Neuropharmacology

Three new 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines, 1-(3-chlorophenyl)-4-[2-(4-fluorophenoxy)-2-phenylethyl]-piperazine 7, 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(2-methoxyphenyl)-piperazine 8, and 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-piperazine 9, modeled after the potent antidepressant fluoxetine and coupled with several functionalized piperazines, have been prepared by chemical synthesis as selective serotonin reuptake inhibitors (SSRIs) with a potentially improved adverse reaction profile. Typical SSRIs, although very effective in the treatment of depression, still face the troublesome side effect of sexual dysfunction. A number of pharmacological agents-notably, drugs in the piperazine class-have been used to reverse SSRI-induced sexual dysfunction, and evidence for developing an improved SSRI by coupling a fluoxetine congener with the pharmacophore of a reversal agent holds promise. Preliminary data indicates that the hydrochloride (HCl) salts 10, 11, and 12 each exhibit single-site binding at the site of the serotonin reuptake transporter (SERT). However, each of the three compounds are much less potent than typical SSRIs, showing micromolar (μM) affinity for the SERT with IC50 values of 1.45 μM, 3.27 μM, and 9.56 μM, respectively. Further biological evaluation of compounds 10, 11, and 12 is needed before definitive conclusions can be made with regard to each compound's potential for use as an SSRI-type candidate which is devoid of sexual side effects. Nevertheless, the initial findings are quite encouraging, thus lending credence to the idea of hybridizing an SSRI congener with that of the pharmacophore of an agent known to reverse or treat SSRI-induced sexual dysfunction.Graphic

Anxiety disorders have a lifetime prevalence which exceeds 15% in the general population and particularly Generalized Anxiety Disorder (GAD) (lifetime prevalence of 5.1%) accounts for second most frequent psychiatric disorder in the primary care setting. Methodology: The present 12 weeks' study was a prospective, randomized clinical study in 60 subjects. Aim of the study is to compare the efficacy between two drugs using HAM-A, HADS, CGI scales. Results: In Paroxetine group there was only very little clinical difference in HAM-A and HADS reduction than Ashwagandha group however the difference did not reach statistical significance. Similarly, reduction in CGI scores did not reach statistical significance. Conclusion: Ashwagandha (Withania Somnifera) when compared was as much efficacious as Paroxetine but had better side effect profile hence could be given in patients not tolerating the side effect of Selective serotonin reuptake inhibitors (SSRIs) or can be given in mild to moderate anxiety as an initial drug.

Cerebroprotein hydrolysate is administered intravenously and/or orally to help treat a range of brain injuries and neurodegenerative conditions effecting the brain including Traumatic Brain Injury (TBI), concussions, injuries resulting from automobile accidents, sports injuries, falls that impact the head, accidents and acts of violence that impact the head and brain including injuries incurred from combat related activities, Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and other neurological conditions that adversely effect the function of the brain and central nervous system. The types of brain injuries and neurodegenerative conditions that may be treated with cerebroprotein hydrolysate range from mild to severe. Cerebroprotein hydrolysate treatment effectively assists the brain in rebuilding neurons, synapses, and neurological tissue by infusing the brain with specific proteins, neuropeptides, and amino acids to assist with brain repair.

Chris Timmermann - Subjective Experiences and the Sensed Presence Phenomenon in Human Research with DMT. Divine Molecule Talks at Tyringham – Part II Exploring Entheogenic Entity Encounters, a private symposium, Tyringham Hall, September 2015 (curator and compère).

Hallucinations possess two main components: (i) a sensory content; and (ii) a sense that the sensory content is real. Influential models of schizophrenic hallucination claim that both the sensory content and the sense of reality can be explained in terms of metacognitive dysfunction. This chapter assesses whether such a claim holds for schizophrenic and drug-induced hallucinations; it further attempts to determine the actual role of metacognition in hallucination and how this role is liable to vary across cultures. It is first argued that the notion of sense of reality is heterogeneous and should therefore be divided into distinct kinds. Next, some monitoring-based models of hallucination are presented. After having briefly distinguished between different levels of metacognitive processing, I show that these monitoring-based models are metacognitive only to a limited extent and that they fail to explain important aspects of the content and sense of reality of hallucinations. I subsequently suggest that the main mechanisms of serotoninergic-hallucinogens are not metacognitive whereas those of anticholinergic-hallucinogens importantly tap into subpersonal metacognitive processes. Looking specifically at the use of ayahuasca across different Amazonian indigenous groups, I put forward the idea that the metacognitive properties of hallucinogenic experiences can be variously exploited or ignored depending on cultural expectations. Finally, I examine how anthropological and linguistic evidence of the ritualized use of hallucinogens supports the existence of multiple metacognitive norms in religion.

Divine Molecule Talks at Tyringham – Part II
Exploring Entheogenic Entity Encounters  – A private symposium. Tyringham Hall, May 29th – June 1st, 2017. (Curator and compère) by Anton Bilton, Dr David Luke & Rory Spowers.

Dr Luis Luna - On Encounters with Entities in the Ayahuasca Realm. A Phenomenological View

Dr Michael Winkelman - Visionary Experiences, Entities and Alien Worlds: A Natural Evolved Psychology

Prof Ralph Metzner - Entheogens, Radical Empiricism and the Nature of Reality

Chris Timmerman - Subjective Experiences and the Sensed Presence Phenomenon in Human Research with DMT

Dr William Richards - Ineffability and Revelation on the Frontiers of Knowledge

Prof Chris M Bache - LSD and DMT Entity Relation

Dr Angela Voss - What is the Daimon? An Exploration of the Oracular Intelligence

Prof Bernard Carr - Making Space and Time for Mind and Psychedelia

Daniel Pinchbeck – Psychedelic Initiations and Ecological Megacrisis

Prof Jeffrey Kripal - Biological Gods: Science (Fiction) and Some Emergent Mythologies

Whitley Streiber - Stories from a Life: a Lifetime of Anomalous and Unexplained Experiences

Dr David Luke – Summary of the Symposium: What we think we know about DMT entities and how to go about exploring them

Multiple personality describes a state in which the integrated functioning of a person's identity, including consciousness, memory and awareness of surroundings, is disrupted or eliminated. Dissociation is a mechanism that allows the mind to separate or compartmentalize certain memories or thoughts from normal consciousness. These symptoms can interfere with a person‗s general functioning, including social activities, work functions, and relationships. People with MPD often have issues with their identities and senses of personal history. MPD is diagnosed nine times more often in females than in males. MPD is rarely diagnosed in children; despite the average age of appearance of the first alter being three years. Dissociation is a psycho physiologic process that alters a person's thoughts, feelings, or actions so that, for a time, certain information is not associated or integrated with other information as it normally. The goals of treatment for MPD are to relieve symptoms, to ensure the safety of the individual, and to "reconnect" the different identities into one well-functioning identity. Treatment also aims to help the person safely express and process painful memories, develop new coping and life skills, restore functioning, and improve relationships. Hence such other information about multiple personality disorder also described in this review.

Anxiety disorders have a lifetime prevalence which exceeds 15% in the general population and particularly Generalized Anxiety Disorder (GAD) (lifetime prevalence of 5.1%) accounts for second most frequent psychiatric disorder in the primary care setting. Methodology: The present 12 weeks' study was a prospective, randomized clinical study in 60 subjects. Aim of the study is to compare the efficacy between two drugs using HAM-A, HADS, CGI scales. Results: In Paroxetine group there was only very little clinical difference in HAM-A and HADS reduction than Ashwagandha group however the difference did not reach statistical significance. Similarly, reduction in CGI scores did not reach statistical significance. Conclusion: Ashwagandha (Withania Somnifera) when compared was as much efficacious as Paroxetine but had better side effect profile hence could be given in patients not tolerating the side effect of Selective serotonin reuptake inhibitors (SSRIs) or can be given in mild to moderate anxiety as an initial drug.

A B S T R A C T Rewards are appetitive events that elicit approach. Groundbreaking findings from neurophysiological experiments in animals, alongside neuropharmacology and neuroimaging research in human samples have identified dopamine as the main neurochemical messenger of global reward processing in the brain. However, dopamine's contribution to the different components of reward processing remains to be precisely defined. To facilitate the informed design and interpretation of reward studies in humans, we have systematically reviewed all existing human pharmacological studies investigating how drug manipulation of the dopamine system affects reward-related behaviour and its neural correlates. Pharmacological experiments in humans face methodological challenges in terms of the: 1) specificity and safety of the available drugs for administration in humans, 2) uncertainties about pre-or post-synaptic modes of action, and 3) possible interactions with inter-individual neuropsychological or genotypic variables. In order to circumvent some of these limitations, future research should rely on the combination of different levels of observation, in integrative pharmaco-genetics-neurobe-havioral approaches, to more completely characterize dopamine's role in both general and modality-specific processing of reward.

Toxins and venom components that target voltage-gated sodium (NaV) channels have evolved numerous times due to the importance of this class of ion channels in the normal physiological function of peripheral and central neurons as well as cardiac and skeletal muscle. NaV channel activators in particular have been isolated from the venom of spiders, wasps, snakes, scorpions, cone snails and sea anemone and are also produced by plants, bacteria and algae. These compounds have provided key insight into the molecular structure, function and pathophysiological roles of NaV channels and are important tools due to their at times exquisite subtype-selectivity. We review the pharmacology of NaV channel activators with particular emphasis on mammalian isoforms and discuss putative applications for these compounds.

In Persian ethnomedicine several herbal remedies and functional foods have been used to treat migraine headache which are mostly summarized in Qarabadin-e-kabir (Aghili-Shirazi MH, 1773). One of them is Citron syrup (Sharbat-e-Balang) containing edible Citrus medica L. fruit juice and sugar. The present study was designed to assess the efficacy and safety of Citron syrup on patients with migraine headache.

Materials and methods
Citron syrup was prepared as described in Qarabadin-e-kabir. In this double blind randomized placebo-controlled clinical trial, ninety patients with migraine headache were allocated to three parallel groups (Citron syrup, propranolol or placebo). Patients received 15 ml of Citron syrup, placebo syrup or 20 mg of propranolol tablet three times daily after a meal for 4 weeks. Primary outcomes were obtained from three measures: the frequency (per month), mean duration (hour) and mean intensity (visual analogue scale “VAS” 0–10 score) of headache attacks evaluated prior to and following 4 weeks of the intervention.

Results
Citron syrup was superior to placebo in reduction of headache attacks intensity (P<0.01) and duration (p<0.0001) and as effective as propranolol in patients with migraine headache (P>0.05). However, unlike propranolol, Citron syrup could not significantly reduce the frequency of attacks compared to placebo. No indication of any serious side effects from Citron syrup was observed.

Conclusion
According to obtained results, Citron syrup as a traditional Persian remedy can be suggested as an effective treatment for decreasing pain intensity and duration of attacks in migraine headache and the effectiveness is comparable to propranolol. However, the syrup did not show significant effect on frequency of attacks.

[[[[[FR]]]]]
Les expériences hallucinogènes déterminent-elles certains contenus culturels ou est-ce au contraire la culture qui détermine le contenu des expériences hallucinogènes ? Certains auteurs ont défendu la thèse d’un déterminisme neuropharmacologique. D’autres ont soutenu la thèse d’un déterminisme culturel. L’une et l’autre de ces thèses souffrent d’une double faiblesse : elles se fondent sur un nombre fort restreint de cas ethnographiques (absence de comparatisme anthropologique) ; elles se fondent sur l’analyse d’un nombre limité de substances (absence de comparatisme neuropharmacologique). J’argue ici en faveur d’une tierce position : celle d’un déterminisme neuropharmacologique faible et pluriel. Après avoir distingué entre différentes classes d’hallucinogènes, et identifié leurs mécanismes d’action et leur effets psychologiques respectifs, j’examine la manière dont les rituels se trouvent distinctement façonnés par les déterminismes neuropharmacologiques. Les rituels à datura (hallucinogène anticholinergique) d’Amérique du Nord sont ainsi comparés aux rituels à ayahuasca (hallucinogène sérotoninergique) d’Amazonie, puis aux rituels impliquant doublement un anticholinergique et un sérotoninergique du groupe jivaro de la Montaña. En conclusion, il est démontré que facteurs culturels et neuropharmacologiques, loin d’être forcément compétitifs, s’avèrent souvent être synergiques.
Most clés : Amériques ; ethnopharmacologie ; hallucinogènes anticholinergiques ; hallucinogènes sérotoninergiques ; neuroanthropologie ; rituel

[[[[[ENG]]]]]
Do hallucinogenic experiences determine cultural contents, or alternatively, does culture determine the contents of hallucinogenic experiences? Some authors have championed the neuropharmacological determinism thesis while others have endorsed the cultural determinism thesis. Both theses have important weaknesses: they are based on the study of a restricted number of ethnographic cases (anthropological comparativism is missing) and they are based on the study of a restricted number of hallucinogenic substances (neuropharmacological comparativism is missing). I will champion a third position: weak and plural neuropharmacological determinism. After having identified different classes of hallucinogens and pinpointed their mechanisms of action and their respective psychological effects, I examine the way rituals are distinctively shaped by neuropharmacological determinisms. Datura-based rituals (i.e., anticholinergic rituals) of North American are thus compared to ayahuasca-based rituals (i.e., serotoninergic rituals) of Amazonia, and subsequently compared to Jivaro rituals of the Montaña involving the use of both anticholinergic and serotoninergic hallucinogens. In conclusion, it is shown that far from being always competitive, cultural and neuropharmacological factors often prove synergetic.

Keywords : Americas ; anticholinergic hallucinogens ; ethnopharmacology ; neuroanthropology ; ritual ; serotoninergic hallucinogens