OPEN Foundation

Salvia / Salvinorin A

Dimensions of consciousness and the psychedelic state

Abstract

It has often been suggested in the popular and academic literature that the psychedelic state qualifies as a higher state of consciousness relative to the state of normal waking awareness. This article subjects this proposal to critical scrutiny, focusing on the question of what it would mean for a state of consciousness to be ‘higher’. We begin by considering the contrast between conscious contents and conscious global states. We then review the changes in conscious global state associated with psychedelic drug use, focusing on the effects of two serotonergic hallucinogens: psilocybin and lysergic acid diethylamide. Limiting our review to findings obtained from lab-based experiments and reported in peer-reviewed journals, we prioritize the more common and reliably induced effects obtained through subjective questionnaires and psychophysical measures. The findings are grouped into three broad categories (sensory perception, cognitive function, and experiences of unity) and demonstrate that although certain aspects of consciousness are improved or enhanced in the psychedelic state, many of the functional capacities that are associated with consciousness are seriously compromised. Psychedelic-induced states of consciousness are indeed remarkable in many ways, but it is inappropriate to regard them as ‘higher’ states of consciousness. The fact that psychedelics affect different aspects of consciousness in fundamentally different ways provides evidence against the unidimensional (or ‘level-based’) view of consciousness, and instead provides strong support for a multidimensional conception of conscious states. The final section of the article considers the implications of this analysis for two prominent theories of consciousness: the Global Workspace Theory and Integrated Information Theory.

Bayne, T., & Carter, O. (2018). Dimensions of consciousness and the psychedelic state. Neuroscience of consciousness2018(1), niy008., 10.1093/nc/niy008
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The Use of Salvia divinorum from a Mazatec Perspective

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.

Maqueda, A. E. (2018). The Use of Salvia divinorum from a Mazatec Perspective. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 55-70. 10.1007/978-3-319-76720-8_4
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Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway

Abstract

This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 μM), or norbinaltorphimine (norBIN, 1 μM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.
Dong, H. P., Zhou, W., Ma, X. X., He, Z. Z., & Wang, Z. H. (2018). Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway. Brazilian Journal of Medical and Biological Research51(5). 10.1590/1414-431X20176714
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Evaluating the abuse potential of psychedelic drugs for medical use in humans

Abstract

Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g. MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e. no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e. schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e. drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates [59]. We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence.
Heal, D. J., Gosden, J., & Smith, S. L. (2018). Evaluating the abuse potential of psychedelic drugs for medical use in humans. Neuropharmacology. 10.1016/j.neuropharm.2018.01.049
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Salvinorin A reduces neuropathic nociception in the insular cortex of the rat

Abstract

BACKGROUND:
Neuropathic pain is one of the most important challenges in public health. The search for novel treatments is important for an adequate relief without adverse effects. In this sense salvinorin A (SA), the main diterpene of the medicinal plant Salvia divinorum is an important antinociceptive compound, which acts as a potent agonist of kappa opioid receptor (KOR) and cannabinoid CB1 receptors.
METHODS:
We evaluated nociceptive responses in a neuropathic pain model induced by the sciatic nerve ligature (SNL) in the right hind paw, after the microinjection of SA, Salvinorin B (SB), KOR and CB1 antagonists directly in the insular cortex (IC) in male wistar rats.
RESULTS:
We found a potent antinociceptive effect with the administration of SA. Moreover, this effect was blocked by the administration of a KOR antagonist as well as the administration of a CB1 antagonist.
CONCLUSION:
Salvinorin A has a potent antinociceptive effect when is administered centrally in the IC by the interaction with KOR and CB1 receptors.
SIGNIFICANCE:
We show evidence on the effectiveness of the administration of salvinorin A in the IC in a rodent model of neuropathic pain. These results support the use of novel compounds like SA as a therapeutic alternative for neuropathic pain relief.
Coffeen, U., Canseco‐Alba, A., Simón‐Arceo, K., Almanza, A., Mercado, F., León‐Olea, M., & Pellicer, F. (2017). Salvinorin A reduces neuropathic nociception in the insular cortex of the rat. European Journal of Pain. 10.1002/ejp.1120
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Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species

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.
Hatipoglu, S. D., Yalcinkaya, B., Akgoz, M., Ozturk, T., Goren, A. C., & Topcu, G. (2017). Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species. Phytochemical Analysis. 10.1002/pca.2703
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Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species

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.
Hatipoglu, S. D., Yalcinkaya, B., Akgoz, M., Ozturk, T., Goren, A. C., & Topcu, G. (2017). Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species. Phytochemical Analysis. 10.1002/pca.2703
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Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats

Abstract

Ethnopharmacological relevance

Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists.

Aim of the study

Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans.

Material and methods

Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30 min, 3 h and 24 h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects.

Results

Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes.

Conclusion

The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications.

Simón-Arceo, K., González-Trujano, M. E., Coffeen, U., Fernández-Mas, R., Mercado, F., Almanza, A., … & Pellicer, F. (2017). Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats. Journal of Ethnopharmacology206, 115-124. 10.1016/j.jep.2017.05.016
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Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:
Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists.
AIM OF THE STUDY:
Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans.
MATERIAL AND METHODS:
Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects.
RESULTS:
Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes.
CONCLUSION:
The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications.
Simón-Arceo, K., González-Trujano, M. E., Coffeen, U., Fernández-Mas, R., Mercado, F., Almanza, A., … & Pellicer, F. (2017). Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats. Journal of Ethnopharmacology206, 115-124. 10.1016/j.jep.2017.05.016
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Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

Abstract

Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a κ-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0.6 ± 0.2 nM at κ; >10000 nM at μ and δ). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.
Sherwood, A. M., Crowley, R. S., Paton, K. F., Biggerstaff, A., Neuenswander, B., Day, V. W., … & Prisinzano, T. E. (2017). Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability. Journal of Medicinal Chemistry60(9), 3866-3878. 10.1021/acs.jmedchem.7b00148
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27 June - Spiritual & Existential Dimensions in Psychedelic Care: Challenges & Insights

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