Plant-derived anxiolytics In my experiences, if I was to try to subjectively rank anxiolytic potency of various plants it would go something like this: Lemon balm < Lower dose Passiflora < Lower dose skullcap < Zizyphus seed < Hops = Valerian < Oral lavender oil 80-160mg = lower dose kava = low dose CBD < Erythrina mulungu < Higher dose 25g+ Passiflora < CBD 600mg + < Higher dose skullcap < High dose kava. Lemon balm Throughout history, lemon balm has been used medicinally to heal wounds, prevent and treat cold sores, soothe nerves, improve sleep, and strengthen the memory and the mind. The ancients are known to steep lemon balm in wine, a traditional medicinal dosage form, for fevers and to uplift the spirits. Lemon balm contains more than 100 chemicals including the flavonoids (quercitrin and rhamnocitrin), which have an antioxidant effect; phenolic acids and tannins, primarily rosmarinic acid; the 7-glucosides (apigenin, kaempferol, quercetin, and luteolin); caffeic and chlorogenic acids; triterpenes; and volatile oils citral a, citral b, (10%-30%), and citronellal (30%-40%) that render its lemony flavor and aroma. Lemon balm treatments were generally associated with improvements in mood and/or cognitive performance [1] Improvements in feelings include “calm”, “secure”, “at ease”, “satisfied”, “comfortable”, “self-confident”, “relaxed”, “content’, “steady” and “pleasant”. 1 "Twenty healthy young participants received single doses of 600, 1000, and 1600 mg of encapsulated dried leaf, or a matching placebo, at 7-day intervals. Cognitive performance and mood were assessed before dose and at 1, 3, and 6 h after dose - data supported the cholinergic receptor-binding properties of M. officinalis and the fact that it acts on mood and cognition in a dose- and time-dependent manner [2] 60 drops/day of lemon balm extract exerted positive effects on cognition in Alzheimer’s Disease Has GABA transaminase inhibition activity via rosmarinic acid thus acting as an indirect GABAergic. Shown to improve mood and mental performance. These effects are believed to involve muscarinic and nicotinic acetylcholine receptors. Positive results have been achieved in a small clinical trial involving Alzheimer patients with mild to moderate symptoms. Lemon balm essential oil has an affinity for gamma-aminobutyric acid A (GABAA) receptors and exerts a net depressant effect on neuronal activity (commensurate with anxiolytic effects). Essential oils obtained from Melissa officinalis leaf showed high acetylcholinesterase and butyrylcholinesterase co-inhibitory activities. They also found that Melissa elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission. Lemon balm essential oil inhibited radioligands binding to the muscarinic M1, 5HT2A, histamine H3 receptors and GABAA receptor channel site. M. officinalis EO displayed broad receptor binding capacity in comparison to L. angustifolia EO, and showed affinity for binding with 5HT1A and the agonist binding site of GABAA receptors. A 50:50 mixture of Melissa and Lavender essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245564/ [2] https://www.ncbi.nlm.nih.gov/pubmed/12888775 CBD Researchers have demonstrated that CBD confers antipsychotic, anxiolytic (anxiety- reducing), and antidepressant effects as a: 2 FAAH inhibitor AEA uptake inhibitor Antagonist of CB1/CB2 receptor agonists (NAM CB1Rs) GPR55 antagonist TRPV1 agonist TRPV2 agonist TRPA1 agonist TRPM8 antagonist 5-HT1A agonist 5-HT2A agonist 5-HT3 agonist Tryptophan degradation inhibitor Adenosine uptake inhibitor and indirect A2A agonist Mu-opioid ligand Mu- and delta-opioid positive allosteric modulator D2 allosteric modulator Dopamine transporter inhibitor GABAA positive allosteric modulator Alpha-1 and alpha-1-beta glycine receptor positive allosteric modulator T-type calcium channel inhibitor PPARγ agonist As a negative allosteric modulator of the CB1 receptor, CBD shows particular promise for treating conditions associated with endocannabinoid excess or over- activity (obesity, metabolic disorders, liver disease, cardiovascular issues) CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism." It has prohedonic effects "CBD is able to potently regulate the activity states of the mesolimbic system both through modulation of DA-related behaviours and release patterns 3 in the NAc, and via functional regulation of VTA DAergic and non-DAergic neuronal substrates" Importantly, for people on other medications, CBD inhibits CYP1A1, 1A2 and 1B1 enzymes, and recent studies have indicated that CBD is also a potent inhibitor of CYP2C19 and CYP3A4. It may interact with other medications metabolized by the same pathway or by inducers/inhibitors of the isoenzymes. Kavalactones Holm et al. (1991) have shown that kavain alters the sensitivity of an area of the Iimbic system (hippocampus), an area indirectly associated with emotional excitability, due to its inhibition of the emotional centers of the brain cortex. It is interesting to note that the researchers found a more pronounced effect when a kava extract was used, than kavain alone. This is probably because kava extracts contain the other kavalactones, which interact with the limbic system more completely than kavain alone. Kavain, along with dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are the most abundant kavalactones. Numerous proteins including γ-aminobutyric acid type A receptors (GABAARs), voltage-gated Na+ and Ca2+ channels, opioid μ and δ receptors, dopamine type-2 receptor, histamine type-1 and 2 receptors, cannabinoid type-1 receptor, and monoamine oxidase type B have been suggested to be the molecular targets for kavalactones. Due to the paucity of robust evidence, however, a consensus on the pharmacology of kavalactones has not yet been reached, but there is a prevailing view on the basis of their benzodiazepine-like pharmacological actions that GABAARs are the main target for kavalactones. The possibility of kavalactones interacting non-specifically with lipid membrane of neurons to exert their psychoactive effects has been raised. However, our mutational studies revealed a near-complete loss of kavain potentiation at α1β3N265Mγ2L GABAARs . The extensively studied β3N265M point mutation is known to selectively abolish the in vitro and in vivo sensitivity of anaesthetics such as etomidate, propofol, pentobarbital and volatile agents. As such, this finding argues strongly against the lipid hypothesis, and supports a direct kavain-GABAAR interaction: enhancement of GABAAR function by kavain occurs in a subtype non-selective and flumazenil-insensitive manner. Interestingly, kavalactones may be neuroprotective - Methysticin administration activates 4 the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD Flavokawains a and B in kava, not the main kavalactones may be responsible for sometimes observed hepatotoxicity Unfortunately, drug-herb interactions are a real possibility and results vary wildly, in one study out of CYP1A2, CYP2D6, CYP2E1, and CYP3A4/5, Kava only affected CYP2E1, producing a 40% reduction. The rest seemed to be unaffected. In another, "Whole kava extract.... caused concentration-dependent decreases in P450 activities, with significant inhibition of the activities of CYP1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%) ... CYP2A6, 2C8, and 2E1 activities were unaffected." and: "the kava extract and the three kava lactones were found to be potent inhibitors of CYPs 1A2, 2C9, 2C19, 2E1, and 3A4" Hops - Humulus lupus The typical use for hops is for sleep disturbances and mood disorders, such as anxiety and restlessness. Data from in vivo studies in rats have shown that a hops extract and its fraction containing alpha-bitter acids (humulones) exert significant sedative and antidepressant effects, whilst hops beta-acids (lupulones) appear to also exhibit antidepressant activity with fewer sedative effects, probably by affecting gamma- aminobutyric acid (GABA) neurotransmission activity. Moreover, in vitro binding experiments have shown that hops interact with certain serotonin (5-HT6) and melatonin (ML1) receptor subtypes, which are involved in various CNS functions related to stress activity, relaxation, circadian rhythms and sleep. Hops and xanthohumol treatment modulated the inflammation and apoptosis of aged brains, exerting a protective effect on damage induced by aging. They are a source of polyphenols and bitter acids and are believed to be very effective in the treatment of 5 metabolic syndrome Valerian Valeriana officinalis extract is a popular herbal medicine used for the treatment of anxiety and sleep disorders. The anxiolytic and sedative effects are mainly attributed to the modulation of GABAergic transmission but the selective interactions of valerian extract and valerenic acid with Group I and Group II mGluR may represent an alternative explanation for the anxiolytic properties of this plant. Binding affinities could also be demonstrated at some of the screened melatonin (ML1 and ML2) and serotonin (5- HT4e, 5-HT6 and 5-HT7) receptor subtypes. A single oral dose of valerian modulates intracortical facilitatory circuits. While none of the valerian extracts displayed sedative effects, they did produce pronounced anxiolytic and antidepressant effects in one study. Valerian root extract may reduce emotional, physical, and behavioral symptoms of premenstrual syndrome. Its pharmacological activity may result from interactions among multiple constituents rather than any one compound or class of compounds. The primary active constituents include valerian’s essential oil and its corresponding sesquiterpenes (valerenic acid), the iridoid esters (valepotriates) 6 Passiflora incarnata The genus Passiflora is popularly used to treat a variety of ailments. predominately anxiety. It is a rich source of flavonoids (flavonoid content ~2.5%). It contains extremely low levels of beta-carboline alkaloids (harmalol, harmol, harmane, harmaline and harmine) and higher levels of flavonoids like orientin, isoorientin, vitexin, and isovitexin in the aerial parts. The recommended daily dosage of dried passion flower is 4-8 grams, some suggest starting at 2g. Echium amoenum - Persian Borage or Gol-e-Gavzaba Commonly used as an anxiolytic remedy and also as a mood enhancer. It has anxiolytic, anti- depressant, anti-OCD, antioxidant, sedative, and anti-inflammatory effects. It's found use in PMS, seems to preliminarily have better efficacy than SSRIs in depression and comparable effectiveness to SSRIs for anxiety Erythrina mulungu Erythravine, one of mulungu’s active alkaloids, may also help reduce anxiety and protect brain function. Shown to be a potent nAChR antagonist. Flavonoids present in this herb are 7 known antioxidants Jujube seed Zizyphus jujube seed has been also traditionally used for psychiatric disorders in Chinese and Korean medicine. Traditionally, one of the main functions of jujube, as described in herbal medicine, is to benefit our brain by calming down the mind and improving quality of sleep. Jujube possesses neuroprotective activities, including protecting neuronal cells against neurotoxin stress, stimulating neuronal differentiation, increasing expression of neurotrophic factors, and promoting memory and learning.The plants secondary metabolites modulate GABAergic activity and the serotonergic system, interestingly the postsynaptic 5-HT1A receptors. Intriguingly, it exhibited significant effects on both the expression and activation of GABAA receptors. It improves memory impairment through BDNF/TrkB signaling and is suggested to have a protective effect against chronic depressive disorders Albizzia julibrissin Albizzia julibrissin "Happy tree": antidepressant-like effect via the 5-HT1A receptor system. Julibroside C1 (0.5mg/kg). shows anxiolytic-like effects, which might be mediated by the 5- HT1A and GABA(A)-benzodiazepine receptor systems. 8