banned substances listed in the Swiss narcotic law.
117. Mahendran, Rathi and Lim, Haikel A. and Tan, Joyce Y.S. and Chua, Shi Min and Winslow, Munidasa, Salvia Divinorum: An Overview of the Usage, Misuse, and Addiction Processes, Asia-Pacific Psychiatry, vol. 8, no. 1, pp. 23--31, 2016. doi: 10.1111/appy.12225. Abstract
     Salvia divinorum, a sage plant with leaves that can produce a psychoactive high, has been used for hundreds of years for its psycho-mimetic effects in religious rituals in South America. Salvia has now become popular mainly with adolescents and young adults for the short-lived relatively pleasant experiences many consider a “legal high” and its ready availability through Internet purchases. The main (psycho)active compound in salvia is Salvinorin A, a potent κ-opioid agonist and although the short and long-term effects have not been examined in sufficient detail, it is widely believed to have low addictive potential and low toxicity. Recent findings, however, seem to suggest that Salvinorin A can precipitate psychiatric symptoms and negatively affect cognition. Its ready availability and increasingly widespread use requires clinicians to have knowledge and awareness of its effects.
118. Vohra, Rais and Seefeld, Andrew and Cantrell, F. Lee and Clark, Richard F., Salvia Divinorum: Exposures Reported to a Statewide Poison Control System over 10 Years, The Journal of Emergency Medicine, vol. 40, no. 6, pp. 643--650, June 2011. doi: 10.1016/j.jemermed.2009.05.019. Abstract
     BACKGROUND: Salvia divinorum, a hallucinogenic herb, has in recent years become popular among teenagers and young adults. Salvia is presently marketed as a "legal" alternative to other drugs of abuse, but little is known about the clinical toxicity of this substance. OBJECTIVES: The purpose of this study is to describe the clinical and demographic features of this emerging substance of recreational abuse using data obtained from the records of a poison control center. METHODS: We performed retrospective review of exposures to the herbal hallucinogen Salvia divinorum as reported to the California Poison Control System (CPCS) over the last 10 years. Demographic and clinical data were collected and compiled from the computerized records of the CPCS for the search terms "salvia" and "sage." RESULTS: There were 37 exposures to S. divinorum and 96 exposures to non-hallucinogenic Salvia species. Eighteen (49\%) of the exposures were to S. divinorum alone. Intentional Salvia exposures resulted in a variety of neurologic, cardiovascular, and gastrointestinal effects. Notably, the use of concomitant substances of abuse was associated with a high rate of complications and psychomotor disturbances. CONCLUSIONS: Intentional use of S. divinorum, whether alone or in combination with alcoholic beverages and other drugs, causes neurologic, cardiovascular, and gastrointestinal effects. This poison-center-based review helps to characterize the clinical toxicity of S. divinorum, but more clinical and pharmacologic research is warranted for this rapidly emerging substance of abuse.
119. Coffeen, Ulises and Pellicer, Francisco, Salvia Divinorum: From Recreational Hallucinogenic Use to Analgesic and Anti-Inflammatory Action, Journal of Pain Research, vol. 12, pp. 1069, 2019. doi: 10.2147/JPR.S188619. Abstract
     Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become ...
120. Perry, Nicolette S. L and Bollen, Chloe and Perry, Elaine K and Ballard, Clive, Salvia for Dementia Therapy: Review of Pharmacological Activity and Pilot Tolerability Clinical Trial, Pharmacology Biochemistry and Behavior, vol. 75, no. 3, pp. 651--659, June 2003. doi: 10.1016/S0091-3057(03)00108-4. Abstract
     S. lavandulaefolia Vahl. (Spanish sage) extracts and constituents have demonstrated anticholinesterase, antioxidant, anti-inflammatory, oestrogenic and CNS depressant (sedative) effects all of which are currently relevant to the treatment of Alzheimer's disease (AD). The essential oil inhibits the enzyme acetylcholinesterase (AChE) from human brain tissue and bovine erythrocyte and individual monoterpenoid constituents inhibit AChE with varying degrees of potency. In vivo AChE inhibition of select brain (striatal and hippocampal over cortical) AChE was obtained following oral administration of the essential oil to rats. In a study in healthy volunteers essential oil administration produced significant effects on cognition. In a pilot open-label study involving oral administration of the essential oil to patients with AD, a significant increase in diastolic and systolic blood pressure was observed in two patients, however this may have been due primarily to preexisting hypertension and there were no abnormalities in other vital signs or blood samples during the trial period. Although an open label trial is not free from practice effects or rater–caregiver expectations, statistically significant differences between baseline and 6 weeks treatment were a reduction in neuropsychiatric symptoms and an improvement in attention.
121. Prisinzano, Thomas E. and Rothman, Richard B., Salvinorin A Analogs as Probes in Opioid Pharmacology, Chemical reviews, vol. 108, no. 5, pp. 1732--1743, May 2008. doi: 10.1021/cr0782269.
122. Butelman, Eduardo R. and Kreek, Mary Jeanne, Salvinorin A, a Kappa-Opioid Receptor Agonist Hallucinogen: Pharmacology and Potential Template for Novel Pharmacotherapeutic Agents in Neuropsychiatric Disorders, Frontiers in Pharmacology, vol. 6, pp. 190, September 2015. doi: 10.3389/fphar.2015.00190. Abstract
     Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.
123. Sheffler, Douglas J. and Roth, Bryan L., Salvinorin A: The ‘Magic Mint’ Hallucinogen Finds a Molecular Target in the Kappa Opioid Receptor, Trends in Pharmacological Sciences, vol. 24, no. 3, pp. 107--109, March 2003. doi: 10.1016/S0165-6147(03)00027-0. Abstract
     Salvinorin A, a neoclerodane diterpene, is the most potent naturally occurring hallucinogen known and rivals the synthetic hallucinogen lysergic acid diethylamide in potency. Recently, the molecular target of salvinorin A was identified as the kappa opioid receptor (KOR). Salvinorin A represents the only known non-nitrogenous KOR selective agonist. Based on the selectivity of salvinorin A for the KOR, this receptor represents a potential molecular target for the development of drugs to treat disorders characterized by alterations in perception, including schizophrenia, Alzheimer's disease and bipolar disorder.
124. Béguin, Cécile and Carlezon, William A. and Cohen, Bruce M. and He, Minsheng and Lee, David Yue-Wei and Richards, Michele R. and Chen, Lee-Yuan Liu, Salvinorin Derivatives and Uses Thereof, no. US20100324131A1, December 2010. url: https://patents.google.com/patent/US20100324131A1/en?oq=US+2010%2f0324131+A1.
125. Béquin, Cécile and Carlezon, William A. and Cohen, Bruce M. and He, Minsheng and Lee, David Yue-Wei and Richards, Michele R. and {Liu-Chen}, Lee-Yuan, Salvinorin Derivatives and Uses Thereof, no. US7629475B2, December 2009. url: https://patents.google.com/patent/US7629475B2/en.
126. Doss, Manoj K. and May, Darrick G. and Johnson, Matthew W. and Clifton, John M. and Hedrick, Sidnee L. and Prisinzano, Thomas E. and Griffiths, Roland R. and Barrett, Frederick S., The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain, Scientific Reports, vol. 10, no. 1, pp. 16392, October 2020. doi: 10.1038/s41598-020-73216-8. Abstract
     Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.
127. John, Trentini F. and French, Larry G. and Erlichman, Joseph S., The Antinociceptive Effect of Salvinorin A in Mice, European Journal of Pharmacology, vol. 545, no. 2, pp. 129--133, September 2006. doi: 10.1016/j.ejphar.2006.06.077. Abstract
     Salvia divinorum is a hallucinogenic plant used by the Mazatec Indians of Mexico for traditional spiritual ceremonies. The active constituent, salvinorin A, induces profound hallucinations, however the biological mechanism for this action is not known. Affinity-binding studies suggest that the biologic activity of salvinorin A involves the κ-opioid receptor. The purpose of this study was to evaluate the antinociceptive effect of salvinorin A in mice. Salvinorin A and opioid receptor antagonists were administered intrathecally and the tail-flick latencies were used as a measure of antinociception. Salvinorin A increased tail-flick latencies in a dose-dependent manner (13.9–23.1~nmol) compared to control trials. Pretreatment with the κ-opioid receptor antagonist nor-binaltorphimine attenuated the salvinorin A induced increase in tail-flick latency. In contrast, neither the μ-opioid receptor antagonist β-funaltrexamine nor δ-opioid receptor antagonist naltrindole significantly affected the antinociceptive response of salvinorin A administration. These data support previous reports that salvinorin A represents a unique non-alkaloidal agonist for the κ-opioid receptor.
128. Imanshahidi, Mohsen and Hosseinzadeh, Hossein, The Pharmacological Effects of Salvia Species on the Central Nervous System, Phytotherapy Research, vol. 20, no. 6, pp. 427--437, 2006. doi: 10.1002/ptr.1898. Abstract
     Salvia is an important genus consisting of about 900 species in the family Lamiaceae. Some species of Salvia have been cultivated world wide for use in folk medicine and for culinary purposes. The dried root of Salvia miltiorrhiza, for example, has been used extensively for the treatment of coronary and cerebrovascular disease, sleep disorders, hepatitis, hepatocirrhosis, chronic renal failure, dysmenorrhea, amenorrhea, carbuncles and ulcers. S. officinalis, S. leriifolia, S. haematodes, S. triloba and S. divinorum are other species with important pharmacological effects. In this review, the pharmacological effects of Salvia species on the central nervous system will be reviewed. These include sedative and hypnotic, hallucinogenic, skeletal muscle relaxant, analgesic, memory enhancing, anticonvulsant, neuroprotective and antiparkinsonian activity, as well as the inhibition of ethanol and morphine withdrawal syndrome. Copyright © 2006 John Wiley \& Sons, Ltd.
129. Appel, Jonathan and {Kim-Appel}, Dohee, The Rise of a New Psychoactive Agent: Salvia Divinorum, International Journal of Mental Health and Addiction, vol. 5, no. 3, pp. 248--253, July 2007. doi: 10.1007/s11469-007-9086-4. Abstract
     Since the 1990s, there has been a rise in the availability and recreational use of a herbal plant called Salvia divinorum. Numerous internet websites have advertised it for sale as a legal herbal alternative to illegal hallucinogens. Initial data surveying use has indicated many young adults are obtaining and using this herb for its psychoactive properties. Reported methods of ingestion for the plant include chewing, and smoking leaves or fortified extracts. Subjective effects of the plant include, affect changes, psychedelic-like changes in perception, and even loss of consciousness. Although the pharmacological properties and possible antidepressant effects have been studied in recent years, little information is known about potential negative impact resulting from recreational use, and scant information about Salvia divinorum currently exists in the psychological and substance abuse literature. While Salvia divinorum appears to be a substance with some therapeutic potential, it also poses some significant dangers as a substance of varying legal status with a potential for abuse.
130. Addy, Peter H and {Garcia-Romeu}, Albert and Metzger, Matthew and Wade, Jenny, The Subjective Experience of Acute, Experimentally-Induced Salvia Divinorum Inebriation, Journal of Psychopharmacology, vol. 29, no. 4, pp. 426--435, April 2015. doi: 10.1177/0269881115570081. Abstract
     This study examined the overall psychological effects of inebriation facilitated by the naturally-occurring plant hallucinogen Salvia divinorum using a double-blind, randomized, placebo-controlled trial. Thirty healthy individuals self-administered Salvia divinorum via combustion and inhalation in a quiet, comfortable research setting. Experimental sessions, post-session interviews, and 8-week follow-up meetings were audio recorded and transcribed to provide the primary qualitative material analyzed here. Additionally, post-session responses to the Hallucinogen Rating Scale provided a quantitative groundwork for mixed-methods discussion. Qualitative data underwent thematic content analysis, being coded independently by three researchers before being collaboratively integrated to provide the final results. Three main themes and 10 subthemes of acute intoxication emerged, encompassing the qualities of the experience, perceptual alterations, and cognitive-affective shifts. The experience was described as having rapid onset and being intense and unique. Participants reported marked changes in auditory, visual, and interoceptive sensory input; losing normal awareness of themselves and their surroundings; and an assortment of delusional phenomena. Additionally, the abuse potential of Salvia divinorum was examined post hoc. These findings are discussed in light of previous research, and provide an initial framework for greater understanding of the subjective effects of Salvia divinorum, an emerging drug of abuse.
131. Maqueda, Ana Elda, The Use of Salvia Divinorum from a Mazatec Perspective, pp. 55--70, 2018. doi: 10.1007/978-3-319-76720-8_4. Abstract
     Salvia divinorum is a medicinal and psychoactive plant endemic to the Sierra Madre Oriental of Oaxaca, Mexico. The Mazatec people have been using the leaves for centuries in ceremonies for its psychoactive properties and as a treatment for arthritis and inflammation, gastrointestinal problems, headaches, and addictions, among other uses. The active principle of Salvia divinorum, the terpene salvinorin A, is a uniquely potent and highly selective kappa-opioid receptor agonist and, as such, has enormous potential for the development of valuable medications. Among them, the most promising include safe and nonaddictive analgesics, neuroprotectors, short-acting anesthetics that do not depress respiration, antidepressants, anti-inflammatories, medications for the treatment of addiction to stimulants and alcohol, and drugs to treat disorders characterized by alterations in perception. The Mazatec consider Salvia divinorum to be a very powerful plant spirit that should be treated with utmost respect, and the preparation for the ceremony requires a strict regimen. They chew the fresh leaves at night while chanting and praying. In the Western use, the dry leaves are potentiated in extracts to be smoked. A lack of information about the appropriate doses and other considerations while smoking the extracts could result in overwhelming experiences due to the high potency and fast onset of the substance. For the Mazatec, smoking the plant is not the preferred mode. How could we create a bridge between the two perspectives? In this chapter, I will try to clarify the best ways to use Salvia divinorum for medicinal, psychotherapeutic, and inner exploration purposes.
132. Johnson, Matthew W and MacLean, Katherine A and Caspers, Michael J and Prisinzano, Thomas E and Griffiths, Roland R, Time Course of Pharmacokinetic and Hormonal Effects of Inhaled High-Dose Salvinorin A in Humans, Journal of Psychopharmacology, vol. 30, no. 4, pp. 323--329, April 2016. doi: 10.1177/0269881116629125. Abstract
     Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the Salvia divinorum plant, which has been used for hallucinogenic effects. Previous research on salvinorin A pharmacokinetics likely underestimated plasma levels typically resulting from the doses administered due to inefficient vaporization and not collecting samples during peak drug effects. Six healthy adults inhaled a single high dose of vaporized salvinorin A (n = 4, 21 mcg/kg; n = 2, 18 mcg/kg). Participant- and monitor-rated effects were assessed every 2 min for 60 min post-inhalation. Blood samples were collected at 13 time points up to 90 min post-inhalation. Drug levels peaked at 2 min and then rapidly decreased. Drug levels were significantly, positively correlated with participant and monitor drug effect ratings. Significant elevations in prolactin were observed beginning 5 min post-inhalation and peaking at 15 min post-inhalation. Cortisol showed inconsistent increases across participants. Hormonal responses were not well correlated with drug levels. This is the first study to demonstrate a direct relationship between changes in plasma levels of salvinorin A and drug effects in humans. The results confirm the efficacy of an inhalation technique for salvinorin A.
133. Giovannini, Peter and Heinrich, Michael, Xki Yoma’ (Our Medicine) and Xki Tienda (Patent Medicine)—Interface between Traditional and Modern Medicine among the Mazatecs of Oaxaca, Mexico, Journal of Ethnopharmacology, vol. 121, no. 3, pp. 383--399, January 2009. doi: 10.1016/j.jep.2008.11.003. Abstract
     Objectives Little is known about the interface of traditional (generally plant based) medicines and of commercially available pharmaceutical (and related) products. Here we provide a case study to understand how and to what extent traditional and modern medicine have been integrated in an indigenous community and whether these two categories offer a meaningful model for understanding medicine selection. Consequently, this paper explores the use and knowledge of medicinal plants and patent medicines among laypeople living in a rural Mazatec indigenous community in Oaxaca, Mexico. Methods This paper is based on field study over a period of approximately 20 months using participant observation, unstructured and structured interviews including freelisting. The medicinal plant species and commercially available pharmaceuticals were assessed using published biomedical information. Main outcomes The local ethnopharmacopoeias, emic concepts of illness, epidemiology, and case studies on therapeutic choice were documented. We found that self-treatment is the most common first therapeutic choice. Many of the plant species used by Mazatecs have recognized therapeutic properties, in some cases in vivo and in vitro studies point to well defined pharmacological effects, and in a few cases clinical evidence is available. Likewise, people commonly use patent medicines that are effective in the treatment of the most common health conditions. However, we also documented the medicinal use of some toxic plant species (Aristolochia spp.) and of some patent medicines that are held to be unsafe in developed countries (sodium metamizole). Conclusions When looking at a complex pluralistic medical system an approach that goes beyond the externally imposed dichotomic categories of traditional and modern medicine can be very useful to shed light on other dimensions that underlie the local use of medicines. With the increasing integration of the Mazatecs with the outside world, the concomitant use of both types of resources is constantly changing and helps the Mazatecs in their struggle for health.