Plant-derived Dopaminergics In my quest for planty dopaminergics I've looked into: Saffron which has been studied and found effective as an antidepressant and in children with ADHD and as combination therapy with methylphenidate in ADHD adults, Lobelia cardinalis (lobinaline), Oroxylum indicum (oroxylin-A) which has some slight benefits in cognitively impaired humans (but reviews by people trying it themselves have been very mixed), Trichilia catigua (dose-dependently inhibited the uptake and increased the release of dopamine) and carvacrol (increased prefrontal and nucleus accumbens dopamine at low doses orally). There's of course the DOPA-rich Mucuna as a precursor. It is considered the CNS bioavailability of L-DOPA without carbidopa/benserazide is 1/5th that of the combinations Ideally, hederagenin, a novel triple reuptake inhibitor of monoamine transporters which also reduces stress hormones and exerts antidepressant effects sounds promising, it's found in quite a few plants including Quinoa but reports of human use have been very mixed. Carvacrol and Monoterpenoid-rich extracts From Oregano In humans, with a supercritical CO2 extract, "a single dose ... induced a state of wakeful relaxation, enhanced vigilance and improved concentration in addition to increased mental capacity but did not affect sleep structure" [1] A single dose increased calmness, vigilance, mental information processing capacity, with an increase in processing speed with the conclusion it "is safe and does not exhibit any adverse side effects at the dosages providing the functional benefits, a result that was also confirmed by behavioural studies". " in vitro profiling revealed that only [an] extract, but none of its constituents, showed the full range of desired activities, namely inhibition of the reuptake of all three monoamine neurotransmitters in addition to reversible inhibition of their inhibiting enzyme. Our data are in line with the well-studied phenomenon that mixtures of natural ingredients, especially phytochemicals, exert synergistic effects that are not present in single ingredients" Carvacrol also exerts several actions on the neuronal system including acetylcholinesterase inhibition as well as having anxiolytic and antidepressant properties having the ability to likely modulate mood and cognitive processes. It also modulates central neurotransmitter pathways, such as dopaminergic, serotonergic and GABAergic systems, a terpene rich oregano extract acting as a triple reuptake inhibitor [2]. It also improves aspects of Parkinson's in animal models [3] It seems to cause a specific increase of DA levels in PFC and "ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects." "Carvacrol is a monoterpenic phenol isolated from aromatic herbs including oregano and thyme. This aromatic phytochemical has anti-inflammatory, analgesic, antiarthritic, antiallergic, anticarcinogenic, antidiabetic, cardioprotective, gastroprotective, hepatoprotective, and neuroprotective properties. This monoterpenoid phenol regulates human ion channels transient receptor potential V3 and A1 causing a sensation of warmth. It is also known that carvacrol can activate PPAR and suppress COX-2 mediated inflammation. Dong et al. demonstrated that enzyme cytochrome P450 2A6 (CYP2A6) is the 1 predominant drug-metabolizing enzyme involved in the metabolism of carvacrol requesting attention when carvacrol is coadministrated with other compounds mainly undergoing CYP2A6-mediated metabolism. Orally administered carvacrol (12.5–50 mg/kg) induces antidepressant effects that seem to be mediated by the dopaminergic brain pathways in mice. Zotti et al. showed that carvacrol administration (12.5 mg/kg, by mouth [PO] for 7 days) can raise 5-HT and dopamine ranges in the hippocampus and prefrontal cortex" Roughly extrapolating, as an antidepressant, mice doses were 12.5-50mg/kg orally, 25mg/kg effective, divide by 12.3 to get the equivalent human dose (2mg/kg), assuming the EO contains 65% carvacrol, 3mg/kg may be effective... Another extrapolation from studies "Extrapolating the doses of carvacrol in these animal studies to relevant human doses gives us a range of oregano oil from 600 mg – 1200 mg per day. The 600 mg per day dose approximates the data from the most recent animal study on mood boosting." [1] https://www.teknoscienze.com/tks_article/animal-and-human-efficacy-data-of-a-brain- active-oregano-extract/ [2] https://www.researchgate.net/.../49728029_Monoamine ... [3] http://www.scielo.br/.../v76n2/0004-282X-anp-76-02-0071.pdf Lobelia cardinalis 'The Penobscot people smoked the dried leaves as a substitute for tobacco. It may also have been chewed'. Lobinaline caused a significant, dose-dependent increase in dopamine release and preclinical and clinical data exist that support nAChR-based ligands as promising therapeutic agents for the treatment of depression, alcohol and drug dependence. The alkaloid has been proposed as a treatment for Parkinson's and psychostimulant abuse [1]. Lobinaline appears to be distinct from nicotine and lobeline in terms of its selectivity and 2 functional effects at nAchRs and is a DAT inhibitor. Compared to other plant metabolites, such as nicotine and lobeline, lobinaline is relatively non-selective with respect to α4β2- and α7-nAchRs Lobinaline displays appropriate pharmacokinetics and low mammalian toxicity in mice relative to lobeline, the most widely studied Lobelia alkaloid. While there is history of traditional use [2] and herbalists suggest it may be a nervine, contemporary use of the plant remains very limited. Lobinaline is devoid of the characteristic actions of lobeline and in mice, lobinaline is less toxic than lobeline (but did lower animals blood pressure) [3]. Toxicology suggests a large quantity ingested is toxic with symptoms reported as being "nausea, vomiting, diarrhea, salivation, exhaustion and weakness, dilation of pupils, convulsions, and coma" but some have used it in smaller quantities as a tea [4]. Lobinaline is an inhibitor of the dopamine transporter (DAT) in vitro and in vivo. It is more potent for inhibiting DAT (IC50 = 11.95 μM) vs lobeline (IC50 = 30-80 μM) [5]. In addition, lobinaline is a weak non-subtype selective partial agonist at nicotinic acetylcholine receptors (nAChRs) and a good free radical scavenger. it is likely that the DAT inhibitory actions are "atypical" in not having abuse liability. Early herbalists noted that a tincture induced the "disposition to sing" and preliminary bioassays by others have noted "...cardinalis is more like nicotine. Seems to give stimulant effects similar to mild nicotine. Seems to have mild aphrodisiac properties. Slight mood lift present it also seems to have anti-depressant properties" [6] The N-oxide has potentially superior dopaminergic activity [7], that said at 25mg/kg it lacked abuse potential in the conditioned place paradigm model and "at the dose we administered does not seem to have a significant effect in the mesolimbic dopaminergic pathways and may not facilitate a role in treating drug abuse" [8] [1] https://pubmed.ncbi.nlm.nih.gov/27105955/ [2] https://www.cargocultcafe.com/cardinal-flower/ [3] https://doi.org/10.1139/cjr38b-055 [4] https://eatwild.weebly.com/blog/cardinal-flower [5] https://doi.org/10.1016%2Fj.fitote.2016.04.013 [6] https://drugs-forum.com/threads/lobelia-cardinalis.213716/ [7] https://pubmed.ncbi.nlm.nih.gov/34648893/ [8] https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1013&context=medsci_etds Hydroxybakuchiols from Psoralea corylifolia Fructus psoraleae ( Psoralea corylifolia ) has been proposed to be a 'Yang Tonic' and it is said Psoralea corylifolia is an excellent tonic remedy, for improving overall health and vitality. 3 The lipophilic extract of seeds acted as monoamine reuptake inhibitor (potent for DA/NE uptake and mild for 5-HT uptake) [Dry Fructus Psoraleae yielded 4% of a petroleum extract that contained hydroxybakuchiols]. Unfortunately, bakuchiols appear to have low absorption [oral bioavailability of isolated bakuchiol was said to be 3.2%] Fructus psoraleae has been used clinically to prevent brain aging and treatment of memory deficit, sexual dysfunction and fatigue syndrome in China for hundreds of years; the fructus psoraleae that is commonly used with a chronic, oral dosing of 9 – 30 g is known to have no toxic or addictive liability as reported by ancient Chinese clinicians. Total furocoumarins from seeds of Psoralea corylifolia improves behavioral and biochemical abnormity in model of depression and the the bakuchiol class of molecules appear to be catecholamine (dopamine and noradrenaline) reuptake inhibitors, with fairly high potencies (in the low micromolar and high nanomolar range) Petroleum extract of Fructus Psoraleae at 20, 200, and 500mg/kg i.p (1.6-41mg/kg human equivalent) has been explored but considering low oral bioavailability, oral doses may need to be higher. The higher human suggested dose range (30g), assuming a 4% yield of lipophilic constituents, is equivalent to 1200mg of petroleum extract. - preliminarily researched as a therapeutic for Parkinson’s disease, depression, Attention Deficit Hyperactivity Disorder (ADHD) and cocaine addiction - had a long-lasting stimulant effect: the long-lasting stimulant effect of FP is characterized by a slower onset and a longer duration of action than cocaine administration 4 - An extract had no intrinsic rewarding or aversive effects on mice in conditioned place preference paradigm - Δ3,2-hydroxybakuchiol strongly increased DA and NE levels and mildly increased 5-HT level - efficacy of Δ3,2-hydroxybakuchiol is similar to that of bupropion - it is speculated that increase in NE and DA by Δ3,2-hydroxybakuchiol could ameliorate insomnia and fatigue and, thus, could be helpful in curing depression - MAO-B inhibitory action - adaptogen-like effect Downsides: -estrogen-like effect -photosensitisation effect -One case study associated Psoralea with hepatotoxicity Others impacting dopamine Hypericum species may act as mild monoamine uptake inhibitors, elevating monoamines levels in some brain areas. Specific DA uptake was inhibited in a dose dependent manner. The potencies for the uptake inhibition of NA, DA and 5-HT were 30, 7 and 1 for one extract Madecassoside, a principal bioactive terpene from Centella asiatica increases DA Flavonoids, viz., daidzein, procyanidin, hesperidin, nobiletin, catechins and orientin and have been reported to enhance catecholamine levels in in vitro and in vivo models. Hesperidin, found majorly in citrus fruits, acts as an antidepressant via increasing DA levels in the striatum Cocoa polyphenolic extract acted as cognition enhancer due to increase in DA turnover Pycnogenol a combination of procyanidins, bioflavonoids and phenolic acid extracts from Pinus pinaster Aiton (Pinaceae) bark restored an induced decrease in DA Chronic but not acute treatment with Ginkgo extract increased dopaminergic transmission in the PFC. Flavonol derivatives from Ginkgo the increase of dopaminergic and cholinergic neurotransmission in the prefrontal cortex Linalyl acetate from clary oil, a well-known phytomedicine from medieval period, have various benefits including relaxation and soothing effect in stress conditions. This important ester compound was reported to play an important role in stimulating the DA pathway system Total saponins extracted from Panax notoginseng increased the levels of dopamine and 5 noradrenaline. Saffron increased dopamine. Plant extracts like Akebia quinata (Houtt.) Decne, Acca sellowiana (O.Berg) Burret also attributed to have catecholamine reuptake inhibition properties (Jin et al., 2012; Martínez- Vázquez et al., 2012). Similarly, extracts from Cullen corylifolium (L.) Medik. and Chaenomeles lagenaria (Loisel.) Koidz have shown mixed inhibition of DAT and NET (Zhao et al., 2008). Common flowering quince, the fruit of Chaenomeles speciosa "is a selective, potent DAT inhibitor" A petroleum ether extract (FP) from Fructus Psoraleae, seeds of Psoralea corylifolia, was a strong DAT/NET inhibitor Review: https://www.ncbi.nlm.nih.gov/pubmed/19585471 6