Wow this is a treasure trove of information on la hoja! I'm glad some good light is finally being shed on her, as opposed to the "pop sensation" of youtube idiocy.

About the mazatec use of this plant, do these papers mean to say that because the leaves as traditionally prepared and used gives only minimal effects, the people who hid the mesoamerican mushroom cult and the use of little leaves from the conquerers for 500 years have no clue as to the power of this plant? Why then the mazatec fears of permanent insanity from using the plant too often or that if the plant is grown near their houses The Sage will curl around them and smother them in their sleep? These sound like warnings from a people who at least have some idea of the magnitude of power within the little leaves... perhaps this is the reason for the cautious preparation and weak product? Not that I am suggesting that the mazatec have an ancient, pre-conquest history with the plant or were its original gardeners, as the J. Ott paper was clear and there probably was a more widespread use of The Sage in the golden age of mesoamerica - I just think that the mazatec have at least some idea of S. divinorum's power.

Not that I have anything but speculation!

AluminumFoilRobots, you raise some good points. They definitely do have a grasp on the power of the plant. Sometimes they use as much as 160 large (hand-sized) leaves, which is a huge dose despite the fact that it's eaten instead of quidded. As to their warnings about the plant causing permanent insanity if not used properly, I find them especially interesting since a very small number of people seem to experience long-term negative psychological consequences after using S. divinorum (see my most on salvia and depersonalization/derealization)... then again, they have similar warnings about mushrooms, so it could just be that these are general warnings applied to visionary substances in Mazatec culture.

On the other hand, there is a certain naïveté in the Mazatec approach: They recognize that it has such powerful potential, and it seems that they often use weaker methods of preparation to mitigate this... but these weaker methods are so highly variable that it almost seems counter-productive. The intensity of the experience when eating leaves depends on how quickly they are eaten, how thoroughly they are chewed, how much the individual salivates, how much saliva is retained in the mouth when swallowing the chewed leaf, etc. What could be a weak dose for one person could be a very strong dose for another; what might be a strong dose for one person could be an uncomfortably powerful dose for another. Much of this variability could be controlled by quidding the leaves; the intensity still depends on the potency of the particular plant and to some extent on how well the leaves are chewed, but on the whole there are a lot less variables involved than in eating or drinking emulsions of the leaves. To me, this seems like strong evidence that the Mazatecs did not experiment too extensively with different ways of ingesting the plant, but instead just employ the same methods that they've found effective with mushrooms or morning glory seeds.

I don't remember reading warnings about the plant smothering you if grown too near a house... do you happen to recall where you came across that tidbit?

Wow, 160 hand-sized leaves! That's basically a full salad bowl!

As to the warnings of insanity, I can see how it could be a blanket warning ( with good reason, there is that ~2% of the population that no dose of psychedelic is good for... I've been responsible for a friend having a terrible experience with mimosa), though I can see it being more applicable to s. Divinorum. I can also see the mazatec logic telling them to use the methods that are effective for teonanacatl and oliloqui, not having the technical knowledge to know about the differences between indoles and neoclerdane diterpenoids!


Also, I believe the bit about the smothering was in the salvia section of Shultz and Hoffman's "Plants of the Gods", though I'm not sure.

And again, thank you for putting this all together!

Here's some notes on another fairly technical dissertation that examines the biosynthetic routes in S. divinorum that form salvinorin A and its neoclerodane brethren. [Since we don't have BB code for superscript text, all references to carbon-13 will simply be written as "13C"]

Kutrzeba, Lukasz. 2009. “Biosynthesis of salvinorin A, a potent hallucinogen from Salvia divinorum Epling & Jativa.” Ph.D. dissertation, Pharmaceutical Sciences: University of Mississippi.


First, a note on extraction of salvinorin A and related compounds: 10 kg fresh leaf were dipped in 1 liter of chloroform for 1 minute, yielding 8.54 g crude extract from which 2.42 g salvinorin A was purified by crystallization from ethanol (0.024% yield fresh weight or 0.2% yield dry weight), indicating efficiency comparable with much more laborious extractions previously reported in the literature. [Incidentally this indicates that dried leaves weigh 12% of the fresh mass, or that 1 g dried leaf is equivalent to 8.25 g fresh leaf]



Terpenoids are generally constructed from one of two pathways, both of which produce isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The mevalonic acid pathway (MVA), also known as the HMG-CoA reductase pathway, was discovered first. The other route is the 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway (MEP/DOXP), sometimes known as the non-mevalonate pathway. Archaea, animals, and fungi utilize the MVA pathway; green algae utilize the MEP pathway; some plants and bacteria are capable of using either.

The proposed biosynthesis route from geranylgeranyl diphosphate is shown below:


Kutrzeba examined the incorporation of 13C in salvinorin A by 13C NMR after feeding with 13C labeled glucose ([1-13C]glucose). Incorporation was entirely consistent with the MEP pathway. Incorporation of 13C in the C-23 methyl ester was speculated to be a result of methylation by enzymatic action of a type III S-adenosyl-L-methionine dependent O-methyltransferase. Labeling present in the acetate ester indicates that the labeled glucose also resulted in labeling of acetyl-CoA:


Experiments using uniformly labeled glucose ([U-13C]glucose) and [1-13C,2,4-2H]deoxy-D-xylulose similarly confirmed incorporation patterns consistent with the MEP pathway. Experiments with [Me-13C]L-methionine were limited due to toxicity, but confirmed that the labeled methyl group incorporated into C-23 in salvinorin A (consistent with the comment on type III SAM-dependent O-methyltransferases above).

Based on isolated genes for the peltate glandular trichomes (the structure to which salvinorin A is localized), Kutrzeba postulates that the terpenoid products of S. divinorum are produced in those structures. He optimized a method for collecting the glandular trichomes by brief abrasion of young leaves with glass beads followed by straining through a series of meshes. He then isolated mRNA from the glands to produce cDNA, which was then sequenced. This turned up the presence of “one carboxy methyltransferase, five acetyl transferases, one diterpene synthase, six dehydrogenases, six reductases, and nine cytochrome P450’s.” At least three acetyltransferases are required to form S. divinorum neoclerodanes (one for C-1 acetylation in salvinorins C, D, and G; one for C-2 acetylation in salvinorins A, C, and E; one for C-17 acetylation in divinatorins C and D), though four or five could be needed depending on how specific the acetyltranferases are for their substrates. Dehydrogenases are required for the formation of the furan ring, for reduction of secondary alcohols to ketones (C-1 in salvinorins A and B, C-2 in salvinorin G), and for reduction of the C-17 alcohol to an aldehyde in divinatorin E; they may also be involved in formation of the lactone ring, though a CYP450 enzyme could similarly mediate that step. A reductase is likely involved in the reduction of the C-3/C-4 double-bond. CYP450 enzymes are involved in the formation of the C-18 acid, oxidation at C-1 and C-2 to form α-oriented hydroxyl moieties, oxygenation at C-12, possibly oxygenation at C-17, and possibly in the formation of the furan ring. The roles of the specific sequenced enzymes were assessed by comparison with known enzymes that have been sequenced and characterized from other plants.

Two possible reaction schemes are proposed for the formation of the furan ring. Kutrzeba suggests that in either case this furan ring formation is likely the first step in the transformation from kolavenol (a simple clerodane structure formed from cyclization of geranylgeranyl diphosphate by a diterpene synthase) to the salvinorin and divinatorin compounds.



Kutrzeba suggests that since the C18 group exists as a free carboxylic acid in only 25% of the terpenoids isolated from S. divinorum (and as the methyl ester in the remainder, including in salvinorin A), we may suppose that methylation via a carboxy methyltransferase occurs early in the biosynthesis.

The carboxy methyltransferase found in the glandular trichomes was isolated and its activity characterized; it was found to be capable of methylating divinatorins A-C and hardwickiic acid, but not salvinorin A acid or salvinorin B acid, again supporting the notion that this methylation occurs early in the biosynthetic pathway.




I was going to refrain from critiquing errors in the paper, but some of them are bothersome enough that I feel obliged to point them out:

“With such exceptions as aminitin, hallucinogenic substances are generally considered physiologically safe.” Aminitin is not a hallucinogenic compound, it’s a toxin that occurs in some species in the genus Amanita (as well as in other genera)… but not in A. muscaria or A. pantherina. The statement is nonsensical. It’s like saying: “With such exceptions as atropine, mashed potatoes are not generally considered hallucinogenic.”

Kutrzeba talks too often of proof: about an experiment “proving the involvement of KOR in modulation of mood states” or that “models proved the hypothesis…” While his sentence construction indicates that English is not his first language, as a scientist he should know that the word “proof” should be assiduously avoided in any but the most extreme circumstances. Data and experiments can support a hypothesis or model, but claiming to prove the hypothesis implies that you know the outcome of every single future experiment that will ever be performed.

Like many others, Kutrzeba cites Valdés et al. 1983 as the source for the claim that S. divinorum has been used for centuries. Valdés et al. note that the use of mushrooms and morning glory seeds were discovered centuries ago, and that all literature on S. divinorum is much more recent. They also reject its identification as pipiltzintzintli and make no claims whatsoever on the antiquity of Mazatec use of the plant. I really don't understand why everyone seems to cite this paper on the subject of the antiquity of S. divinorum use.

..this is great Entropymancer, thanks
will save page and study tonight...

Thanks nen888

There's a lot more to come... these notes aren't particularly organized, I just want to make sure people can have access to the information in these dissertations and theses... they are hard to acquire through interlibrary loans, and they're rarely cited in the literature.

I can promise that it won't be too much longer before a much more comprehensive and organized treatment of Salvia divinorum is available

Lawrence, Jonathan Farrel. 2008. “I. Studies toward the total synthesis of eleutherobin. II. Total synthesis of salvinorin A.” Ph.D. dissertation: Harvard University.

Unless you're working towards synthesis of novel salvinorin analogues, there's not much to recommend reading the full dissertation rather than the much shorter published summary of the work (Scheerer et al. 2007; pdf link below) where the author first reported this total synthesis which yields salvinorin A at 4.5%. After that 2007 publication, a Japanese team reported their own total synthesis with 0.15% yield (Nozawa et al. 2008) which Lawrence discusses. He also summarizes some recent partial synthesis work (Burns & Forsyth 2008).

While synthesis is not an attractive route to salvinorin A due to low yields and the ease of extraction from S. divinorum, it does have implications for the development of novel salvinorin analogues. Many analogues have been explored through semi-synthetic methods (using salvinorin A as a starting material), there are some modifications that cannot be effectively achieved through these semi-synthetic methods. This is really the utility of total synthesis: it allows researchers to explore structural modifications beyond those available using salvinorin A as the starting material. The synthesis reported by Lawrence specifically allows for modifications at the C-5, C-9, and C-12 positions. He also proposes a route to incorporate aromatic substituents in place of the furan ring.

The paper reports Rf values, refractive indices, and data from NMR and IR spectra for: salvinorin B, 8-epi-salvinorin B, and salvinorin A (as well as numerous intermediates in the reported syntheses).


Related Reading

• Scheerer, J.R., J.F. Lawrence, G.C. Wang, and D.A. Evans. 2007. "Asymmetric synthesis of salvinorin A, a potent κ opioid receptor agonist." Journal of the American Chemical Society 129(29): 8968-8969. [pdf from sagewisdom.org]
  
• Nozawa, M., Y. Suka, T. Hoshi, T. Suzuki, and H. Hagiwara. 2008. "Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A." Organic Letters 10(7): 1365-1368. [pdf from sagewisdom.org]
  
• Burns, A.C., and C.J. Forsyth. 2008. "Intramolecular Diels-Alder/Tsuji allylation assembly of the functionalized trans-decalin of salvinorin A." Organic Letters 10(1): 97-100. [pdf from sagewisdom.org]

Lovell, Kimberly M. 2011. “The synthesis and pharmacological evaluation of salvinorin A analogues as opioid receptor probes.” Ph.D. dissertation, Medicinal Chemistry: University of Kansas.

The article starts with a meandering treatment of the history of natural products in medicine, then goes into a largely-satisfying, up-to-date summary of pharmacological work on salvinorin A.

Lovell was a coauthor on Simpson et al. 2009, which looked at the furan ring. She reiterates hepatotoxicity concerns from that paper related to the presence of the furan ring.

Many new analogues are reported beyond those from Simpson et al. 2009. The depiction of one class of compounds is somewhat confusing. I believe there is an error in the figure, that the structures would be correctly represented by replacing “NR2” with “R” (that is to say, I don’t think the R-groups are doubly substituated on the nitrogen, but are instead singly substituated on the adjacent carbon). I’m trying to contact Dr. Lovell to clarify this point. [Edit: Dr. Lovell has confirmed this is a typo, the figure should have "R" in place of "NR2"]



More new compounds (note 188-190 were obtained as mixtures of E and Z isomers)



The paper contains synthesis, physical description, melting point, data from 13C NMR, 1H NMR spectra, and HPLC chromatograms for the reported compounds.

None of the amine or amide derivatives showed significant affinity at μ- or δ-opioid receptors; 162–165 had some affinity for the κ-opioid receptor, with Ki of 410, 510, 300, and 560 nM, respectively (assayed against [3H]U69593 in Chinese hamster ovary cells expressing human opioid receptors). Several of the ketone derivatives proved to have good affinity for the KOR (beyond those reported in Simpson et al. 2009), with Ki of 40 nM (175), 81 nM (116), 36 nM (117), and 31 nM (180). Others showed moderate to weak affinity: 110 nM (171), 220 nM (176) 150 nM (179), and 320 nM (184). In all cases, MOR and DOR affinity was > 1 μM. Among the furan derivatives there were also a couple compounds with high affinity: 8.7 nM (185) and 44 nM (190); also one with moderate/weak affinity: 450 nM (187). Compare these figures with a Ki of 7.4 nM for salvinorin A for the KOR. Also of note, two compounds had moderate MOR affinity: 230 nM (190) and 470 nM (187); two others were weaker: 1300 nM (189) and 1400 nM (185), both roughly equipotent with salvinorin A at that receptor (1370 nM). The only comment with any noteworthy affinity for the DOR was 190 at 670 nM.

The fact that 2-furanyl salvinorin A (175) retained good affinity and efficacy implies that (in terms of the receptor binding pocket) the furan ring is probably not stabilized as much by H-bonding (as Yan et al. 2005 suggest) but instead primarily stabilized through aromatic and hydrophobic interactions (as Singh et al. 2006 suggest).

Summary of structure activity relationship information from the reported compounds:




Lovell also looks at effective salvinorin A delivery. Typically ethanol or DMSO are components of the administration vehicle; unfortunately DMSO and ethanol both affect results of analgesia assays. Lovell considers a β-cyclodextrin, Capsitol®, as a potential alternative and found that 0.25 M capsitol in water was able to dissolve 0.5 mg/ml salvinorin A.



Related reading

• Simpson, D.S., K.M. Lovell, A. Lozama, N. Han, V.W. Day, C.M. Dersch, R.B. Rothman, and T.E. Prisinzano. 2009. "Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors." Organic & Biomolecular Chemistry 7(18): 3748-3756. [pdf from sagewisdom.org]

Part 6 of the talk Entropy posted. You missed including this last segment. the 4 part youtube video is complete though.

Good catch PsilocbeChild, I've edited the link into the post.

And now some notes on another thesis:


Lozama, A. 2010. “Preparation of neoclerodane diterpenes as probes for the opioid receptor system.” Ph.D. thesis, Pharmacy: University of Iowa.

Chapter 1 contains a meandering history of natural products and their roles in drug development and the elucidation of various aspects of neurochemistry, followed by a summary of terpene biosynthesis and clerodane classification… Capable and informative, but old hat after having read so many similar treatments of the subject. Chapter 2 summarizes previous chemical and pharmacological investigations of salvinorin A along with SAR data from previous work with semisynthetic analogues.


The new research undertaken for this paper focuses on exploring more analogues at the C-2 position as well as to explore furan analogues/isostere – this latter aim being much the same as Lovell’s dissertation; Lozama was a coauthor along with Lovell on a paper reporting several such compounds (Simpson et al. 2009).

Since the μ-affinity of herkinorin was not present in its sulfonate analogue, Lozama explored substituted phenyl sulfonates (80–83). In modifying the furan ring, he examined mono- and di-brominated analogues (84 and 85; 84 had been previously reported in Simpson et al. 2007). Considering the opioid activities of salvinicins A and B inspired the synthesis of further analogues (78, 86–89; 78 and 86 had been previously reported in Simpson et al. 2007). Lozama also explored replacing the furan ring with cyclic and aromatic amides (90–96; all six previously reported in Simpson et al. 2009).



Here’s where things get really wild. Lozama employed a variety of dienophiles to undergo Diels-Alder reactions with salvinorin A to form cycloadducts. The chemical properties of furan rings generally and salvinorin A in particular present difficulties for this reaction. The majority of attempted syntheses were unsuccessful, but Lozama was able to produce a handful of cycloadducts (97–99, 102–104); some of these products were deoxygenated to produce a variety of non-heterocyclic analogues (105–107)



Receptor affinity data for these compounds:



A few of the compounds were tested for affinity (but are not listed above): 102 had no affinity at any opioid receptors up to 13 mM, but 103 exhibited Ki = 290 nM at the κ-opioid receptor... impressive for a derivative with so much extra bulk.

The paper also includes complete information on synthesis of each analogue, physical appearance, melting point, 1H- and 13C-NMR spectral data, 1H-NMR spectra, and HPLC chromatograms.






Related reading

• Simpson, D.S., P.L. Katavic, A. Lozama, W.W. Harding, D. Parrish, J.R. Deschamps, C.M. Dersch, J.S. Partilla, R.B. Rothman, H. Navarro, and T.E. Prisinzano. 2007. "Synthetic studies of neoclerodane diterpenes from Salvia divinorum: preparation and opioid receptor activity of salvinicin analogues." Journal of Medicinal Chemistry 50(15): 3596-3603. [pdf from sagewisdom.org]
  
• Simpson, D.S., K.M. Lovell, A. Lozama, N. Han, V.W. Day, C.M. Dersch, R.B. Rothman, and T.E. Prisinzano. 2009. "Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors." Organic & Biomolecular Chemistry 7(18): 3748-3756. [pdf from sagewisdom.org]

McGovern, D.L. 2009. “Salvinorin A: fragment synthesis and modeling studies.” Ph.D. dissertation: Virginia Commonwealth University.


McGovern considers the calculated free binding energies and observed free binding energies for salvinorin A and morphine. For morphine, the calculated value is somewhat higher than the observed value, indicating that not all functional groups are involved in binding (consistent with observations that some functional groups may be removed from morphine without significantly altering binding activity). For salvinorin A, the calculated value is much larger than the observed value, indicating that large portions of the molecule are not involved in binding (again consistent with empirical studies)

McGovern synthesized the A-ring fragment of salvinorin A (methyl 3-acetoxy-4-oxocyclohexane carboxylate; see image below) to investigate whether it might have any affinity for the opioid receptors. No affinity was observed for any opioid receptor subtype (Ki > 10 mM)



Receptor affinity for numerous analogues were considered using a comparative molecular field analysis (CoMFA) technique on salvinorin analogues differing at the C-2 position (analogues differing at other loci were excluded because they tended to have either very high or very low affinity with few mid-range data points). Compounds were divided into two groups based on which radioligand was used to assay affinity. Data from assays with [125I]IOXY were used to generate Model 1 while data from assays with [3H]diprenorphine were used to generate Model 2. Several algorithms for aligning the ligands in the receptor were tested, and it was found that the best fit was obtained with the “receptor-docked alignment, in which many of the molecules’ docked position and/or orientation deviated from salvinorin A (some by as much as 4.5 Å)” while poorer fits were obtained by algorithms that constrained the core of the ligands in the same position and orientation as the core of salvinorin A. This indicates that the analogues likely bind in a manner similar to, but not identical with salvinorin A.

[Refer to figures below] In Model 1, we see a region of limited bulk tolerance (for chains up to about four carbons in length) around the C-2 position, which corresponds with a hydrophobic pocket formed by Y312, Y323, and I316. A region of bulk intolerance was seen behind C-1, corresponding with the region occupied by the intracellular loop EL2. Areas where electronegativity enhances affinity are positioned around esters (C-2, C-7–C-10) or carbonyl oxygens (C-1, C-7). An area where electropositivity would enhance binding is seen also, corresponding to E297 on TM6 [I wonder if a C-3 propanamine or butyramine be able to advantageously access this region considering adjacent region of bulk tolerance]. From Model 2, we see a large electronegative contour around the C-2 position; this contour falls within H-bonding distance of H304, near the extracellular region of TM7. The electropositive region near the C-2 carbonyl oxygen appears to correlate with E209, and could potentially explain the high affinity of some amine analogues (e.g. the β-N-isopropylamine analogue of salvinorin A, which has a reported Ki of 2.3 nM [Béguin et al. 2006]).


Model 1


Model 2




The fact that the high affinity of the β-N-isopropylamine analogue is not shared by its α-epimer, while we see the opposite trend with ester analogues (for which the affinity of the β-epimer is lower than that of the α-epimer) appears to support the docking scheme proposed by McGovern. See the stereoview of the proposed docking scheme:

Nygård, E.A. 2007. “Listening to the sage: the experience of learning from the Salvia divinorum altered state.” Ph.D. dissertation, Transpersonal Psychology: Institute of Transpersonal Psychology.



This is about the touchy-feeliest scholarly paper I’ve read. It culminates in the author “creatively synthesizing” the collected data in the form of sculptures constructed from found art on a local beach. Wow.

One of Nygård’s informants reported that drinking a cup of tea brewed from Artemisia cappilaris (a vasodilator used in traditional Chinese medicine under the name Yin Chen Hao) before using S. divinorum extends the experience and makes the content “easier to grasp.” This was reported by two other informants as well; I suspect Nygård drew his informants from an online discussion group where this combination was in vogue.

Another informant reported developing a massage oil as a vehicle for S. divinorum administration capable of producing a very mild experience.

An informant reported that Banisteriopsis caapi combined synergistically with S. divinorum, allowing access to a more “telempathic” (telepathic/empathic) experience. An informant reported the combination of Peganum harmala and S. divinorum to be substantially more visual and subjectively different than either S. divinorum or P. harmala alone. An informant reported that P. harmala significantly altered the effect of S. divinorum, but had difficulty articulating the nature of this alteration. [It occurs to me that this effect could result from interactions with dopamine; κ-opioid agonists modulate certain parts of the dopamine system in the brain, and harmine/harmaline prevent the metabolism of dopamine by MAO]

One informant commented on the phenomenon of experiencing a headache the day after ingesting S. divinorum, and also noted increased urination for a couple hours after ingesting the plant. He also reported sweating accompanied by a body temperature decrease of 1 °F.

Commonalities in describing the experience:

• Not always fun (11/13)
  
• Enhanced perception of interconnections (9/13)
  
• Intuitions about the nature of reality (9/13) – for some, this was a significant motivation for their use of the plant.
  
• “Transegoic” or transpersonal phenomena (8/13)
  
• Catalyzes creativity (8/13)
  
• Access to transcendent, mystical, or meditative states (7/13)
  
• Utility of the altered state in problem-solving (5/13)
  
• Increased body awareness (4/13)
  
• Enhanced sexual or erotic effects at low dose (3/13)

All participants felt they had substantially changed for the better through the use of S. divinorum. The changes were often unintentional (12/13) and/or gradual (11/13), though sudden changes were not uncommon (5/13). Commonalities in long-term changes after using the plant:

• Transpersonal changes (8/13)
  
• Enhanced emotional control or awareness (7/13)
  
• Increased intuition (6/13)
  
• Prolonged stress reduction (6/13) – Appears to occur in two distinct ways: 1.) through insight into a particular stressor or anxiety while under the influence which confers long-term relief, and 2.) though a relatively short-term (<2 week) “afterglow” which may be experienced regardless of specific insights.
  
• Positive cognitive changes (6/13)
  
• Increased engagement with the present moment (5/13)
  
• Decreased substance use/abuse (4/13)

Tincture was the most-preferred route of administration in this sample, and many felt that the smoked experience was too intense or not conducive to working productively with the altered state. Those who preferred smoking either enjoyed the intensity and found it conducive to the effects they were seeking or because the short duration of effect was more convenient for their life circumstances.

An informant asserted that consensus reality is essentially a fabrication: “This is just a play we’re living in. This is just a dream within a dream, for us to learn from. It’s all for experience. It’s kindergarten. And once you get through that point you get to go make your own worlds!”

“Boundaries disappear since you see everything as consciousness, and you are that. I watched a lizard, which was myself, move across the ground, which was also myself.”

Techniques used to maximize useful effects from S. divinorum:

• “Preloading” – focusing on an intended subject through meditation, prayer, or writing prior to the experience.
  
• Meditation or prayer to establish a conducive mindset (without focus on an intended subject)
  
• Secure the environment
  
• Reduce potential external distractions (light/noise/etc.)
  
• Ritualistic behavior to enhance continuity between experiences

Pandit, D. 2007. “Ligand-based drug design: 1. Conformational studies of GBR 12909 analogues as cocaine antagonists; II. 3D-QSAR studies of salvinorin A analogs as kappa opioid agonists.” Ph.D. dissertation, Chemistry: New Jersey Institute of Technology.


Pandit used comparative molecular field analysis (CoMFA), a type of 3 dimensional quantitative structure activity relationship modeling (3D-QSAR), to explore the binding of salvinorin A analogues modified at the C-2 position – very similar to the analysis performed in McGovern’s 2009 thesis.

She notes that the proposed models for salvinorin A binding to the KOR have generally been based on homology models deriving in part from the structure of rhodopsin (since transmembrane receptors are difficult to crystallize as a result of which no X-ray structure of the KOR yet exists) [This is specifically in reference to Yan et al. 2005; Kane et al. 2006; and Singh et al. 2006]. This method has some significant potential shortcomings considering that homology of at least 50% is recommended to obtain good models using homology modeling techniques, while homology between rhodopsin and the κ-opioid receptor is less than 30%. The CoMFA technique operates independent of the protein structure, and so could provide helpful complementary data.

To ensure the integrity of the method in producing valid results, Pandit used only analogues whose affinity had been tested in a single laboratory in order to eliminate any variation in the data that could stem from subtle differences in protocol. Compounds were aligned using the standard database alignment algorithm of the software (SYBYL). The 2-butanoate analogue was selected as the template for aligning the compounds.

A model was obtained with r^2=0.857. It indicated that binding affinity in the model comes from 47% steric effects and 53% electrostatic effects. It was found that including H-bonding among the modeling criteria decreased the model’s predictive capacity, likely indicating that H-bonding is not a significant factor for binding C-2 substituents.

A steric/electrostatic contour map was generated (poor graphic quality due to the document being provided as a mediocre black & white scan of a color photo):



Green indicates bulk tolerance. Yellow indicates bulk intolerance. Red indicates preference for electronegativity. Blue indicates preference for electropositivity.

To seek validation of the model, Ki were predicted for a number of analogues that have not yet been synthesized, and those with high predicted affinity were recommended to Dr. Prisinzano for synthesis; at the time this paper was published, affinity testing was underway at the Rothman lab, though I’ve yet to see data published on these suggested compounds. The compounds and their predicted affinities are as follows:

Phipps, S.M. 2009. “The neuropharmacological assesment [sic] of Salvia divinorum Epling and Jativa-M.” Ph.D. dissertation: University of Florida.



Wow, what an infuriating paper! Phipps starts off with a typo in the title, and things only go downhill from there. Many times his typos, transposed words, and missing phrases completely disrupt sentences and force the reader to guess at the author’s intended meaning. Not only does he seem to have foregone any proof-reading, the paper doesn’t appear to have even been subjected to a simple spell check. Phipps tips his hat to such pioneers as R. Gordon Wasson, but Wasson (a stickler for proper grammar and lucidly constructed arguments) would have been frankly appalled at such careless writing. Still, the actual experimental data is a very helpful contribution to the field (once you get past the fact that the bar graphs aren’t even labeled when he presents his results!)… I only wish that a modicum of care had been given to its presentation.



Phipps characterized and analyzed the activity of several extracted fractions of S. divinorum (after extracting, each sample was then freeze-dried after rotovapping off excess alcohol in the latter two cases):

Water extract: 10 g leaf in 200 ml water at ~50 °C, agitated by magnetic stir bar for 1 hr. Brownish in appearance. HPLC indicated the presence of two phenolic compounds (caffeic acid [0.1% of extract mass] and rosmarinic acid [0.2% of extract mass]), salvinorin A [below limit of quantification], an unidentified catechin, and an unidentified flavone.

Ethanol extract: 10 g leaf in 200 ml 60% ethanol at ~22 °C, agitated for 1 hr. Greenish in appearance. HPLC indicated the absence of the catechin peak seen in the water extract, and an increase in terpenoid concentration. Salvinorin A constituted 2% of extract mass, caffeic acid 0.04%, and rosmarinic acid 0.6%.

Methanol extract: 10 g leaf in 200 ml 80% methanol at ~22 °C, agitated for 1 hr. Greener than the ethanol extract. HPLC indicated the absence of the catechin peak seen in the water extract, and an increase in terpenoid concentration. Salvinorin A constituted 3.5% of extract mass, caffeic acid 0.03%, and rosmarinic acid 0.7%.

Antidepressant activity was tested by forced swim test and tail suspension test, while an open field test was employed to gauge possible locomotor effects. The dosages employed are said to be based on “the case report by Jones,” but no author by that name is cited in the references. From context, I suspect this is simply another typo, and he meant to refer to the case reports by Hanes (2001, 2003).

In the forced swim test, 25 mg/kg and 50 mg/kg doses of the water extract were administered orally. 50 mg/kg significantly decreased immobility (p < 0.05) in the swim test, but no significant mobility changes in the open field test.

In the tail suspension test, only 50 mg/kg of the water extract (administered orally) significantly decreased immobility (while 25 mg/kg and 100 mg/kg of the same failed to do so). Neither the ethanol or methanol extract had significant effects at 12.5, 25, or 50 mg/kg (orally). Salvinorin A produced no significant effects at 5 or 10 mg/kg (orally), nor at 2.5, 5, or 10 mg/kg intraperitoneally. Needless to say, these results provide some serious food for thought.

The water extract was screened for affinity at the TRPV3 receptor (involved in the perception of warmth on the skin, as well as occurring in the CNS where their role is largely unknown… the choice to screen against this receptor stems from the apparent antidepressant and anxiolytic activity of incensole [a terpenoid from frankincense] at this site). The extract was found to have essentially no affinity.

Dopaminergic activity was examined through use of the compulsive gnawing test. In mice, the dopaminergic drug apomorphine elicits compulsive gnawing when coadministered with other drugs that produce dopaminergic effects (e.g. the dopamine reuptake inhibitor bupropion). Coadministration with salvinorin A produced significant compulsive gnawing (in a dose-dependent manner) at 2.5, 5, and 10 mg/kg i.p., but not at 1 mg/kg i.p or at 5 or 10 mg/kg p.o. (nor did any of the water or alcohol extracts elicit gnawing at 50 mg/kg p.o.) The KOR agonist U-69593 produced no such behavior. The KOR antagonist norBNI (at 10 and 20 mg/kg) failed to antagonize the gnawing elicited by salvinorin A; the gnawing behavior was successfully antagonized by haloperidol (dopamine antagonist). This seems to indicate that the dopaminergic activity of salvinorin A is not mediated through its action at the KOR.


Some limitations of this study: The purpose of oral administration was ostensibly to mimic Hanes’ report of antidepressant effects, but that report involved quidding as the primary route of administration. Oral administration is hardly a useful approximation of buccal absorption. Additionally the water preparation was purportedly designed to mimic traditional preparation on a metate (which would likely break open the glandular trichomes – a point that Phipps mentions), yet simple agitation with a magnetic stir-bar was employed instead (a method not likely to break open trichomes).

Stevens, S.A. 2010. “Extraction and photodegradation of the plant species Salvia divinorum.” Masters thesis, Forensic Science: University of California Davis.


100 mg of powdered S. divinorum was stirred with 15 ml ethyl acetate for 10 minutes, at which point the mixture with filtered and the filtrate washed with 5 ml ethyl acetate. The sample was then diluted to 25 ml with more ethyl acetate and analyzed by GC-FID. This extraction was found to have 111% ± 22% efficiency. The relatively wide standard deviation results from the assumption that powdered leaf would be homogenous in its concentration of salvinorin A, which was evidently not the case – still, the experiment does establish the extraction as having good efficiency. The limit of quantitation for this method was 5 ppm.

Average concentration of salvinorin A in the leaf was 0.398% ± 0.018%.

Solutions of leaf extract in ethyl acetate were left in the hood at ambient temperature in clear sealed containers and analyzed over the course of 12 days, indicating that salvinorin A degraded in solution with a half life of 2.41 days. By contrast, pure salvinorin A in ethyl acetate maintained its concentration, indicating that degradation is facilitated by some plant constituent present in the extract.

Photodegradation of salvinorin A in ethyl acetate was measured by bombarding a 100 ppm solution with 300 nm UV light and testing the concentration after set intervals. Under these high intensity conditions (the radiation from the apparatus being more than double that provided by the sun on a partly cloudy February day), salvinorin A degraded with a half life 5.83 ± 0.77 minutes.

Since salvinorin A is insoluble in water, photodegradation in water approximated by using a solution of 20 ppm salvinorin A in 5% methanol. In this solution, salvinorin A degraded with a half life of 15.9 minutes.

The UV-degraded samples were analyzed for stable breakdown products that might serve as metabolic markers and extend the window of detection. No good candidates were found from degradation in 5% methanol. Two possible candidates were identified from degradation in ethyl acetate, but neither was stable in the presence of UV bombardment, making them relatively poor candidates. Their potential use as biomarkers is also suspect as in vivo metabolism likely differs from ex vivo UV degradation.

Stewart, D.J. 2005. “Phytochemical investigation of Salvia divinorum.” Ph.D. dissertation: University of Mississippi.


Plants grown hydroponically with a nutrient solution providing very little phosphate produced leaves that contained 0.02% salvinorin A (an order of magnitude less than typical leaves). Plants grown in a more phosphorous-rich nutrient solution showed a four-fold increase in salvinorin A over the low-phosphorous plants.

It was found that 14C-labeled mevalonic acid did not incorporated into salvinorin A when that radiolabeled compound was fed to S. divinorum. This indicated that salvinorin A biosynthesis likely did not occur through the MVA pathway (this was prior to Kutrzeba’s experiments demonstrating unequivocally that biosynthesis proceeds via the DOXP pathway, and considering that both Stewart and Kutrzeba were advised by Zjawiony, I wouldn’t be surprised if this was the impetus for Kutrzeba’s study)

Stewart isolated a compound which had not been reported in the published literature. He characterized it using 1H and 13C NMR, and named the compound “divinatorin D.” Unbeknownst to Stewart, another team had recently isolated two new divinatorins, divinatorins D and E (Lee & Ma et al. 2005). This paper was submitted for publication two months before Stewart submitted his dissertation, so their names take precedent (although it was not published until several months after Stewart’s thesis). Stewart’s “divinatorin D” is the compound that is currently recognized as divinatorin E.

Stewart reports some C-2 bioisosteres of salvinorin A that were not included in Prisinzano & Rothman’s 2008 review paper, nor have they been mentioned in any journal publications since (as far as I can recall… admittedly my analogue notes are still begging for organization):



Considering McGovern’s modeling study, I’d be very interested in the affinity of the β-azide as well as the α-bromide and α-chloride (all of which I suspect would have higher affinities than the epimers analyzed in this study).

Optical rotations, 13C-NMR, and MS data are reported for salvinorins A and B, divinatorin A, hardwickiic acid, β-sitosterol, ursolic acid, divinatorin E (named divinatorin D in this paper); previous data points as well as syntheses and 1H-NMR are reported for the C-2 propionate, heptanoate, pivalate, p-bromobenzoate, trichloroethylcarbonate, ethylcarbonate, piperonylate, naphthoate, cyclopropanecarboxylate, butanoate, valerate, hexanoate, formate, trichloroacetate, and trifluoroacetate esters, as well as for the C-2 bromide, chloride, thioacetate, azide, and amide.

Tidgewell, K.J. 2007. “Development of novel analgesics from the neoclerodane diterpene natural product salvinorin A.” Ph.D. thesis, Pharmacy: University of Iowa.


In addition to analogues reported previously (e.g. in Tidgewell et al. 2006), Tidgewell reports several analogues that are not included Prisinzano & Rothman’s 2008 review paper:



The effects of herkinorin and selected analogues on β-arrestin2 (βarr2) translocation were examined. Herkinorin (salvinoryl-2-benzoate), salvinoryl-2-4’-bromobenzoate (92), salvinoryl-2-4’-methoxybenzoate (95), salvinoryl-2-4’-nitrobenzoate (98) are all unable to induce robust translocation of βarr2-GFP to the plasma membrane, even in the presence of GRK2 over-expression. The benzamide bioisostere (115) induces robust translocation both in the presence and absence of GRK2 over-expression. For comparison, morphine can only induce robust translocation in the presence of GRK2 over-expression, while DAMGO induces robust translocation both in the presence and absence of GRK2 over-expression.

Receptor internalization was similarly investigated. DAMGO induces robust MOR internalization (with or without GRK2 overexpression), while morphine can only do so in the presence of GRK2 overexpression. Herkinorin, 92, 95, and 98 are unable to do so in either condition, while 115 induces robust internalization under both conditions. This is consistent with the indicated βarr2 recruitment abilities of these compounds.

Phosphorylation of downstream MAP kinases (ERK1/ERK2) was examined to further probe the signaling of selected analogues. All compounds (herkinorin, 92, 95, 98, and 115) were found to act like DAMGO in terms of inducing an MOR-mediated dose-dependent increase in ERK phosphorylation which is blocked by naloxone

In vivo antinociceptive activity was examined by use of the formalin assay in rats (this assay has two distinct phases: initial chemically-induced pain, and subsequent pain from inflammation). 1 mg/kg herkinorin significantly reduced flinching during peak of the second phase, while 10 mg/kg significantly reduced flinching over the entire second phase. Pretreatment with the opioid antagonist naloxone reversed the observed analgesia. Injection of herkinorin into the contralateral paw (the paw which was not injected with formalin) shows no significant difference from administration of vehicle, indicating that herkinorin acts peripherally rather than centrally (by contrast, morphine is centrally acting and abates flinching regardless of the paw into which it is injected).

In vivo tolerance was examined through the formalin assay, with 10 mg/kg herkinorin administered daily for five days, conducting the formalin assay on the fifth day. There was a slight increase in flinching during the peak (30-35 minutes after formalin injection), but otherwise no significant differences were observed between the analgesic effect (as indicated by number of flinches) on the fifth day versus the first day, indicating no development of tolerance during this period. Herkinorin thus appears to have a reduced potential for development of tolerance compared to other MOR agonist opioids.

Cross-tolerance was examined using morphine-tolerant animals. While morphine and fentanyl showed virtually no analgesia in morphine-tolerant animals, herkinorin (10 mg/kg) showed a significant analgesic response on par with its effect in morphine-naïve animals. This strongly supports the notion that the mechanism of tolerance for herkinorin differs significantly from typical μ-opioid agonists.

In summary, the C-1 carbonyl affects whether the compound exhibits agonist or antagonist activity. Alteration of the C-2 ester linkage to an amide alters receptor regulation. Addition of substituents to the benzene ring of herkinorin alters both affinity and selectivity.

An improved extraction method was reported. Leaf was steeped in xylene at room temperature overnight, twice. Solvent was removed, and the resulting green tar was recrystallized first from methanol, then from ethyl acetate/hexanes to yield salvinorin A.

Syntheses, 1H-NMR data (and spectra in an appendix), IUPAC name, melting point, etc. reported for numerous analogues.

[Tidgewell mistakenly states that J.B. Johnson was from Sweden; he was actually American, though his most significant paper mentioning S. divinorum was published in a Swedish journal of ethnological studies (the article itself was in English)]

Valdés, Leander Jerome Julian, III. 1983. “The pharmacognosy of Salvia divinorum (Epling & Jativa-M): an investigation of ska Maria Pastora.” Ph.D. thesis, Pharmacognosy: University of Michigan.


[This thesis is from an era where works were composed on a typewriter, and makes me reflect on how much I take the tools of modern word processing for granted. Simple formatting (underlining text, applying diacritics) took much more than a few simple keystrokes. Editing must have been painstaking labor… you couldn’t simply add a paragraph or modify a sentence without having to retype an entire chapter. And yet the paper appears to have been edited more capably than some modern theses composed using technology that makes editing a trivial feat.]

For background reading on Mazatec culture, Valdés recommends:

• Villa Rojas, A. 1955. Los Mazatecos y el Problema Indígena de la Cuenca del Papaloapan. México.
  
• Benitez, F. 1975. Los Indios de Mexico. Volume III. México.

Traditional names: ska María Pastora, ska María, ska Pastora, hojas de María, hojas de la Pastora, hierba de María, yerba de María, la María.

An account not in my notes, from Roquet 1971:


From unpublished field notes of Alvarez de Castillo: 25 to 40 pairs were crushed by hand in a little water and served from a gourd for divination or curing of illness. The healer prayed to the saints who would cure the patient.

Valdés includes much of an account of a Mazatec ceremony from Díaz 1975. This includes the curandera’s prayer chant (much resembling that of Don Alejandro in Valdés et al. 1983). The leaves were counted out in pairs (for a total of 25 to 50 pairs) and passed through copal smoke while the curandera chanted, after which they were crushed by hand in a gourd full of water. “The subject was encouraged to listen to the Shepherdess (Salvia) sing and relate the experience to the shaman.” It was said that madness could result if one did not abstain from sex for one week prior to the ceremony.

Díaz 1975 also reported the use of S. divinorum in the training of shaman. One progresses from S. divinorum to R. corymbosa, and ultimately to Psilocybe spp.

Valdés says that dried leaves sent to Hofmann were found to be inactive. This appears consistent with Wasson’s comments in the personal communication (which has since been published; see Valdés 1999A) from which Valdés inferred this information. Still, we know that salvinorin A is in fact quite stable, so the lack of activity must have resulted from the precise method of ingestion... after all oral administration of S. divinorum is finicky business.

Valdés presents the details of Díaz’s chemical investigations. Upon seeing Díaz’s procedures, it’s clear that his cat assay was wholly ineffective. The separation methods were aimed more toward isolating alkaloids – a mistake that’s quite understandable. But the fraction which tested “positive” could not possibly have contained any salvinorin A (or related compounds). Further, the one fraction from Valdés extraction experiments which likely would have contained salvinorin A (a precipitate obtained by extracting the leaves with ethanol, concentrating the ethanol, then adding an equal quantity of water) was not assayed. Díaz reports a number of observed Rf values but unfailingly fails to report the eluent used to obtain them. Shoddy work on the whole.

Valdés comments on the “jealous and secretive nature of native shamans.”

Valdés reports (presumably from Don Alejandro) that one should be at least 30 years old before beginning to train as a curandero, to ensure the degree of maturity necessary for the task.

Don Alejandro relays an interesting origin myth tying Christianity and curanderismo:


There is also a vivid description of Don Alejandro’s typical experience of visiting heaven through the use of S. divinorum.

Valdés approximates the weight of fresh leaves used by the Mazatecs at 2.5 g/leaf.

Don Alejandro had some Coleus spp. plants growing near his house. When questioned about them, he said that they were not medicinal but rather that his daughter had bought them at the market because they were pretty.

According to Don Alejandro, eating too many Psilocybe spp. mushrooms can “leave one crazy.” The Wassons had similarly noted a belief that misuse of the mushrooms can lead to madness (Wasson & Wasson 1957)

Valdés was unable to produce any seeds from self-pollination experiments, and cited a personal communication from one M.L. Wilcox supporting the notion that the plants are self-sterile. He did produce seeds through cross-pollination, but a thermostat mishap killed the seeds before he could determine if they were viable.

“The plant grows best in partial to full sunlight in rich soil with heavy watering and good drainage.”

According to Emboden (Valdés cites a single page from the 1980 Ethno-Pharmacology Society Newsletter), Epling was terminally ill at the time he was composing the description of S. divinorum, and this might have contributed to the inclusion of an error (with regards to flower color).

Although Emboden had already printed a corrected description of the plant in 1979, and Valdés was familiar with Emboden’s work (citing it in his bibliography), Valdés composed his own revised description of the species.

Valdés describes in detail his protocols for animal assays examining the effect of S. divinorum extracts on conditioned feeding behavior in rats, on emergent behavior (limb flick assay) in cats, and on motor function in mice. I can’t help but be repulsed by some of the methods employed, particularly with regards to cats. Throughout the literature mention is made of Valdés injecting tannin-rich extracts in cats, leading to kidney failure in two cats (one of which died)… what isn’t mentioned is that some of the cats (at least one; number unspecified) also died before ever being given a drug; they were simply unable to survive the “conditioning period” after being acquired by the researchers.

“[T]here is no definitive evidence that divinorin A is a hallucinogen…” [nor would there be for another decade, a situation which Valdés could have remedied by simply ingesting the compound]

Salvinorin A: Rf = 0.68 with CHCl3/MeOH/H2O (100:10:1); Rf = 0.83 with hexane/ethyl acetate (1:2) [in both cases the compound was visualized as a purplish-red spot using p-anisaldehyde reagent]; mp 242–244 °C... [more physical data given in the paper]

Salvinorin B: Rf = 0.58 with CHCl3/MeOH/H2O (100:10:1); Rf = 0.71 with hexane/ethyl acetate (1:2) [in both cases the compound was visualized as a purplish-red spot using p-anisaldehyde reagent]; mp 251–254 °C... [more physical data given in the paper]

Rasakham, K. 2008. “Kappa opioid receptor regulation of ERK1/2 MAP kinase signaling cascade: molecular mechanisms modulating cocaine reward.” Ph.D. dissertation, Psychology: Northeastern University.

A very well-written paper. So well-written that all of the salient points are capably summarized in the abstract. The reader only needs to consult the main text if they're interested in details on the employed methodologies.

This thread has now covered all relevant dissertations and theses published as of two months ago. Considering that three were published in 2010 and two in 2011, I think we can expect more to be published in the coming months or years, but for now we're up to date.

In reading the papers, I noticed that one cited some patent applications. This is of course another source of information that I hadn't previously considered. Fortunately patent databases are readily searchable and the documents freely available. I've found three patents and ten patent applications that have relevance to S. divinorum and salvinorin A. Many of these are continuations (or continuations in part) of earlier applications; I have elected to leave these earlier applications off the list and include only their most recent incarnations. In one case, an application seeks to expand a patent that has already been granted, and in that case I've included both the patent (Béguin et al. 2009) and the most recent application (Béguin et al. 2010).

There is one application that I can't help but remark on: Cummins 2009 application, "Oral compositions containing botanical extracts." In itself, this is a fairly uninteresting attempt to grab up intellectual property by including as many potential preparations as possible. What makes it entertaining is that the patent (if granted) would be assigned assigned to Colgate-Palmolive... So strange but true, Colgate is seeking a patent on toothpaste that includes S. divinorum extract as a constituent!

Anyway, on to the links:

• Béguin, C., W.A. Carlezon Jr., B. Cohen, M. He, D.Y. Lee, M.R. Richards, and L.-Y. Liu-Chen. 2009. "Salvinorin derivatives and uses thereof." US Patent 7629475, filed 14 Mar 2005, issued 08 Dec 2009. [Link]
  
  
• Béguin, C., W.A. Carlezon Jr., B. Cohen, M. He, D.Y. Lee, M.R. Richards, and L.-Y. Liu-Chen. 2010. "Salvinorin derivatives and uses thereof." US Patent Application No. 12/851758 filed 06 Aug 2010. Publication No. 2010/0324131 A1 published 23 Dec 2010. [Link]
  
  
• Bohn, L.M., and T.E. Prisinzano. 2009. "Opioid receptor ligands." US Patent Application No. 11/917314 filed 16 Jun 2006. Publication No. 2009/0088466 A1 published 02 Apr 2009. [Link]
  
  
• Cummins, D. 2009. "Oral compositions containing botanical extracts." US Patent Application No. 12/243669 filed 01 Oct 2008. Publication No. 2009/0087501 A1 published 02 Apr 2009. [Link]
  
  
• Fitzgerald, S.P., R.I. McConnell, P.A. Lowry, and E. Benchikh. 2010. "Immunoassay." US Patent Application No. 12/662651 filed 27 Apr 2010. Publication No. 2010/0291600 A1 published 18 Nov 2010. [Link]
  
  
• González, E.J. 2011. "Chewing gum formula for enhancing psycho-spirituality." US Patent Application No. 12/541163 filed 14 Aug 2009. Publication No. 2011/0038915 A1 published 17 Feb 2011. [Link]
  
  
• Holaday, J.W., and P. Magistro. 2011. "Hybrid opioid compounds and compositions." US Patent Application No. 13/24298 filed 09 Feb 2011. Publication No. 2011/0245287 A1 published 06 Oct 2011. [Link]
  
  
• Michalow, A. 2010. "Methods for regulating neurotransmitter systems by inducing counteradaptations." US Patent Application No. 12/627018 filed 30 Nov 2009. Publication No. 2010/0173926 published 08 Jul 2010. [Link]
  
  
• Oronsky, B.T., and N.C. Oronsky. 2009. "Combination therapy for bipolar disorder." US Patent Application No. 12/422156 filed 10 Apr 2009. Publication No. 2009/0311347 A1 published 17 Dec 2009. [Link]
  
  
• Prisinzano, T.E. 2010. "Therapeutic compounds." US Patent Application No. 12/513093 filed 02 Nov 2007. Publication No. 2010/0179217 A1 published 15 Jul 2010. [Link]
  
  
• Prisinzano, T.E., and R.B. Rothman. 2010. "Opioid receptor ligands and methods for their preparation." US Patent 7728001, filed 12 Sep 2005, issued 01 Jun 2010. [Link]
  
  
• Riggs-Sauthier, J., B.-L. Deng, and T. Riley. 2010. "Oligomer-opioid agonist conjugates." US Patent Application No. 12/558395 filed 11 Sep 2009. Publication No. 2010/0048602 A1 published 25 Feb 2010. [Link]
  
  
• Zjawiony, J., H. Fahmy, D.J. Stewart, and B. Roth. 2010. "Agents with selective κ-opioid receptor affinity." US Patent 7687538, filed 29 Jul 2005, issued 30 Mar 2010. [Link]