OPEN Foundation

Salvia / Salvinorin A

Editorial (Thematic Issue: Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’)

Editorial

Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’

We are witnessing a revival of psychedelic research. An increasing number of studies investigating the therapeutic use of psychedelics are currently underway at some of the most renowned universities. Dedicating a second issue of ‘Current Drug Abuse Reviews’ to psychedelics aims to keep up with this blossoming field. With the availability of modern scientific instruments, psychedelic research is once again gaining a firm foothold in academia.

The idea of this special issue originated at the Interdisciplinary Conference on Psychedelic Research, organised by the OPEN Foundation in 2012. OPEN was founded in 2007 in the Netherlands, in order to stimulate and advance scientific research into psychedelics. This special issue of CDAR takes an interdisciplinary approach to the topic of psychedelics and mental health, while maintaining a particular focus on applications of psychedelics in the fields of substance abuse and addiction. This special issue also takes a critical look at some widespread assumptions about psychedelics, introduces new ideas and suggests novel directions for future research.

Kortekaas, R., & Breeksema, J. J. (2015). Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’. Current Drug Abuse Reviews, 7(2), 69-70. https://dx.doi.org/10.2174/1874473708666150120114604

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Articles in this special issue:

Editorial (Thematic Issue: Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’)
Ayahuasca, Psychedelic Studies and Health Sciences: The Politics of Knowledge and Inquiry into an Amazonian Plant Brew
Crisis Intervention Related to the Use of Psychoactive Substances in Recreational Settings – Evaluating the Kosmicare Project at Boom Festival
Psychedelics as Medicines for Substance Abuse Rehabilitation: Evaluating Treatments with LSD, Peyote, Ibogaine and Ayahuasca
A Qualitative Report on the Subjective Experience of Intravenous Psilocybin Administered in an fMRI Environment
Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders

Editorial (Thematic Issue: Introduction to 'Beneficial Effects of Psychedelics with a Special Focus on Addictions')

Editorial

Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’

We are witnessing a revival of psychedelic research. An increasing number of studies investigating the therapeutic use of psychedelics are currently underway at some of the most renowned universities. Dedicating a second issue of ‘Current Drug Abuse Reviews’ to psychedelics aims to keep up with this blossoming field. With the availability of modern scientific instruments, psychedelic research is once again gaining a firm foothold in academia.

The idea of this special issue originated at the Interdisciplinary Conference on Psychedelic Research, organised by the OPEN Foundation in 2012. OPEN was founded in 2007 in the Netherlands, in order to stimulate and advance scientific research into psychedelics. This special issue of CDAR takes an interdisciplinary approach to the topic of psychedelics and mental health, while maintaining a particular focus on applications of psychedelics in the fields of substance abuse and addiction. This special issue also takes a critical look at some widespread assumptions about psychedelics, introduces new ideas and suggests novel directions for future research.

Kortekaas, R., & Breeksema, J. J. (2015). Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’. Current Drug Abuse Reviews, 7(2), 69-70. https://dx.doi.org/10.2174/1874473708666150120114604

Link to full text

Articles in this special issue:

Editorial (Thematic Issue: Introduction to ‘Beneficial Effects of Psychedelics with a Special Focus on Addictions’)
Ayahuasca, Psychedelic Studies and Health Sciences: The Politics of Knowledge and Inquiry into an Amazonian Plant Brew
Crisis Intervention Related to the Use of Psychoactive Substances in Recreational Settings – Evaluating the Kosmicare Project at Boom Festival
Psychedelics as Medicines for Substance Abuse Rehabilitation: Evaluating Treatments with LSD, Peyote, Ibogaine and Ayahuasca
A Qualitative Report on the Subjective Experience of Intravenous Psilocybin Administered in an fMRI Environment
Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders

Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders

Abstract

Pharmacological treatments are available for alcohol, nicotine, and opioid dependence, and several drugs for cannabis-related disorders are currently under investigation. On the other hand, psychostimulant abuse and dependence lacks pharmacological treatment. Mesolimbic dopaminergic neurons mediate the motivation to use drugs and drug-induced euphoria, and psychostimulants (cocaine, amphetamine, and methamphetamine) produce their effects in these neurons, which may be modulated by the opioid system. Salvinorin A is a κ-opioid receptor agonist extracted from Salvia divinorum, a hallucinogenic plant used in magico-ritual contexts by Mazateca Indians in México. Salvinorin A and its analogues have demonstrated anti-addiction effects in animal models using psychostimulants by attenuating dopamine release, sensitization, and other neurochemical and behavioral alterations associated with acute and prolonged administration of these drugs. The objective of the present article is to present an overview of the preclinical evidence suggesting anti-addictive effects of salvinorin A and its analogues.

dos Santos, R. G., Crippa, J. A., Machado-de-Sousa, J. P., & Hallak, J. E. (2015). Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders. Current Drug Abuse Reviews, 7(2), 128-132. https://dx.doi.org/10.2174/1874473708666150107122741

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Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues

Abstract

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.

Riley, A. P., Groer, C. E., Young, D., Ewald, A. W., Kivell, B. M., & Prisinzano, T. E. (2014). Synthesis and Kappa Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues. Journal of medicinal chemistry. https://dx.doi.org/10.1021/jm501521d
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Online questionnaire about the use of Salvia

OLYMPUS DIGITAL CAMERADid you ever use Salvia divinorum? Researchers at Harvard University are eager to know what you experienced. In a completely anonymous online questionnaire you will be asked questions about your use, experiences, and some personality characteristics. The outcomes will be used for a scientific study. Participation is without any obligations, and no personally-identifiable information will be collected. Answering all questions will approximately take 45 minutes to 1 hour. The results of this study will be published in a renowned scientific magazine. Would you like to share your Salvia experience(s) and contribute to science? Then this is your chance!

Click here to participate.

Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

Abstract

The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.

Polepally, P. R., Setola, V., Vardy, E., Roth, B. L., Mosier, P. D., & Zjawiony, J. (2014). Michael Acceptor Approach to the Design of New Salvinorin A-Based High Affinity Ligands to the Kappa-Opioid Receptor. Planta Medica, 78(5), 818-829. https://dx.doi.org/10.1016/j.ejmech.2014.07.077
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Does the Nervous System Have an Intrinsic Archaic Language? Entoptic Images and Phosphenes

Abstract

Psychoactive plants have been consumed by many cultures, cults and groups during religious rituals and ceremonies for centuries and they have been influential on the eruption of the many images, secret and religious symbols, esoteric geometrical shapes, archetypes, religious figures, philosophy of religions since the dawn of Homo sapiens. Some of the psychoactive plants used for religious purposes were; narcotic analgesics (opium), THC (cannabis), psilocybin (magic mushrooms), mescaline (peyote), ibogaine (Tabernanthe iboga), DMT (Ayahuasca and phalaris species), peganum harmala, bufotenin, muscimol (Amanita muscaria), Thujone (Absinthe, Arthemisia absinthium), ephedra, mandragora, star lotus, salvia divinorum etc. An important property of these natural chemicals is to induce the human psyche to perceive some optical forms and shapes, which are existent in the subconscious and collective unconsciousness, and which emerge during some certain trance states and ASCs. Some of these simple geometric forms are called entoptic images and phosphenes. Entopic images and phosphenes have been found in various cultural art work and the drawings of cave walls, which were formed during the shamanic religious rituals since the Neolithic times. Also entoptic images exist in many folkloric, traditional and cultures geometrical shapes. Long before the creation of languages, visual perception and information was the only source for the mankind to perceive outer world, as it is the only one in the primate world. This article reviews the possibility of an ancient forgotten visual sign and symbol language, which is genetically existent in the human brain and that, emerges out during ASCs, trance states and the consciousness altered by the psychoactive plants. The basics of this geometrical sign and symbol language may have generated the formation of some archetypal symbols and concepts, which are yet to be discovered. Near to this, emerging of many attributes of the sub-or-un-consciousness, during those “psychedelic plant journeys” had had a prodigious impact on the formation and creation of many religious “figures, characters, creatures, archetype images” that today exist, not only in the mythology, but also in many religions, as well, such as angels, spirits, Jinns, demons, Satan, mythological creatures, supra-natural creatures, gods, and goddesses. Mystical and religious experiences during the rituals using psychoactive plants may have also helped the archaic ancestral information, coded in the limbic system, to come out onto the consciousness, which may also have helped the evolution of the hominoids and Homo sapiens.

Sayin, H. U. (2014). Does the Nervous System Have an Intrinsic Archaic Language? Entoptic Images and Phosphenes. Neuroquantology, 12(3), 427-445. https://dx.doi.org/10.14704/nq.2014.12.3.756
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The Therapeutic Potentials of Salvinorin A

Salvia divinorum is a sprawling perennial herb found in the Sierra Mazatec region of Mexico. It has a history of use as a divinatory psychedelic, and has been widely available since the mid 1990s primarily as a smoked herb. Jean Basset Johnson was the first to document its use in 1939. R. Gordon Wasson, better known for his ‘discovery’ of the psilocybin mushroom, continued to document the Salvia divinorum herb and eventually confirmed its psychoactivity on himself in ‘A new Mexican psychotropic drug from the mint family’ published in Botanical Museum Leaflets (1962). Salvia divinorum remained an obscure psychedelic until the mid 1990s when Daniel Siebert, a then still unknown independent researcher, began self experimentation and documented its effects extensively. The Salvia divinorum experience is rather elusive, that is to say its effects seem to vary even more tremendously then other psychedelics, both between people and across sessions.

The molecule, or more specifically; ‘neoclerodane diterpenoid’ (not to be confused with ‘alkaloid’, which always contains a nitrogen atom), behind the dramatic effects of Salvia divinorum is the extremely potent Salvinorin A. “Essentially inactive if taken orally”, says Valdés in ‘Salvia divinorum and the unique diterpene hallucinogen, Salvinorin A’ (1994), “the compound is effective in doses of 200 to 500 mcg when smoked”. This makes Salvinorin A the first documented diterpene hallucinogen and the most potent naturally occurring hallucinogen thus far isolated”. “Salvinorin A”, says Siebert in ‘Salvia divinorum and Salvinorin A: new pharmacological findings’ (1994), “produces effects which are subjectively identical to those experienced when the whole herb is ingested. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity”.

This compound is interesting for many reasons, but recently it has come to the attention of researchers because it acts as a kappa opioid receptor agonist (Roth, 2002). It is the first known compound acting on this receptor that is not an alkaloid. The κ-opioid receptor is a protein and is one of four related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, motor control, and mood. Wang et al. (2013) demonstrated that “administration of Salvinorin A after hypoxia/ischemia preserves cerebral autoregulation via the κ-opioid receptor pathway”, ultimately presenting a novel opportunity for the prevention of prenatal cerebral hypoxia/ischemia. Fichna et al. (2012) investigated the effect of Salvinorin A (administered intraperitoneally once a day) on acute pain, oedema and formalin-induced persistent pain in mice. The researchers concluded that Salvinorin A exerts analgesic actions and also shows moderate anti-inflammatory effects.

More recently Salvinorin A was used to research the relationship between the claustrum (a sheet of neurons which is attached to the neocortex in the center of the brain) and consciousness. Stiefel et al. (2014) suggests that “the consciousness-altering effects of S. divinorum/salvinorin A are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the cortex, mainly in prefrontal areas”. This finding leads them to believe that Salvinorin A might be new evidence in favour of the ‘Crick and Koch theory’ (1990) which claims that the claustrum is the “conductor of consciousness”, not unlike the philosopher René Descartes claimed for the pineal gland.

Dr. Karl Hanes, researcher at the ‘Cognitive-Behavioural Treatment Centre’ in Melbourne Australia, reported on a treatment-resistant depressed patient (Ms. G) under his care and the management of her symptoms of depression through Salvia (2001). “During a review consultation some seven months after discontinuing cognitive-behavioural therapy”, says Hanes, “Ms. G claimed to have found relief from her symptoms of depression with use of the herb Salvia divinorum. A HAM-D score of 2 confirmed remission of her symptoms of depression at this time. Ms. G claims that she discovered its antidepressant effects accidentally after smoking the herb and had later developed a method of oral consumption which she claimed maintained its antidepressant effects even after she abstained from using it for up to a week”. Preliminary research (animal models) asserts Ms. G’s case and shows that Salvinorin A might become a therapeutic agent in the treatment of depression.

Carlezon et al. (2006) found that Salvinorin A “decreased extracellular concentrations of dopamine within the nucleus accumbens, a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT)”. Butelman et al. (2004) showed that “the naturally occurring hallucinogen Salvinorin A produces discriminative stimulus effects similar to those of a high efficacy κ-agonist in non-human primates” (rhesus monkeys). Much research is done in the field of addiction and focuses primarily on Salvinorin A’s supposed anti-addictive effects. Activating the kappa-opioid receptors (KORs or KOPrs) produces anti-addictive effects by regulating dopamine levels in the brain (Kivel et al., 2014). The κ-opioid receptor may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction. “Activation of KORs”, says Tomasiewicz (2008), “reduces the reward-related effects of cocaine. Inasmuch as cocaine-induced behavioral stimulation in rodents may model key aspects of enhanced mood in humans, these findings raise the possibility that KOR agonists might ameliorate symptoms of conditions characterized by increased motivation and hyperfunction of brain reward systems, such as mania and stimulant intoxication”. These are obviously very exciting effects. “The development of KOPr-selective agents with improved drug-like characteristics” says Carlezon (2009), “would facilitate preclinical and clinical studies designed to evaluate the possibility that KOPrs are a feasible target for new medications”.

“Unfortunately”, says Kivel (2014), “classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use”. Acute activation of kappa opioid receptors produces ‘anti-cocaine’ like effects, but because of considerate adverse effects their clinical use has remained limited (Simonson, 2014). Salvinorin seems to sidestep this problem. “Salvinorin A and its semi-synthetic analogs”, says Simonson (2014), “have been shown to have potent KOPr agonist activity and may induce a unique response with similar anti-cocaine addiction effects as the classic KOPr agonists but with a different side effect profile”. Salvinorin A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with remarkable reduction of side effects.

However, there are still many obstacles to be overcome. For instance, a major problem is Salvinorin A’s rapid metabolism in the human body. Because of the short length of activation, Salvinorin as such will probably not be a good candidate for clinical development. In an effort to re-engineer Salvinorin’s pharmacokinetics, researchers have sought to produce kappa-opioid receptor agonists based on the structure of Salvinorin A that do have the desired length of activity. “While work in this field is still in progress”, says Kivel (2014), “several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects”. These new analogs will eventually provide the characteristics sought after by clinical researchers for treatment.

Given the reemergence of interest into psychedelics and their potential as therapeutic agents it is hardly surprising that Salvia divinorum would attract attention. Salvia manifests a powerful psychedelic experience which is grounded in a unique neurochemical process which seems to have anti-addictive potential. It is surely a substance worth exploring within the psychiatric and psychopharmacological disciplines in the future.


 
References
Butelman, E. R., Harris, T. J., & Kreek, M. J. (2004). The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology, 172(2), 220-224.
Carlezon, W. A., Béguin, C., DiNieri, J. A., Baumann, M. H., Richards, M. R., Todtenkopf, M. S., … & Cohen, B. M. (2006). Depressive-like effects of the κ-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. Journal of Pharmacology and Experimental Therapeutics, 316(1), 440-447.
Carlezon, W. A., Béguin, C., Knoll, A. T., & Cohen, B. M. (2009). Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacology & therapeutics, 123(3), 334-343.
Crick, F. & Koch, C. (1990) Towards a neurobiological theory of consciousness. Seminars in the Neurosciences, 2, 263-275.
Fichna, J., Dicay, M., Lewellyn, K., Janecka, A., Zjawiony, J. K., MacNaughton, W. K., & Storr, M. A. (2012). Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors. Inflammatory bowel diseases, 18(6), 1137-1145.
Hanes, K. R. (2001). Antidepressant effects of the herb Salvia divinorum. Journal of Clinical Psychopharmacology, 21, 634-635.
Johnson, J. B. (1939). The Elements of Mazatec Witchcraft. Ethnological Studies, 9.
Kivell, B. M., Ewald, A. W., & Prisinzano, T. E. (2013). Salvinorin a analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse. Advances in pharmacology (San Diego, Calif.), 69, 481-511.
Roth, B. L., Baner, K., Westkaemper, R., Siebert, D., Rice, K. C., Steinberg, S., … & Rothman, R. B. (2002). Salvinorin A: a potent naturally occurring nonnitrogenous κ opioid selective agonist. Proceedings of the National Academy of Sciences, 99(18), 11934-11939.
Siebert, D. J. (1994). Salvia divinorum and salvinorin A: new pharmacologic findings. Journal of ethnopharmacology, 43(1), 53-56.
Simonson, B., Morani, A. S., Ewald, A. W. M., Walker, L., Kumar, N., Simpson, D., … & Kivell, B. M. (2014). Pharmacology and anti‐addiction effects of the novel kappa opioid receptor agonist Mesyl Sal B, a potent and long‐acting analogue of salvinorin A. British journal of pharmacology.
Stiefel K, M., Merrifield A., Holcombe A. (2014). The claustrum’s proposed role in consciousness is supported by the effect and target localization of Salvia Divinorum. Frontiers in Integrative Neuroscience. 8(20). doi:10.3389/fnint.2014.00020
Tomasiewicz, H. C., Todtenkopf, M. S., Chartoff, E. H., Cohen, B. M., & Carlezon Jr, W. A. (2008). The kappa-opioid agonist U69, 593 blocks cocaine-induced enhancement of brain stimulation reward. Biological psychiatry, 64(11), 982-988.
Valdés, L. J. (1994). Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. Journal of psychoactive drugs, 26(3), 277-283.
Wang Z., Ma N., Riley J., Armstead WM., Liu R (2013). Autoregulation Preservation by Salvinorin A After Brain Hypoxia/Ischemia and Reperfusion in Piglet Model. Trans Periop & Pain Med. doi:10.4000/2330-4871.1000001
Wasson, R. G. (1962). A new Mexican psychotropic drug from the mint family. Botanical Museum Leaflets, Harvard University, 77-84.

The Consumption of Psychoactive Plants in Ancient Global and Anatolian Cultures During Religious Rituals: The Roots of the Eruption of Mythological Figures and Common Symbols in Religions and Myths

Abstract

Psychoactive plants which contain hallucinogenic molecules that induce a form of altered states of consciousness (H-ASC) have been widely used during the religious rituals of many cultures throughout the centuries, while the consumption of these plants for spiritual and religious purposes is as old as human history. Some of those cultures were shaman and pagan subcultures; African native religions; Bwiti Cult; South American native religions; Amazon Cultures; Central American Cultures; Mexican subcultures; Aztec, Maya and Inca; Wiccan and witch subcultures; Satanists; American Indians; Greek and Hellenistic cultures; Sufis; Hassan Sabbah’s Hashissins; Hindu, Indian and Tibetan cultures; some of the Nordic subcultures etc. Some of the psychoactive ingredients of the plants that were used during these religious rituals were; narcotic analgesics (opium), THC (cannabis), psilocybin (magic mushrooms), mescaline (peyote), ibogaine (Tabernanthe iboga), DMT (Ayahuasca and phalaris species), Peganum harmala, bufotenin, muscimol (Amanita muscaria), thujone (absinthe, Arthemisia absinthium), ephedra, mandragora, star lotus, Salvia divinorum etc. The main purposes of the practice of these plants were: spiritual healing; to contact with spirits; to contact with the souls of ancestors; to reach enlightenment (Nirvana or Satori); to become a master shaman, pagan or witch; to reach so-called-other realities, etc. Such “psychedelic-philosophical plant rituals” changed participating persons’ psychology, philosophy and personality to a great degree. In these two successive articles, the consumption of psychedelic plants during religious rituals is reviewed and it is hypothesized that the images, Figures, illusions and hallucinations experienced during these “plant trips” had a great impact on the formation and creation of many Figures, characters, creatures, archetype images that exist not only in the mythology, but also in many religions, as well, such as angels, demons, Satan, mythological creatures, gods, goddesses etc. In the Middle East and Anatolia, within many hermetic and pagan religions, Greek and Hellenic cultures psychoactive plant use was a serious part of the religious rituals, such as Dionysian rituals or Witch’s’ Sabbaths. Although the impact of the “psychedelic experience and imagination” was enormous to the configuration of many religious and mythological characters, and archetypes, this fact has been underestimated and even unnoticed by many historians and anthropologists, because of the quasi-ethical trends of “anti-drug-brain-washed Western Societies”.
Sayin, H. U. (2014). The Consumption of Psychoactive Plants in Ancient Global and Anatolian Cultures During Religious Rituals: The Roots of the Eruption of Mythological Figures and Common Symbols in Religions and Myths. NeuroQuantology, 12(2), 276-296. https://dx.doi.org/10.14704/nq.2014.12.2.753
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The induction of synaesthesia with chemical agents: a systematic review

Abstract

Despite the general consensus that synaesthesia emerges at an early developmental stage and is only rarely acquired during adulthood, the transient induction of synaesthesia with chemical agents has been frequently reported in research on different psychoactive substances. Nevertheless, these effects remain poorly understood and have not been systematically incorporated. Here we review the known published studies in which chemical agents were observed to elicit synaesthesia. Across studies there is consistent evidence that serotonin agonists elicit transient experiences of synaesthesia. Despite convergent results across studies, studies investigating the induction of synaesthesia with chemical agents have numerous methodological limitations and little experimental research has been conducted. Cumulatively, these studies implicate the serotonergic system in synaesthesia and have implications for the neurochemical mechanisms underlying this phenomenon but methodological limitations in this research area preclude making firm conclusions regarding whether chemical agents can induce genuine synaesthesia.

Luke, D. P., & Terhune, D. B. (2013). The induction of synaesthesia with chemical agents: a systematic review. Frontiers in Psychology, 4, 1-11. http://dx.doi.org/10.3389/fpsyg.2013.00753
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