How Nature is Guiding The Quest for Novel Mental Health Treatments Not to be used as medical advice or to self-treat any condition Innovative treatments for severe mental illness have been slow to come to any useful fruition, leading to the consideration of natural products as therapeutic leads. As mentioned in an earlier presentation, many modern CNS drugs are derived from nature. Take for example the treatment of cognitive disorders: Mood and Anxiety Disorders etc A major breakthrough in the historical treatment of depression was the serendipitious discovery of the mood-elevating properties of a class of drugs called monoamine oxidase inhibitors. While using some early versions of these drugs like isoniazid for other illnesses like tuberculosis, it was discovered they had pronounced effects on the patient's mood, sometimes making patients inappropriately happy. This class of drugs has often been limited in clinical utility due to an array of serious contraindications, including in terms of diet. The discovery of selective, reversible MAO-A inhibitors which bind to the enzyme less 'tightly' and in a reversible manner has made them more clinically useful. Many molecules in Nature's Pharmacopoeia inhibit this enzyme which thus slows the degradation of monoamines in the brain. Some natural products are particularly potent inhibitors of this enzyme. A class of natural molecules called β-carbolines can inhibit monoamine oxidase enzymes which are normally classified into two subtypes, MAO-A and MAO-B. The first class is typically used for it's antidepressant properties as it primarily degrades serotonin and norepinephrine, while MAO-B inhibition is typically used for Parkinson's as it has greater selectivity for dopamine. These potent molecules have demonstrated an array of clinical, neuroprotective and restorative effects on the brain, including increasing hippocampal neurogenesis, the birth of new cells in the brain and have guided the search for new molecules which have different therapeutic properties, for example 9-methyl-β-carboline which seems to be a potent neurorestorative. 1 The later invention of tricyclics, then serotonin reuptake inhibitors largely replaced their clinical use. Paradoxically, serotonin reuptake inhibitors existed in nature and were utilised far before their modern discovery, having a traditional use for mood related complaints. An example is the mesembrine-type alkaloids, found in Mesembryanthemum sp . such as Sceletium Boophone disticha alkaloids also impact serotonin reuptake and have traditional use. An array of natural products have been found to be efficacious in mental illnesses, in a meta-analysis, strongest evidence for support was for St John’s wort for depression, along with curcumin, and saffron. Perhaps the most well known mood plant is St John's Wort ( Hypericum perforatum ). It works by slowing the reuptake of monoamines in the synaptic cleft, similarly to conventional modern antidepressants. It does however like many plants have the possibility to cause interactions with other medicines so due caution is required [1]. One aspect of many natural products therapeutic effect, aside from modulating neurotransmitters etc, is the ability to increase brain-derived neurotrophic factor, BDNF. This is considered to be 'miracle-grow' for the brain. Many compounds have this effect but it is just one aspect of their pharmacological action on the brain Other examples include Lavender ( Lavandula angustifolia ) where it is now common to see the essential oil used in capsules orally. In some studies, it has shown efficacy similar to both SSRIs (for mood) and benzodiazepines (for anxiety) [2, 3]. Whilst the potency of medicinal herbs can sometimes be a hindering factor for their use, extractions of the active constituents sometimes yield potentially effective medicines. Take for example chamomile, which in a concentrated form, seems to potentially rival stronger conventional medicines [4], although the inital results should be interpreted with caution. Shorter term, chamomile extract produced a clinically meaningful reduction in generalised anxiety disorder symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. In a similar fashion, even plants like oregano ( Origanum vulgare ) are being researched as extracts for mental health benefits. As a herb, it's rich in flavonoids and active monoterpenoids like carvacrol. In humans, with an 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 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" [5]. 2 Many other Lamiaceae are utilised for their benefits on the brain, from common culinary ones like Rosemary and Sage ( Salvia officinalis ) [6] to Spearmint ( Mentha spicata ) [7, 8] to Lemon Balm ( Melissa officinalis ) [9] There is mounting evidence of beneficial cognitive and mood effects of sage but although Salvia officinalis seems to have positive, acute, cognitive-enhancing and mood effects, its effects over longer-term ingestion require study. A randomised placebo-controlled trial in healthy young participants found 300–600 mg encapsulated dried Salvia leaf improved mood and cognitive functions after a single dose. Spearmint may be a beneficial nutritional intervention for cognitive health. Recent studies show that compounds isolated from Mentha spicata are promising for neurodegenerative therapy Improved cognitive function task scores after spearmint suggest improved reasoning, significantly improved attention/concentration and planning from baseline after 30 days of treatment. Day one, subjects experienced acutely improved attention/concentration from pre- supplementation. It was well-tolerated and may improve certain aspects of cognitive function. Using spearmint as an extract improved quality of working memory and spatial working memory accuracy, caused improvement in ability to fall asleep. Overall treatment effects were evident for vigor-activity, total mood disturbance, and alertness and behaviour following wakefulness, with trends observed for improvements after spearmint Lemon balm treatments were generally associated with improvements in mood and/or cognitive performance. Improvements in feelings include “calm”, “secure”, “at ease”, “satisfied”, “comfortable”, “self-confident”, “relaxed”, “content’, “steady” and “pleasant”. Saffron ( Crocus sativus ) is becoming more utilised in modern herbal medicine where it's benefits include: - reduction of depression and anxiety symptoms (on par with conventional medications) [10, 11] - reduction of cognitive complaints (on par with conventional medications for Alzheimer's) - reduction of ADHD symptoms in children [12, 13] As mentioned in an earlier presentation, Sceletium tortuosum has a novel mechanism of action that may be superior to SSRIs for some people, including pro-cognitive benefits [14, 15] Some herbs like Ashwagandha ( Withania somnifera ) have been found effective in 3 augmenting conventional medications, for example in bipolar disorder and severe mental illness: Studies suggest that Withania somnifera may treat a broad spectrum of symptoms in serious mental illness: it "provides significant benefits, with minimal side effects, for negative, general, and total symptoms and stress in patients with recent exacerbation" [16] and recently, that was replicated for depression and anxiety symptoms [17]. It also improves cognitive capacity in bipolar disorder and appears to have a benign side-effect profile [18]. Turmeric ( Curcuma longa ) has also been employed as a medicine for the brain. Curcuminoids, one active constituent, may be used as an effective and safe modality for treatment in patients with depression, with a better tolerability profile and safety than SSRIs [19] and also as an augmentation option. It also may reduce some of the metabolic side- effects of conventional medications eg when added to antipsychotics Supplementation of curcuminoids to standard antidepressants showed a significant reduction of anxiety and depression in patients with major depressive disorder Moreover, curcumin extracts significantly improved depressive symptoms and demonstrated anxiolytic effects in patients with atypical depression. An diverse range of plants, from Kava, to Passionflower, to Skullcap, to Brahmi have shown some merits. As examples of how Traditional Chinese Medicine (TCM) is guiding innovation, Gardenia jasminoides is one example that demonstrates rapid-acting antidepressant properties, similar to ketamine [20]. A new frontier in mental health is the psychedelic therapies eg psilocybin for treatment resistant depression. Severe Mental Illnesses One classic example of nature guiding modern treatments in mental health is reserpine. It induces a depletion of neurotransmitters called monoamines in the brain and can be used to study such. It was also used initally as an antipsychotic, despite limitations to it's use 4 In the quest for novel and safe interventions, Nature's Pharmacopoeia has slowly been studied. One example of a common dietary addition, namely Cinnamon, forms a metabolite from the aroma molecule cinnamaldehyde, called benzoic acid. This has been researched quite extensively in many conditions where it seems to have an array of protective and restorative aspects on the brain with minimal toxicity. It has demonstrated some significant reductions in symptoms of severe mental illness and in early trials, it was implemented as a novel early intervention for psychosis [21, 22, 23, 24]. Other molecules from nature including green tea's calming component, L-theanine have also been explored with early signs of clinical benefits in psychosis [25, 26]. Other molecules, including cannabidiol, a benign hemp constituent (lacking the overt psychoactivity of other constituents) has demonstrated efficacy on par with conventional antipsychotics whilst also having a more benign side-effect profile in initial studies, along with potential to treat depression and anxiety [27]. Other tea constituents have displayed beneficial activities including theacrine from Camellia assamica var. kucha (kucha) which displays potent antidepressant activity via boosting hippocampal neurogenesis, among other properties. Other areas where 'food as medicine' is being explored include the use of pungent compounds from Brassica's - glucosinolates - which form isothiocyanates. These induce detoxification enzymes and increase neuroprotective responses, alongside other pharmacological aspects of benefit to the brain. It is as such being researched in autism, mood and psychotic disorders and cognitive disorders [28, 29, 30, 31, 32]. Natural products as add-ons to conventional pharmacotherapy have been studied, for example Ginkgo biloba which shows superior efficacy to placebo in reducing total and 5 negative scores in schizophrenia [33]. Some other examples of Nature guiding the search for new therapeutics include alkaloids such as alstonine or l-stepholidine which may not just have some novel mechanisms of action but also potential factors that may lead to superior efficacy. L-stepholidine l-stepholidine, acting on the brain's dopamine system, demonstrates robust antipsychotic activity in humans (both positive and negative symptoms) and is currently used clinically in China. It demonstrates a unique binding profile that may lead to benefits over existing drugs [34]. Alstonine As a plant: It is used traditionally as a plant medicine named ‘uhuma obi-nwok’, in Igbo ‘the heart of man’. The plant is used to treat different types of ‘madness’, epilepsy, and is in general considered to be a sedative. To treat severe ‘madness’ the ground root is boiled in water (a piece of root about 10 cm long and 5 cm in diameter is prepared in 250 ml of water) until the liquid turns into a reddish-brown in color; the initial loading dose for an adult is one cup. The alkaloid is considered an innovative treatment for schizophrenia as it not only increases social interaction but also averts social deficits attributable to negative symptoms of schizophrenia. It has potential as a drug for the management of negative symptoms in schizophrenia [35, 36]. Exploring more of Nature's medicine cabinet 6 Anti-schizophrenic drugs have variable efficacy in different patients, with often poor efficacy and sometimes with debilitating side-effects. There is a great need of more efficacious and safer remedies. Phytochemicals offer potential and diverse alternatives to allopathic anti schizophrenic medicines due to their wide array of biological activities such as anti-inflammatory activity, anti-oxidant potential, affecting neurotransmission, and modulating cell signaling pathways Review: https://doi.org/10.3389/fphar.2022.895668 Addictive disorders Tabernanthe iboga (Iboga) has demonstrated robust anti-addictive potentials but several effects, including intense challenging visionary experiences and cardiac side-effects have limited it's clinical utility. There have been attempts to create new molecules devoid of such effects that retain the anti-addictive nature [37]. These include a 'tabernanthalog' molecule. Other related molecules from the Apocynaceae have been found to have anti-addictive properties, whilst lacking side-effects for example catharanthine from Catharanthus roseus has been proposed to be a pharmacological treatment for addiction without the adverse side effects associated with ibogaine. References Meta-analysis: Sarris J, Marx W, Ashton MM, Ng CH, Galvao-Coelho N, Ayati Z, Zhang ZJ, Kasper S, Ravindran A, Harvey BH, Lopresti A, Mischoulon D, Amsterdam J, Yatham LN, Berk M. Plant-based Medicines (Phytoceuticals) in the Treatment of Psychiatric Disorders: A Meta-review of Meta-analyses of Randomized Controlled Trials Can J Psychiatry. 2021 Oct;66(10):849-862. https://doi.org/10.1177%2F0706743720979917 [1] Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis. J Affect Disord. 2017 Mar 1;210:211-221. . Epub 2017 Jan 3. PMID: 28064110. https://doi.org/10.1016/j.jad.2016.12.048 [2] Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Schläfke S, Dienel A. Lavender oil preparation Silexan is effective in generalized anxiety disorder--a randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol. 2014 Jun;17(6):859-69. https://doi.org/10.1017/S1461145714000017 [3] Woelk H, Schläfke S. A multi-center, double-blind, randomised study of the Lavender oil preparation Silexan in comparison to Lorazepam for generalized anxiety disorder. Phytomedicine. 2010 Feb;17(2):94-9. . https://doi.org/10.1016/j.phymed.2009.10.006 [4] Keefe JR, Mao JJ, Soeller I, Li QS, Amsterdam JD. Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder. Phytomedicine. 2016 Dec 15;23(14):1699-1705. https://doi.org/10.1016/j.phymed.2016.10.013 [5] Zotti M, Colaianna M, Morgese MG, Tucci P, Schiavone S, Avato P, Trabace L. Carvacrol: 7 from ancient flavoring to neuromodulatory agent. Molecules. 2013 May 24;18(6):6161-72. https://doi.org/10.3390%2Fmolecules18066161 [6] Lopresti, A.L. Salvia (Sage): A Review of its Potential Cognitive-Enhancing and Protective Effects. Drugs R D 17, 53–64 (2017). https://doi.org/10.1007/s40268-016-0157-5 [7] Kelli A. Herrlinger, Kristin M. Nieman, Kristen D. Sanoshy, Brenda A. Fonseca, Joanne A. Lasrado, Arianne L. Schild, Kevin C. Maki, Keith A. Wesnes, and Michael A. Ceddia Spearmint Extract Improves Working Memory in Men and Women with Age-Associated Memory Impairment The Journal of Alternative and Complementary Medicine 2018 24:1, 37-47 https://doi.org/10.1089/acm.2016.0379 [8] Paul H. Falcone, Kristin M. Nieman, Aaron C. Tribby, Roxanne M. Vogel, Jordan M. Joy, Jordan R. Moon, Chantelle A. Slayton, Micah M. Henigman, Joanne A. Lasrado, Brandon J. Lewis, Brenda A. Fonseca, Kelli A. Herrlinger, The attention-enhancing effects of spearmint extract supplementation in healthy men and women: a randomized, double-blind, placebo- controlled, parallel trial, Nutrition Research, Volume 64, 2019, Pages 24-38, https://doi.org/10.1016/j.nutres.2018.11.012 [9] Scholey A, Gibbs A, Neale C, Perry N, Ossoukhova A, Bilog V, Kras M, Scholz C, Sass M, Buchwald-Werner S. Anti-stress effects of lemon balm-containing foods. Nutrients. 2014 Oct 30;6(11):4805-21. https://doi.org/10.3390%2Fnu6114805 [10] Ghajar A, Neishabouri SM, Velayati N, Jahangard L, Matinnia N, Haghighi M, Ghaleiha A, Afarideh M, Salimi S, Meysamie A, Akhondzadeh S. Crocus sativus L. versus Citalopram in the Treatment of Major Depressive Disorder with Anxious Distress: A Double-Blind, Controlled Clinical Trial. Pharmacopsychiatry. 2017 Jul;50(4):152-160. https://doi.org/10.1055/s-0042-116159 [11] Kell G, Rao A, Beccaria G, Clayton P, Inarejos-García AM, Prodanov M. affron® a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. Complement Ther Med. 2017 Aug;33:58-64. https://doi.org/10.1016/j.ctim.2017.06.001 [12] Sara Baziar, Ali Aqamolaei, Ebrahim Khadem, Seyyed Hosein Mortazavi, Sina Naderi, Erfan Sahebolzamani, Amirhosein Mortezaei, Shakiba Jalilevand, Mohammad-Reza Mohammadi, Mahsa Shahmirzadi, and Shahin Akhondzadeh Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study Journal of Child and Adolescent Psychopharmacology 2019 29:3, 205-212 https://doi.org/10.1089/cap.2018.0146 [13] Blasco-Fontecilla, H.; Moyano-Ramírez, E.; Méndez-González, O.; Rodrigo-Yanguas, M.; Martin-Moratinos, M.; Bella-Fernández, M. Effectivity of Saffron Extract (Saffr’Activ) on Treatment for Children and Adolescents with Attention Deficit/Hyperactivity Disorder (ADHD): A Clinical Effectivity Study. Nutrients 2022, 14, 4046. 8 https://doi.org/10.3390/nu14194046 [14] Olatunji TL, Siebert F, Adetunji AE, Harvey BH, Gericke J, Hamman JH, Van der Kooy F. Sceletium tortuosum: A review on its phytochemistry, pharmacokinetics, biological, pre- clinical and clinical activities. J Ethnopharmacol. 2022 Apr 6;287:114711. doi: https://doi.org/10.1016/j.jep.2021.114711 [15] Manganyi MC, Bezuidenhout CC, Regnier T, Ateba CN. A Chewable Cure "Kanna" (2021) Biological and Pharmaceutical Properties of Sceletium tortuosum. Molecules. 28;26(9):2557. https://doi.org/10.3390%2Fmolecules26092557 [16] Chengappa KNR, Brar JS, Gannon JM, Schlicht PJ. Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. 2018 Jul 10;79(5):17m11826. https://doi.org/10.4088/JCP.17m11826 [17] Gannon JM, Brar J, Rai A, Chengappa KNR. Effects of a standardized extract of Withania somnifera (Ashwagandha) on depression and anxiety symptoms in persons with schizophrenia participating in a randomized, placebo-controlled clinical trial. Ann Clin Psychiatry. 2019 May;31(2):123-129 [18]Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo- controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013 Nov;74(11):1076-83. doi: https://doi.org/10.4088/JCP.13m08413 [19] Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical Use of Curcumin in Depression: A Meta- Analysis. J Am Med Dir Assoc. 2017 Jun 1;18(6):503-508. https://doi.org/10.1016/j.jamda.2016.12.071 [20] Li Ren, Gang Chen, Rapid antidepressant effects of Yueju: A new look at the function and mechanism of an old herbal medicine,Journal of Ethnopharmacology,Volume 203, 2017, Pages 226-232, https://doi.org/10.1016/j.jep.2017.03.042 [21] Ryan, A., Baker, A., Dark, F. et al. The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial. Trials 18, 165 (2017). https://doi.org/10.1186/s13063-017-1908-5 [22] Scott JG, Baker A, Lim CCW, et al. Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(11):e2024335. https://doi.org/10.1001/jamanetworkopen.2020.24335 [23] Lin C, Chen P, Wang S, Lane H. Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2021;4(4):e216156. https://doi.org/10.1001/ jamanetworkopen.2021.6156 9 [24] Lin CH, Wang SH, Lane HY. Effects of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, on Perceived Stress and Cognitive Function Among Patients With Late-Life Depression: A Randomized, Double-Blind, Sertraline- and Placebo-Controlled Trial. Int J Neuropsychopharmacol. 2022 Aug 4;25(7):545-555. https://doi.org/ 10.1093/ijnp/pyac006 [25] Shamabadi A, Fattollahzadeh-Noor S, Fallahpour B, A Basti F, Khodaei Ardakani MR, Akhondzadeh S. L-Theanine adjunct to risperidone in the treatment of chronic schizophrenia inpatients: a randomized, double-blind, placebo-controlled clinical trial. Psychopharmacology (Berl). 2023 Dec;240(12):2631-2640. https://doi.org/10.1007/s00213-023-06458-9 [26] Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry. 2011 Jan;72(1):34-42. ). https://doi.org/10.4088/JCP.09m05324gre [27] García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules. 2020 Nov 19;10(11):1575. doi: 10.3390/biom10111575. [28] Kanwaljit Singh, Susan L. Connors et al. Sulforaphane treatment of autism spectrum disorder (ASD)] PNAS 2014, 111 (43) 15550-15555 https://doi.org/10.1073/pnas.1416940111 [29] Lynch R, Diggins EL, Connors SL, et al. Sulforaphane from Broccoli Reduces Symptoms of Autism: A Follow-up Case Series from a Randomized Double-blind Study. Global Advances in Health and Medicine. 2017;6 https://doi.org/10.1177/2164957x17735826 [30] Magner, M.; Thorová, K et al. Sulforaphane Treatment in Children with Autism: A Prospective Randomized Double-Blind Study. Nutrients 2023, 15, 718. https://doi.org/10.3390/nu15030718 [31] Panjwani AA, Liu H, Fahey JW. Crucifers and related vegetables and supplements for neurologic disorders: what is the evidence? Curr Opin Clin Nutr Metab Care. 2018 Nov;21(6):451-457 https://doi.org/10.1097/mco.0000000000000511 [32] Connolly EL, Sim M, et al. Glucosinolates From Cruciferous Vegetables and Their Potential Role in Chronic Disease: Investigating the Preclinical and Clinical Evidence. Front Pharmacol. 2021 Oct 26;12:767975 https://doi.org/10.3389/fphar.2021.7679754 [33] Singh V, Singh SP, Chan K. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol. 2010 Mar;13(2):257-71. https://doi.org/10.1017/S1461145709990654 [34] Natesan, S., Reckless, G.E., Barlow, K.B.L. et al. The antipsychotic potential of l- stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist. 10 Psychopharmacology 199, 275–289 (2008). https://doi.org/10.1007/s00213-008-1172-1 [35] Elisabetsky, E., Costa-Campos, L., The Alkaloid Alstonine: A Review of Its Pharmacological Properties, Evidence-Based Complementary and Alternative Medicine, 3, 787923, 10 pages, 2006. https://doi.org/10.1093/ecam/nek011 [36] Linck VM, Ganzella M, Herrmann AP, Okunji CO, Souza DO, Antonelli MC, Elisabetsky E. Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima nitida). Phytomedicine. 2015 Jan 15;22(1):52-5. https://doi.org/10.1016/j.phymed.2014.10.010http [37] Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021 Jan;589(7842):474-479. https://doi.org/10.1038/s41586-020-3008-z 11