Alchemica

Do any of the nornicotine dominant Nicotiana have a history of traditional interesting use? I'm trying to suss out the novel tobacco's. I'm sick of relapsing on boring NRT nicotine only. From what I can find, N. tabacum, N, rustica, N. alata, N. langsdorffii all contain nicotine; N. sylvestris and N. rusbyi [N. tomentosiformis] contain nornicotine, while N. glauca contains anabasine. I've used N. glauca cautiously but didn't get heavily into it [covered the potential anti-addictive nature of anabasine in [1]] and the major nicotine containing Nicotianas. I want something different. I want to know what nornicotine is like as a dominant alkaloid? Exploring some cotinine would be neat, the predominate metabolite of nicotine, which has been "shown to reduce depression, anxiety, and fear-related behaviour as well as memory impairment in animal models of depression, PTSD, and Alzheimer's disease." [2]. "Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine." [3] Note: the nornicotine in Duboisia hopwoodii has been stated in one (albeit old) paper to be d-nornicotine contrary to what is found in Nicotiana, which may be more toxic, potentially giving rise to the statement "Twentieth century chemical analysis found that both nicotine and nornicotine, a drug four times as toxic as nicotine, are usually present in Duboisia" [4]. Nornicotine occurs in several species, such as Nicotiana sylvestris and some Australian species [5]. N. sylvestris contained 0.44% alkaloids in one study but in another, had a total alkaloid concentration of 1%, nornicotine comprising 95% of the alkaloids [6]. Another reference [8] gives 4.8mg/g alkaloids, 82.2 % of that being nicotine. Nicotiana langsdorffii contained 0.22% alkaloids, 73% being nicotine, the rest nornicotine [7]. It is the dominant alkaloid in N. thyrsiflora (94.3% of the 5.1mg/g total alkaloids). It is said "The heated leaves of Nicotiana thrysiflora are used for rheumatism." In Nicotiana tomentosiformis, nornicotine makes up 79% of the 1.1mg/g total alkaloids. N. glutinosa contains 7.4mg/g with 77.4% of that being nornicotine [8]. "About 0.8% of nicotine is metabolized to nornicotine in the periphery. However, the biotransformation of nicotine to nornicotine also appears to occur locally in the brain, and brain concentrations of nornicotine have been shown to exceed those in the periphery" [9]. Nornicotine is proposed to result in additional activation of a7-type receptors, which may be important for effects on cognition and attention. Nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism [10]. "The nAChRs mediating the nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance" Both nicotine and nornicotine were relatively potent partial agonists of rat α7 receptors with efficacies of approximately 60% and 50%, respectively, compared with ACh The efficacies of nicotine and nornicotine for α4β2 receptors were relatively low, compared with ACh, although nicotine was rather more potent than nornicotine and ACh. Nicotine was relatively efficacious for α3β4 receptors, although less potent at α4β2 receptors. Nornicotine was a relatively poor agonist for α4β2 and α3β4 receptors. The half-life of nornicotine in brain is 166 min, which is three times longer than that of nicotine (52 min) [1] http://www.shaman-australis.com/forum/index.php?/topic/45354-n-glauca-and-anabasine-as-anti-addictive-agents-some-theory/ [2] https://en.wikipedia.org/wiki/Cotinine [3] https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+8034 [4] https://en.wikipedia.org/wiki/Pituri [5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727613/ [6] https://academic.oup.com/jee/article-abstract/30/5/724/2201756?redirectedFrom=fulltext [7] https://naldc.nal.usda.gov/download/IND43969765/PDF [8] https://www.degruyter.com/downloadpdf/j/cttr.1990.14.issue-6/cttr-2013-0610/cttr-2013-0610.xml [9] https://pdfs.semanticscholar.org/6a2f/0b3328d07bab7dc4bd6164172bcecb9e25b5.pdf [10] https://www.ncbi.nlm.nih.gov/pubmed/17146768 For more nicotine containing plants: For a breakdown of normal tobacco: Nicotiana tabacum Alkaloids 11.462 mg/g Nicotine 94.8% Nornicotine 3.0% Anabasine 0.3% Anatabine 1.9% N. alata is generally very low on nicotine but allows the other non-alkaloid constituents of tobacco's medicine to be explored. N. megalosiphon contained 0.22% alkaloids, 100% being nicotine N. quadrivalvis had in one study a nicotine content of approximately 0.16% in one study. It was the main native tobacco that was once widely cultivated by numerous tribes for medicinal and religious purposes Another reference gives Alkaloids 7.76 mg/g Nicotine 94% One early trier found the such tobacco "very pleasant," adding, "it does not affect the nerves in the same manner..." Nicotiana clevelandii Alkaloids 8.945 mg/g Nicotine 98.5% Nornicotine 0.3% Anatabine 1.2% Thanks @Micromegas

Ethnopharmacology of Love Background: Elixirs conferring eternal youth or inducing amatory and erotic attraction have been searched for without success. Lovesickness is a widespread affliction resulting from unrequited love and/or the impossibility for physical and emotional union. The symptoms are reflections of altered dopamine, serotonin, noradrenaline, testosterone and cortisol levels and range from frenzy and intrusive thinking to despair and depression, sharing traits with the neurochemistry of addiction and compulsive behavior disorder. Although it can seriously impact the quality of life, lovesickness is currently not considered in official disease classification systems. Consequently, no official therapeutic guidelines exist, leaving subjects to seek the cure on their own. Methods: We review literature of the past 2000 years dealing with the concept, diagnosis and the healing of lovesickness and contextualize it with neurochemical, ethnomedical, and ethnographic data. Since neurobiological and pharmacological connections between the love drive and the sex drive exist, we review also the literature about herbal an- and aphrodisiacs, focusing on their excitatory or calmative potential. Results: An overall consensus regarding socio-behavioral regimes exists for dealing with lovesickness from historical through contemporary literature. The herbal drugs used for treating lovesickness or inducing love passion do not possess the alleged properties. The pharmacological effects of aphrodisiacs are heterogeneous, including dopaminergic and adrenergic activities, but there is no evidence for any serotonergic effects. The libido-regulating properties of anaphrodisiacs seem to be associated with sedative and toxic effects or decreasing testosterone levels. CB2 receptors expressed on dopaminergic neurons of the ventral tegmental area, part of the brain’s reward circuit, implicated with addiction, orgasm and strong emotions such as love, might constitute a new therapeutic target. Conclusion: The common food additive and CB2 agonist β-caryophyllene might have the potential to attenuate dopaminergic firing, quenching the reward and thus motivation associated with romantic love. From Greek mythology to modern history, cultural expressions and implications of love, sex and procreation is and was organized along hierarchical lines that put men on top. The neuronal predispositions and activities associated with falling in love will probably forever remain nature’s and Eros’ secret. Copaiba oil, ~50% β-caryophyllene, appears safe orally at low doses An update on the pharmacology of BCP - orally active potent CB2 full agonist and PPARα/γ agonist. - Analgesic, anti-inflammatory, anti-amyloidogenic, insulin-sensitising, anti-alcoholism, anti-cancer, cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, antimicrobial and immune-modulator effects - Exerts anxiolytic and the anti-depressant effects via CB2 agonism - Activates TrkA receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors - potent antagonist of α7-nAChRs - exhibits synergy with µ-opioid receptor dependent pathways - Neuroprotection via prevention of microglial activation and inflammatory cytokine and chemokine expression: β-caryophyllene reduced astrogliosis and microglial activation as well as the levels of COX-2 protein and the mRNA levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the cerebral cortex, inhibits pathways triggered by the activation of toll like receptor complex - CB2Rs modulate striatal dopamine release - PPARγ activation prevents the negative emotional effects of stress and exerts anxiolytic actions - CB2 agonists may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation. β-caryophyllene is an attractive molecule with therapeutic potential for the treatment of pain, Alzheimer's disease, anxiety, depression, Parkinson's, schizophrenia, various neurodegenerative conditions, brain injury, diabetes and metabolic disorders

Yeah, feel you on that, sorry to hear things are a struggle for you. I got disconnected again and the only way I've recently been able to reconnect is through plants. It takes my head off the social situation which is hard to manage with anxiety, social anhedonia and not finding common ground etc. Churned out a bunch of Ashwagandha tubestocks through winter that did well in the greenhouse, ready for spring. Joined the local grow free group. I've been forcing myself to connect with new people, even strangers, by giving the plants away. It just makes an awkward social encounter more positive. A reason to try. Just breaking that pattern of isolation through a plant can be potent. You can rebuild some social skills etc. Transfer interests from one domain to another etc

Tomorrow, spike those ketones in the name of a healthy brain experiment and see what I think of it as a "neurotherapeutic" and "promising anxiolytic strategy" [1], see if there are hints of enjoyable prosociality which would be nice. "Use of βHB as an efficient neurotherapeutic relies on increasing blood βHB levels so as to encourage entry of βHB to the brain." [2] The main problem with using βHB as a therapeutic lies in being able to deliver sufficient βHB to the brain, due to the limited uptake of βHB across the blood brain barrier and the difficulty in sustaining high enough levels of βHB in the blood - uptake can be increased by instigation of dietary changes, such as a high fat diet or regular ingestion of medium chain fatty acids. Any keto nuts suggest better (other than ketone esters) than BHB+MCTs? I want to feel it as acutely as possible... Thinking to go from intermittent fasting/low carb to using short term BHB + MCTs as my diet for a bit. Ketone bodies upregulate neurotrophins, reduce neuroinflammation and hyperexcitability, causing potent neuroprotection. They also drive growth and myelination, enhance synaptic plasticity, cognition and neuronal stress resistance, improving learning and memory. Exogenous ketones also improve oxygen utilisation, especially in the central nervous system There are concerns regarding the level of Ca and K provided by supplementing BHB salts, which can rise to toxic levels if excessive doses are administered, so adherence to dose recommendations is required [3] In the body, "Exogenous ketone supplementation causes blood glucose to decrease significantly, likely due to the acute increase in insulin sensitivity. Therefore, exogenous ketones may present a potential therapy for type-2 diabetics via regulation of blood glucose.". "BHB + MCT raises blood BHB levels much higher than BHB or MCT in isolation, with a peak just over 1.30mmol/L. Even more important is that blood BHB levels do not seem to readily fall back to the normal levels of 0.2mmol/L. Even after 8 hours blood BHB levels are 0.5mmol/L, which is over double the normal level, and they look to be only very gradually falling. Blood BHB levels look like they will be elevated for the best part of a day, but the most significant rise being between 1 and 4 hours after ingestion." [4] Consumption of MCTs produces a mild ketosis which has been estimated to contribute up to 8–9% to brain energy metabolism and it is well tolerated. In comparison, "In human tests, 30ml of MCT oil was able to raise blood BHB levels to about 0.55 mmol/L. This is just over half the effect that BHB salt supplementation had. MCT oil supplementation spiked blood BHB levels at just under an hour, and drops to normal levels after 3 hours. Interestingly, BHB levels continue to fall below normal levels of 0.20mmol/L to 0.12mmol/L. The low blood BHB levels show no real indication of normalising after 8 hours." While the low ketone levels generated by MCT supplementation have been demonstrated to partially reverse the memory deficits of Alzheimer’s dementia, exogenous ketones have the potential for greater memory-improving effects, with maximum effect likely occurring at a beta-hydroxybutyrate blood level of 4 mmol/L or higher, the level at which ketone transport into the brain is maximised. Human pilot studies and case studies suggest that ketogenic diet and ketogenic supplement-induced ketosis is a potential therapeutic approach in the treatment of epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia Ketone bodies may exert their effects through modulation of GABAergic, glutamatergic, and adenosinergic system. Administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS. Noted antidepressive and anxiolytic effects It an efficient mitochondrial fuel, improving energy metabolism Enhances GABAA receptor function, upregulates GABAergic activity [may increase GABA concentration], enhances inhibitory glycine receptors Decreases brain glutamate, alters the response of NMDA receptors, L-type Ca2+ channels, reduces neuronal firing rates, mediated in part by Katp channel activity and GABAB signaling It interacts with an inflammasome in immune cells to reduce production of inflammatory cytokines and reduce inflammation. inhibitor of histone deacetylases resulting in upregulation of genes involved in protection against oxidative stress and regulation of metabolism Supplementation with βHB has been shown to extend the lifespan of C. elegans by 20% [1] https://www.frontiersin.org/articles/…/fnmol.2016.00137/full [2] https://www.ncbi.nlm.nih.gov/pubmed/27826689 [3] https://blog.undoctored.com/beware-exogenous-ketones/ [4] https://ketosource.co.uk/exogenous-ketones-how-they-work/ By afternoon, I'm normally crashing in mood, grumpy and tired, not that the morning is much better. I got a paradoxical lift changing my diet for once, but then the typical diet shift anergia kicked in. From a couple of days of IF, gave the BHB salts a whirl. Solid dose, 12g BHB and some MCTs. Really, the ketone elevations offered by even large doses of the salts aren't that huge but "can help your body transition into ketosis with less misery and hunger pangs." potentially. The combo of MCTs and BHB is said to be better for BHB elevations. Beta hydroxybutyric acid is antidepressive and anxiolytic. It enhances inhibitory glycine receptors at concentrations observed in humans clinically. In addition, beta-hydroxybutyric acid enhances GABAA receptor function at these concentrations. Subanesthetic concentrations may contribute to lethargy and impairment of consciousness [1] and has abilities to alter physical properties of cell membranes [2] [1] https://www.ncbi.nlm.nih.gov/pubmed/17717222 [2] https://www.ncbi.nlm.nih.gov/pubmed/23339286 By 45min, there's a very mild energetic lift, wouldn't say much more than MCTs alone. Some restoring energy, stability of mood again and a little potential anxiolysis. Functionally nice as a mild meal tonic. Enough to get another bout of exercise in, which seemed to attune me to it more. It was pleasant exercise. Just a calm, centred functional bit of exercise. Didn't feel so neurotic. Got for another bit of exercise - just level headed. All in all, maybe the BHB salts are useful but not likely to be problematic. It may be therapeutically useful to for the times I crave alcohol (I've now been abstinent quite awhile), "In ethanol dependence, it is suggested the following occurs "energy deficiency (“starvation”) of the brain → stimulation of production of ketone bodies → partial transition of the brain from exclusive using of glucose as the energy substrate to partial use of ketone bodies as such substrate. Under such conditions, the brain begins to be dependent, to a significant extent, on the level of these bodies in the blood, i.e., on the degree of ketonemia. With any decrease in this index, the biological requirement to replenish the amount of these compounds develops. Since rapid synthesis of ketone bodies can be readily initiated by introduction of ethanol into the organism, this organism tries to realize the corresponding behavioral reaction, i.e., to consume alcohol." [1] MCTs themselves compensate for the brain energy deficits in direct proportion to the level of plasma ketones achieved. MCT-fed rats exhibited reduced anxiety-like behaviors and enhanced social behaviour [2] Data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production [3] [1] https://link.springer.com/article/10.1007/s11062-016-9596-4 [2] https://www.ncbi.nlm.nih.gov/pubmed/29908242 [3] https://www.ncbi.nlm.nih.gov/pubmed/27517611

Recently got into the fasting. I like the mood stability and uplift. Firstly has anyone used the commercial 'BHB exogenous ketone' salts and got an acute nice noteworthy mood reaction? There are commercial βHB salt products - quite pricey - but I want to know if anyone has heard of the cheap ketone esters, particularly super cheap (and fragrant!) ethyl acetoacetate, being used safely orally? I'm not going to slack off using will power to fast for my added uplift but I'm curious... it could be quite nice as an acute quite enjoyable mood lifter. Is it the βHB, or is acetoacetate a nice mood lifter? Ketones, particularly BHB, upregulate GABAergic tone but are they 'enjoyable' acutely orally administered? "...researchers don’t know the exact cause of these [euphoric] feelings. Acetoacetate, acetone and BHB, or any of their metabolites, may all be involved, as well as the effects of low blood sugar, which can cause euphoria and giddiness." People felt remarkably well, and experienced a mild intoxication: not dissimilar to the effects of ethanol. Bloom speculated that acetoacetate had caused the inexplicable jubilation. [1] Aside from acute prosocial anxiolytic effects which I deem as an important therapeutic area to address in many conditions, I'm also primarily looking for sustainable better health in my life, as are many people with epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia etc. My intermittent fasting is proving interesting, mood stabilising and uplifting in conjunction with other measures, pushed that quite a bit but it's personally not sustainable to run an extreme 'deprivation diet'. Just skipping breakfast and healthy meals at the other times with my exercise is probably my best bet. There are a few suggestions on ways to stay in a fasting state during IF [1]. Caved in and thought I had to try the most economical βHB salts, to get a gauge on it's effects. Probably get around to doing some trials with that this week. It is suggested elevations of β-hydroxybutyrate may partly mediate the beneficial effect of IF in CNS conditions. "Brain BHB concentration increased from a nonfasted level of 0.05 +/- 0.05 to 0.60 +/- 0.26 mM (after second day of fasting), increasing further to 0.98 +/- 0.16 mM (after the third day of fasting)" [2] While βHB salts or other supplements "aren’t a great fat loss tool – they’re simply ways of increasing your blood ketones" and increase energy in, I'm more generally looking for the therapeutic benefits of ketones on the brain for the moment. Both would be nice - I'm getting really good kJ intake reductions and maintaining my exercise so hoping. Unfortunately, with exogenous ketone administration, blood βHB reached low levels (<1 mM) and a high amount of salts, consumed βHB, was required to achieve ketosis. That said, this is still roughly equivalent to three days of fasting. That said, gastrointestinal symptoms were reported in a large number of participants. βHB has antidepressant and antianxiety-like effects and results in modulation of multiple systems, including GABA, Glu, adenosine, neurotrophic etc and even in the presence of glucose exerts beneficial CNS effects, also exerting epigenetic effects (β-hydroxybutyrate is a HDAC inhibitor). Dietary ketone salts are often racemic mixtures of the two optical isoforms of βHB, despite the metabolism and actions of L-βHB being poorly understood ~12 or ~24 g orally administered ketone salts elevated D-βHB concentrations (D-βHB Cmax 1.0 mM) which returned to baseline within 3–4 h. [3] [Another study found 0.5 g/kg bw at 2 h elevated D-βHB, with a mean value of 0.598 ± 0.300 mM [4], 0.38 g/kg bw caused only a rise to 0.3-0.4 mM βHB in trained athletes [5]. The ketone salts contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h. L-βHB is still neuroprotective but not much is known about it's CNS effects More cheaply, one can increase βHB in the brain 90 minutes after ingesting coconut/MCT oil, which improved paragraph recall in adults with impaired memory. Preliminary studies also show ketones can improve working memory in both young and old subjects [1] http://siimland.com/what-breaks-a-fast-while-intermittent-fasting/ [2] https://www.ncbi.nlm.nih.gov/pubmed/11043913 [3] https://dx.doi.org/10.3389%2Ffphys.2017.00848 [4] https://www.ncbi.nlm.nih.gov/pubmed/29850235 [5] https://www.ncbi.nlm.nih.gov/pubmed/29966721 "Conversion of ketone bodies (KBs) to ketone esters (KEs) eliminates KB acidity, making the KEs suitable vehicles for the delivery of KBs to the blood circulation via the gastrointestinal route. Ingestion of KE can directly increase plasma KBs to levels within the range achieved during fasting. The degree of KB elevation attained is readily controlled by the dose size Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of βHB are safe and well tolerated in animals and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans" [2] While 1,3-butanediol esters are ideal as they are readily metabolised in a manner similar to ethanol without the deleterious effect of ethanol metabolism, with subsequent conversion to βHB and, eventually (at the peripheral tissue level), to AcAc, I'm curious if ethyl acetoacetate might be healingly enjoyable orally administered? While using diet is superior for weight loss than supplementation, there are a few people talking of acute βHB effects @12g of the salts: "...there was an unmistakable uplift in mental clarity, mood and energy. This continued for a number of hours. The energy & focus was clean" It seems βHB is nicely anxiolytic in studies but maybe not intoxicating, the anxiolysis correlated with increased level of βHB . Human pilot studies and case studies suggest that ketogenic diet and ketogenic supplement-induced ketosis is a potential therapeutic approach in the treatment of epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia. Ketone bodies may exert their effects through modulation of GABAergic, glutamatergic, and adenosinergic system It has also been demonstrated that administration of exogenous ketone supplements (normal food + ketone supplements and/or medium chain triglyceride/MCT), such as ketone ester (KE), ketone salt (KS) or their combination with MCT oil (e.g., KSMCT) induce rapid and sustained nutritional ketosis https://www.frontiersin.org/.../10.../fnbeh.2018.00029/full "Administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS" [6] Just curious, couldn't spot it done anywhere... From risk assessment of Ethyl Acetoacetate Acetoacetate is an endogenous product of accelerated fat metabolism. Absorption of ethyl acetoacetate via the oral route is demonstrated in animals It may be anticipated that ethyl acetoacetate is partially cleaved already in the gastrointestinal tract due to acidic pH values or by bacterial activity. In a first metabolic step the absorbed portion of ethyl acetoacetate will be hydrolysed into 3-oxobutanoic acid and ethanol by the unspecific esterases of the blood. The acid moiety is an endogenous product within the lipid metabolism and is further metabolized predominantly to carbon dioxide and water; ethanol will be metabolized on known pathways. In animals, acute toxicity by the oral, dermal, and inhalative routes is low as judged by tests with rats. The substance demonstrated no or only mild skin irritation and mild eye irritation in tests with rabbits. Valid human or animal data on sensitization are not available. Following repeated oral exposure of ethyl acetoacetate in rats, no treatment-related adverse effects (including haematology, clinical chemistry, gross necropsy and histopathology) were reported up to 1,000 mg/kg bw/d. Note: Levels above 10 mmol/L of ketone bodies are associated with ketoacidosis.

Thanks for the kind words @Xperiment Likewise, had been wondering how you were traveling. Hope things are OK, feel free to chat with a message if ever needed. It's nice to not be in the continued pep of mixed weird moods, which turned into a bit of a nose dive, driven by grief and anger and other emotions I was struggling with in part but it's nice to get a day like today where I had the balance of positive mood, social contact, meaningful activity all working etc.

I needed a bit of extra help with my mood over winter so went back on a minimal SSRI dose. Recently, I've been cautiously exploring how things like turmeric and saffron to go with that SSRI, which I don't find alone effective. The spices etc seem quite tailorable to be used to 'level up' when mood needs a more acute lift. . I've explored conventional pharmacotherapy extensively, shifting thinking/psychological stuff and other strategies, with little sustained benefits, at many times the side-effects of conventional pharmacotherapy caused more problems than solutions and sent me off dangerously self-medicating. Also I've explored herbal options too, finding some that some helped somewhat with excellent side-effect profiles. I'm currently giving the synergy of healthy dietary phytochemicals and minimal Western medicine a go. Does it hold promise, the best of both worlds for treatment resistant conditions? I still side with improvements being bio-psychosocial-spiritual but if you're biologically bed-ridden/housebound with debilitating symptoms, you can't tackle the other dimensions properly. One thing I'll say, is conventional pharmacotherapy as a standalone for mental illness is poorly effective for MANY people. Even coupled with psychological stuff. That said, our plant medicines aren't panaceas. Diet doesn't cure everything. The medicinal spices had enough potential merit, tolerability, evidence-base and safety to make it something worth considering as continued tools, especially useful for milder symptoms but efficacy waned relying on it as standalone for myself, as things like my fermented turmeric concoctions. While curcumin alone shows antidepressant efficacy, supplementary administration of curcumin to antidepressant therapy may reverse the development of depression and enhance the outcome of antidepressant treatment, also offering more rapid relief of depressive symptoms [1]. Same with saffron, it's got me through some really dark times off antidepressants but once again, efficacy waned for mood. Saffron did seem unique for psychotic spectrum stuff, crocins not only modulate the HPA axis and NMDARs but the DAergic system in a way that may be of relevance for schizophrenia-like behavioural deficits. These spices are useful tools and seem to have limited potential for interactions with SSRIs. While saffron is useful alone, showing efficacy equal to SSRIs [2], saffron could effectively prevent reaching the criteria of metabolic syndrome [3] and it significantly augmented SSRIs, both reducing side effects [4,5] and augmenting efficacy [6] I normally use bulk Iranian saffron but spotted a cheap Saffron + Curcumin (BCM-95, which is turmeric volatiles enhancing the bioavailability of curcumin, so piperine interactions with pharmaceuticals aren't problematic). I found I could kind of chase a saffron buzz a bit, as this product, I might be more sparing. [1] https://www.ncbi.nlm.nih.gov/pubmed/26066335 [2] https://www.ncbi.nlm.nih.gov/pubmed/27701683 [3] https://www.ncbi.nlm.nih.gov/pubmed/24955550 [4,5] https://www.ncbi.nlm.nih.gov/pubmed/23280545 https://www.ncbi.nlm.nih.gov/pubmed/22552758 [6] https://www.ncbi.nlm.nih.gov/pubmed/25484177 My mood has been so pathological, absolutely crap, so I'm trying a few things at once. Got into waking early (partial sleep deprivation as needed), keeping up exercise and skipping breakfast and having ALCAR as a meal replacement. have to tackle my body and brain at the same time particularly before they get even more out of whack, the two are linked. Things like saffron are established as being useful preventing metabolic abnormalities but ALCAR is cheap. "Scientists have noted a connection between depressive disorders, primarily seen as brain-based, and, insulin resistance (IR), a modifiable metabolic pro-inflammatory state that is typically seen as peripheral. Treating IR can with drugs or behavioural interventions can ameliorate, or possibly prevent, depressive disorder and its long-term consequences including dementia at various stages of the life course. Acetyl-L-Carnitine (LAC) is an endogenous molecule that regulates glutamate homeostasis and promotes healthy mitochondrial function, among other actions. Acetyl-L-carnitine presents a significant link between altered peripheral and neural function in the context of stress and depression. It has epigenetic action in reactivating neuroplasticity by restoring an inhibitory tone upon the release of glutamate driven by elevation of a stress-induced decrease in histone acetylation. Administration is also known to ameliorate insulin sensitivity in patients with type 2 diabetes Disruption of LAC function is an example of a molecular mediator that indicates a lack of resilience leading to negative outcomes. Indeed, epigenetic alteration of LAC is a marker of IR. Importantly, modulation of LAC levels is an example of capacity for flexible adaptation—thus LAC function can be reinstated and result in amelioration of changes associated with glutamatergic damage. LAC supplementation while targeting IR (i.e., reducing peripheral hyperglycemia, hyperinsulinemia, and hypertriglyceridemia) leads to antidepressant-like responses seen after few days of administration, while responses to standard antidepressant medications require repeated weeks of administration in the same animal models" https://www.ncbi.nlm.nih.gov/pubmed/29180223 Full text: http://sci-hub.tw/10.1016/j.neuropharm.2017.11.038 Quickly, that combination resulted in a good mood improvement and symptom reduction.

I can do you a turmeric and a un-ID'd galangal if you cover postage? Also Alpinia zerumbet. They're all shoots off the main plant. A. zerumbet is truly a multi-purpose ginger plant with promising medicinal properties." [1] "Shell ginger is an exceptional multi-targeted plant for human use, considering various organs, diseases, and mechanistic actions. As it presently stands, the plant’s potential for human life is likely underestimated." Apparently, Alpinia zerumbet has leaves that make a tasty tea. I've tasted a little bit of rhizome, got quite a refreshing taste, the tea from the leaves is personally quite mild in flavour but pleasant. Leaf extracts of A. zerumbet and A. zerumbet ‘Variegata’ ranked first and second among five Alpinia species screened for phenolic contents and antioxidant activities There was some interest on kava forums with regard to it, even though the kavalactones might not be the more renowned 'euphoric' ones. Alpinia zerumbet has anti-hypertensive, anti-obesity, anti-diabetic and sedative etc properties. The major bioactive phytochemicals are dihydro-5,6-dehydrokawain 0.41% in leaves and 0.35% in rhizomes and 5,6-dehydrokawain [Desmethoxyyangonin], and essential oils, phenols, phenolic acids, and fatty acids. Kava is able to increase dopamine levels in the nucleus accumbens and desmethoxyyangonin likely contributes to this effect. Literature now suggest that culinary shell ginger may contribute to longevity [2] The kavalactones are found in fresh leaves, stems and rhizomes range from the highest amounts of dihydro-5,6-dehydrokawain per fresh weight were detected in leaves, followed by rhizomes, and stems, whereas the reversed constellation was found for 5,6-dehydrokawain with the highest contents in rhizomes and lowest ones in leaves. Leaves, at higher doses, exert antidepressant effects through the dopaminergic and/or noradrenergic system, with antioxidant and anxiolytic-like effects [3]. It also contains labdane-type diterpenes and leaves contained considerable amounts of total polyphenols. The 'Variegata' is an aromatic medicinal plant, its foliage producing an intense, unique fragrant odour due to 1,8-cineole, p-cymene, humulene, camphor, linalool, (E)-methyl cinnamate, gamma-cadinene, humulene oxide II and a-terpineol. [1] https://www.researchgate.net/…/321396609_Alpinia_zerumbet_a… [2] https://www.ncbi.nlm.nih.gov/pubmed/29385084 [3] https://www.ncbi.nlm.nih.gov/pubmed/25885936

Have some more Morning Glory (white seeds) light blue and purple flowers if anyone is interested. Can do three people free. Post here and then shoot me a PM. .

What doses of Salvia guarantitica are people finding active? Even though my interest in sedative plants has declined recently, on the contrary I now need pep... There were questions as to how effective Salvia guaranitica would be: . That said, I want to find exactly what the "high concentrations" of cirsiliol are in the plant, I can't spot anything? It may be feasible to get 2mg/kg (active i.p dose in mice), which is quite low in human equivalence - that said, It does seem odd to me that a flavonoid is reasonably potent with it's low affinity? Salvia guaranitica is used as a traditional medicinal plant used in Latin America as sedative. Studies demonstrated the presence of cirsiliol in its extracts and found that this flavonoid is a competitive low affinity benzodiazepine receptor ligand. Sedative and hypnotic properties of the ethanolic extracts of S. guaranitica (Medina et al., 1989) have been associated with the presence of high concentrations of the flavonoid cirsiliol and caffeic acid ethyl ester (Mader et al., 1996). Cirsiliol 2 mg/Kg, i. p. significantly decreased the number of head dips and rearings in the holeboard test, which indicates sedative action (Wolfman et aI., 1994). Moreover, cirsiliol at a dose of 4 mg/Kg, i. p., exerted hypnotic effects [1] Salvia guaranitica extracts and its active principle cirsiliol, possess sedative and hypnotic properties at a dose equivalent to 3g of the fresh leaf; cirsiliol produces these effects probably acting on the benzodiazepine receptor. [2] It also contains caffeic acid ethyl ester, also with affinity for GABAARs. The paper states: "additional active principles present in Salvia guaranitica and possessing synergistic action with cirsiliol can not be totally ruled out" Saw a great initiative from beyondblue - they've released a Salvia guaranitica - 'Black and Bloom'. Not only do you get a pretty plant but a traditional medicine plant. As I'm finding, these plants are tough as seem to thrive. Proceeds from the sale of Black and Bloom go to the beyondblue foundation. Hopefully more plant retailers start to sell these, first time I've spotted them. With a hardly responsive GABAergic system and having a baseline of a really low mood, they seem mild. Plants are relatively small but some oral experiments, in conjunction with some healthy dietary modification: "Amistad": At 4g fresh younger leaf, easily a placebo, nothing really noted other than possible very mild relaxation "Black and Bloom" At 4g fresh mature large leaf, it seemed very mildly calming, easily placebo. At 8g still relatively mild, easily placebo. "Black Cobalt" mature large leaves, jumped in at 10g and this one seemed possibly more active but it was more likely I was having a slightly better day @ 7g spent morning in the garden and felt OK, easily placebo

I've been continuing this quite awhile hoping it would make a standalone anti-depressant option for me. The seasonal shift has been intense for me. If anything, it's brought some stability but actually confronted me with new levels of existential distress That classic K10 question "how often did you feel worthless" so pressing... this scary crushing sense of my mortality imbuing this impetus to do things worthwhile and positive even when things are a struggle. Normally, I'd be in quite a suicidal state, where you're actually encouraging that process of death to hurry up but when you start seeing the bigger picture, in a more clear-headed and less pathological state of mind... Coming out of that seemingly super-inflammatory state - I strongly believe inflammatory mediators, as research suggests, strongly promote a general trade-off towards focusing on immediate (often maladaptive) versus delayed (often more eudaimonic) outcomes while leading from everything to mood issues, anger problems to impulsivity - has been strange, not being pepped pathologically, forcing me to be reconsidering what the hell I'm doing with life. It's not easy finding that meaning, purpose and contribution when you're not feeling the greatest but I'm trying to make small positive vibrational shifts. Probiotic turmerics, even with saffron, is not providing good stable uplift - Been sticking with it, hoping the mood support would be adequate.. It's easing some symptoms but the mood has been incredibly 'sanely depressing'. Been trying to give the anhedonic, anergic, apathetic moods a kick in the arse by keeping up exercise (it's reduced in vigour as I'm just so drained), gardening and exerting meaning and purpose but it's not working very well. Been chipping away at incremental meaningful stuff but plagued by quite an intense and anergic dysphoria, at best anhedonia - what I was trying to keep on top of and had slight success for a bit... Been painfully fighting the inner death drive with lots of potting up plants for others and propagating things that will hopefully cope with the weather, sounds small but all I can manage. The "life output" trays are filling up again, trying to give the barrage of morbid looping thoughts the finger but it's a battle. Trying to assert some simple meaning and break my mind from the loops of depressogenic thoughts, maintain some behavioural activation even though it's so energetically hard, haven't had a energetic shift like this in a long time. Been a long time without my serotonin transporters occupied and continual serotonergics... finding aiming for the social can amplify things the wrong way at the moment, yet trying to not get extra disconnected.

Yeah I sort of came to the conclusion it probably needs longer term dosing over acute. At 3g I got mild effects improved sleep quality (with atypical vivid dreams) but I'm not the best test subject. I don't know how stable the galphimines are thermally but I probably wouldn't smoke, if anything "The plant’s dried leaves and flowers are macerated in alcohol and shaken by hand to obtain the required potency." [1] That said, I had someone with diagnosed GAD try it and they found it gave them an early sleep and said "Definitely find it calming". Maybe if there's nothing too pathological, like hyper-excitability etc, it's not too effective?

I'll sort out the above. No problems @mole. OK we'll leave it there. If anyone gets desperate for some seed, let me know, otherwise it's available other places, let me know if you can't find others.

Can spare a few people some free seed [and/or smallish quantities of research material (in exchange for an opinion in a thread)]. I'll say the first three people? Can probably do more if someone's really keen, just keeping some seed for plant meets etc. Post here then shoot me a PM. "Best time to sow is late autumn and winter in good quality seed raising mix, cover lightly as seeds need light to germinate. Place in a warm sunny position. Don't plant out until late spring/early summer, keep moist on transplant. Don't overfeed - likes impoverished soil" High-quality evidence was found to exist for the use of Galphimia glauca (galphimia) for anxiety disorders [1] Dose: Dried herb 0.6–1 g per day standardized to 0.175–0.348 mg of galphimine B Clinical trials showing equivalence to synthetic anxiolytics No adverse reactions found in studies Generalized anxiety, GAD While emerging data is encouraging, further placebo-controlled studies are needed. Galphimines have been identified as active compounds in galphimia, with the nor-secotriterpenes galphimine A and galphimine B, being shown to have the strongest anxiolytic activity. Galphimine B has been considered the primary active constituent for galphimia’s anxiolytic and sedative effect, and is the constituent standardized for clinical trials. Galphimine B has been shown to interact with serotonergic transmission in the dorsal hippocampus in rats. This occurs by increasing the frequency of neuronal discharge in CA1 cells, resulting in activation of 5HT(1A) receptors. One study in mice demonstrated that galphimines cross the blood–brain barrier, with galphimine A found to have an effect on the central nervous system. 2.5.3 Evidence of Efficacy 2.5.3.1 Preclinical A number of galphimine constituents, including galphimine B, were evaluated for their anxiolytic effects in mice using the EPM. Mice were intraperitoneally administered 15 mg/kg of a galaphimine derivative 1 hour before testing. An anxiolytic-like effect in the mice was found for both galphimine A and galphimine B, with a significant increase in the time spent in and number of entries into the open arm in the EPM. A second study on mice used a methanolic extract (standardized for galphimine B, 8.3 mg/g) at different doses (125, 250, 500, 1000 and 2000 mg/kg), which were orally administered at three different times (24, 18 and 1 hour before the test). Significant anxiolytic-like effects were found in the light–dark paradigm test and the EPM, but not the forced swimming test. 2.5.3.2 Clinical Two clinical trials have found galphimia to be an effective anxiolytic. The first was a 4-week, positive-controlled double-blind RCT, with a cohort of 152 patients with a DSM-IV diagnosis of GAD and HAMA scores ≥19 . The two groups received either galphimia aqueous extract (310 mg standardized to 0.348 mg of galphimine B), or the benzodiazepine lorazepam (1 mg). Each treatment was administered in capsule form (identical in appearance) twice daily. Both groups demonstrated a significant reduction in anxiety symptoms. There were no significant side effects reported in the galphimia group, which contrasted with the lorazepam group, in which over 21 % of people reported excessive sedation. https://neupsykey.com/herbal-anxiolytics-with-sedative-actions/ "0.175 mg of galphimine-B and administered for 15 weeks to patients with generalized anxiety disorder, showed greater anxiolytic effectiveness than that obtained with lorazepam, with high percentages of therapeutic tolerability and safety." [2, 3] Galphimia glauca has been used for many years in Mexican traditional medicine for treating mental diseases, particularly nervous hyperexcitability disorders. This plant contains galphimines which have been shown to possess the ability of modifying the frequency of discharge of dopaminergic neurons in the Ventral tegmental area [4]. Galphimine-B appears to be an allosteric modulator of 5HT1A receptors [5] It was capable of blocking positive and cognitive symptoms associated with psychosis induced by ketamine [6] Anti-inflammatory activity and chemical profile of Galphimia glauca. [1] https://www.ncbi.nlm.nih.gov/pubmed/29575228 [2] https://www.ncbi.nlm.nih.gov/pubmed/22828921 [3] https://www.ncbi.nlm.nih.gov/pubmed/17562493 [4] https://www.ncbi.nlm.nih.gov/pubmed/12567277 [5] https://www.ncbi.nlm.nih.gov/pubmed/21742023 [6] https://www.ncbi.nlm.nih.gov/pubmed/29710504

I'm not sure about how long SSRI medications induce changes to 5-HT2ARs particularly with relevance to being 'constitutionally right' for tryptamines, mindperformer is likely more versed, but there are some imaging studies with regard to depression. I'd say a lot of the binding potentials change depending on the course of the illness, too? A remitted depression etc being different. More so, binding pattern for 5-HT1A/2A seems to change in depression and might be long term ...findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT2A receptors. The correlation of increased 5-HT2A receptor binding potential with increased scores on Dysfunctional Attitudes Scale" [1] Higher 5-HT1A receptor binding potential has been found in major depressive disorder (MDD) during and between major depressive episodes. [2]