Medicinal Plants for Insomnia Related to Anxiety: An Updated Review^{[ # ]}

Abstract

Sleep disorders are common among the general population and can generate health problems such as insomnia and anxiety. In addition to standard drugs and psychological interventions, there are different complementary plant-based therapies used to treat insomnia and anxiety. This review aimed to find and examine the most recent research on the use of herbal medicines for treating anxiety and insomnia as compiled from clinical trials, as well as to assess the safety and efficacy of these medicines and to elucidate their possible mechanisms of action. The process entailed a search of PubMed, Scopus, and the Cochrane Library databases from 2010 to 2020. The search terms included “sleep disorder”, “insomnia”, “sedative”, “hypnotic”, “anxiety”, “anxiolytic”, and “clinical trial”, combined with the search terms “herbs” and “medicinal plants”, in addition to individual herbal medicines by both their common and scientific names. This updated review, which focuses mainly on clinical trials, includes research on 23 medicinal plants and their combinations. Essential oils and their associations have also been reviewed. The efficacy of medicinal plants depends on treatment duration, types of study subjects, administration route, and treatment method. More clinical trials with an adequate, standardized design are necessary, as are more preclinical studies to continue studying the mechanisms of action. As a result of our work, we can conclude that the 3 plants with the most potential are valerian, passionflower, and ashwagandha, with the combination of valerian with hops and passionflower giving the best results in the clinical tests.

Key words

medicinal plants - essential oils - sleep disorders - insomnia - anxiety - clinical trials

^# Dedicated to Professor Arnold Vlietinck on the occasion of his 80th birthday.

Publication History

Received: 07 January 2021

Accepted after revision: 09 May 2021

Article published online:
11 June 2021

• References

• 1 Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms 2006; 21: 482-493
• 2 Hirshkowitz M, Rose MW, Sharafkhaneh A. Neurotransmitters, Neurochemistry, and clinical Pharmacology of Sleep. In: Chokroverty S. ed. Sleep Disorders Medicine: Basic Science technical Considerations, and clinical Aspects. 3rd ed.. Philadelphia: Saunders Elsevier; 2009: 67-79
• 3 Ribeiro FM, Vieira LB, Pires RG, Olmo RP, Ferguson SS. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res 2017; 115: 179-191
• 4 Grafe LA, Bhatnagar S. Orexins and stress. Front Neuroendocrinol 2018; 51: 132-145
• 5 Szymusiak R, McGinty D. Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 2008; 1129: 275-286
• 6 Savage K, Firth J, Stough C, Sarris J. GABA-modulating phytomedicines for anxiety: a systematic review of preclinical and clinical evidence. Phytother Res 2018; 32: 3-18
• 7 McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med 2007; 8: 302-330
• 8 Pavlova MK, Latreille V. Sleep Disorders. Am J Med 2019; 132: 292-299
• 9 Sateia MJ. International classification of sleep disorders, third edition: highlights and modifications. Chest 2014; 146: 1387-1394
• 10 Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med 2017; 13: 307-349
• 11 Kavan MG, Elsasser GN, Barone EJ. Generalized anxiety disorder: practical assessment and management. Am Fam Physician 2009; 79: 785-791
• 12 Monti JM, Monti D. Sleep disturbance in generalized anxiety disorder and its treatment. Sleep Med Rev 2000; 4: 263-276
• 13 Staner L. Sleep and anxiety disorders. Dialogues Clin Neurosci 2003; 5: 249-258
• 14 Hoge EA, Ivkovic A, Fricchione GL. Generalized anxiety disorder: diagnosis and treatment. BMJ 2012; 345: e7500
• 15 Schanzer B, Rivas-Grajales AM, Khan A, Mathew SJ. Novel investigational therapeutics for generalized anxiety disorder (GAD). Expert Opin Investig Drugs 2019; 28: 1003-1012
• 16 Jansson-Fröjmark M, Lindblom K. A bidirectional relationship between anxiety and depression, and insomnia? A prospective study in the general population. J Psychosom Res 2008; 64: 443-449
• 17 Bragantini D, Sivertsen B, Gehrman P, Lydersen S, Güzey IC. Differences in anxiety levels among symptoms of insomnia. The HUNT study. Sleep Health 2019; 5: 370-375
• 18 Lie JD, Tu KN, Shen DD, Wong BM. Pharmacological treatment of insomnia. Pharm Therap 2015; 40: 759-771
• 19 Sarris J, Byrne GJ. A systematic review of insomnia and complementary medicine. Sleep Med Rev 2011; 15: 99-106
• 20 Leach MJ, Page AT. Herbal medicine for insomnia: a systematic review and meta-analysis. Sleep Med Rev 2015; 24: 1-12
• 21 Sarris J, McIntyre E, Camfield DA. Plant-based medicines for anxiety disorders, Part 1. CNS Drugs 2013; 27: 207-219
• 22 Sarris J, McIntyre E. Herbal Anxiolytics with sedative Actions. In: Camfield D, McIntyre E, Sarris J. eds. Evidence-based herbal and nutritional Treatments for Anxiety in psychiatric Disorders. Stuttgart: Springer; 2017: 11-31
• 23 The Plant List. A working list of all known plant species. Royal Botanic Gardens, Kew and Missouri Botanical Garden. Accessed January 11–15, and January 18–22, 2021 at: http://www.theplantlist.org/
• 24 Plushner SL. Valerian: Valeriana officinalis . Am J Health Syst Pharm 2000; 57: 328 333, 335
• 25 Hattesohl M, Feistel B, Sievers H, Lehnfeld R, Hegger M, Winterhoff H. Extracts of Valeriana officinalis L. s.l. show anxiolytic and antidepressant effects but neither sedative nor myorelaxant properties. Phytomedicine 2008; 15: 2-15
• 26 Patocka J, Jakl J. Biomedically relevant chemical constituents of Valeriana officinalis . J Appl Biomed 2010; 8: 11-18
• 27 Felgentreff F, Becker A, Meier B, Brattström A. Valerian extract characterized by high valerenic acid and low acetoxy valerenic acid contents demonstrates anxiolytic activity. Phytomedicine 2012; 19: 1216-1222
• 28 Gonulalan EM, Bayazeid O, Yalcin FN, Demirezer LO. The roles of valerenic acid on BDNF expression in the SH-SY5Y cell. Saudi Pharm J 2018; 26: 960-964
• 29 Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry 2000; 33: 47-53
• 30 Ziegler G, Ploch M, Miettinen-Baumann A, Collet W. Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non organic insomnia – a randomized, double-blind, comparative clinical study. Eur J Med Res 2002; 7: 480-486
• 31 Diaper A, Hindmarch I. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res 2004; 18: 831-836
• 32 Taibi DM, Vitiello MV, Barsness S, Elmer GW, Anderson GD, Landis CA. A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Med 2009; 10: 319-328
• 33 Taavoni S, Ekbatani N, Kashaniyan M, Haghani H. Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial. Menopause 2011; 18: 951-955
• 34 Barton DL, Atherton PJ, Bauer BA, Moore jr. DF, Mattar BI, Lavasseur BI, Rowland jr. KM, Zon RT, Lelindqwister NA, Nagargoje GG, Morgenthaler TI, Sloan JA, Loprinzi CL. The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: a phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5). J Support Oncol 2011; 9: 24-31
• 35 Roh D, Jung JH, Yoon KH, Lee CH, Kang LY, Lee S, Shin K, Kim DH. Valerian extract alters functional brain connectivity: a randomized double-blind placebo-controlled trial. Phytother Res 2019; 33: 939-948
• 36 Farah GJ, Ferreira GZ, Danieletto-Zanna CF, Luppi CR, Jacomacci WP. Assessment of Valeriana officinalis L. (valerian) for conscious sedation of patients during the extraction of impacted mandibular third molars: a randomized, split-mouth, double-blind, crossover study. J Oral Maxillofac Surg 2019; 77: 1796.e1-1796.e8
• 37 Miroddi M, Calapai G, Navarra M, Minciullo PL, Gangemi S. Passiflora incarnata L.: ethnopharmacology, clinical application, safety and evaluation of clinical trials. J Ethnopharmacol 2013; 150: 791-804
• 38 Dhawan K, Kumar S, Sharma A. Anti-anxiety studies on extracts of Passiflora incarnata Linneaus. J Ethnopharmacol 2001; 78: 165-170
• 39 Grundmann O, Wang J, McGregor GP, Butterweck V. Anxiolytic activity of a phytochemically characterized Passiflora incarnata extract is mediated via the GABAergic system. Planta Med 2008; 74: 1769-1773
• 40 Guerrero FA, Medina GM. Effect of a medicinal plant (Passiflora incarnata L.) on sleep. Sleep Sci 2017; 10: 96-100
• 41 Akhondzadeh S, Naghavi HR, Vazirian M, Shayeganpour A, Rashidi H, Khani M. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. J Clin Pharm Ther 2001; 26: 363-367
• 42 Ngan A, Conduit R. A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflower) herbal tea on subjective sleep quality. Phytother Res 2011; 25: 1153-1159
• 43 Movafegh A, Alizadeh R, Hajimohamadi F, Esfehani F, Nejatfar M. Preoperative oral Passiflora incarnata reduces anxiety in ambulatory surgery patients: a double-blind, placebo-controlled study. Anesth Analg 2008; 106: 1728-1732
• 44 Dantas LP, de Oliveira-Ribeiro A, de Almeida-Souza LM, Groppo FC. Effects of Passiflora incarnata and midazolam for control of anxiety in patients undergoing dental extraction. Med Oral Patol Oral Cir Bucal 2017; 22: 95-101
• 45 Lee J, Jung HY, Lee SI, Choi JH, Kim SG. Effects of Passiflora incarnata Linnaeus on polysomnographic sleep parameters in subjects with insomnia disorder: a double-blind randomized placebo-controlled study. Int Clin Psychopharmacol 2020; 35: 29-35
• 46 Graziano S, Orsolini L, Rotolo MC, Tittarelli R, Schifano F, Pichini S. Herbal highs: review on psychoactive effects and neuropharmacology. Curr Neuropharmacol 2017; 15: 750-761
• 47 Salehi B, Zakaria ZA, Gyawali R, Ibrahim SA, Rajkovic J. Piper species: a comprehensive review on their phytochemistry, biological activities and applications. Molecules 2019; 24: 1364
• 48 Chua HC, Christensen ET, Hoestgaard-Jensen K, Hartiadi LY, Ramzan I, Jensen AA, Absalom NL, Chebib M. Kavain, the major constituent of the anxiolytic kava extract, potentiates GABA_A receptors: functional characteristics and molecular mechanism. PLoS One 2016; 11: e0157700
• 49 Shinomiya K, Inoue T, Utsu Y, Tokunaga S, Masuoka T, Ohmori A, Kamei C. Effects of kava-kava extract on the sleep-wake cycle in sleep-disturbed rats. Psychopharmacology (Berl) 2005; 180: 564-569
• 50 Tsutsui R, Shinomiya K, Takeda Y, Obara Y, Kitamura Y, Kamei C. Hypnotic. J Pharmacol Sci 2009; 111: 293-298
• 51 Lehrl S. Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders. Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. J Affect Disord 2004; 78: 101-110
• 52 Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2013; 33: 643-648
• 53 Kuchta K, de Nicola P, Schmidt M. Randomized, dose-controlled double-blind trial: efficacy of an ethanolic kava (Piper methysticum rhizome) extract for the treatment of anxiety in elderly patients. Tradit Kampo Med 2018; 5: 3-10
• 54 Sarris J, Byrne GJ, Bousman CA, Cribb L, Savage KM, Holmes O, Murphy J, Macdonald P, Short A, Nazareth S, Jennings E, Thomas SR, Ogden E, Chamoli S, Scholey A, Stough C. Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study. Aust N Z J Psychiatry 2020; 54: 288-297
• 55 Sharma A, Angulo-Bejarano PI, Madariaga-Navarrete A, Oza G, Iqbal HMN, Cardoso-Taketa A, Luisa Villarreal M. Multidisciplinary investigations on Galphimia glauca: A Mexican medicinal plant with pharmacological potential. Molecules 2018; 23: 2985
• 56 Herrera-Ruiz M, González-Cortazar M, Jiménez-Ferrer JE, Zamilpa A, Álvarez L, Ramírez G, Tortoriello J. Anxiolytic effect of natural galphimines from Galphimia glauca and their chemical derivatives. J Nat Prod 2006; 69: 59-61
• 57 Herrera-Ruiz M, Jiménez-Ferrer JE, De Lima TC, Avilés-Montes D, Pérez-García D, González-Cortazar M, Tortoriello J. Anxiolytic and antidepressant-like activity of a standardized extract from Galphimia glauca . Phytomedicine 2006; 13: 23-28
• 58 Jiménez-Ferrer JE, Herrera-Ruiz M, Ramírez-García R, Herrera-Arellano A, Tortoriello J. Interaction of the natural anxiolytic galphimine-B with serotonergic drugs on dorsal hippocampus in rats. J Ethnopharmacol 2011; 137: 724-729
• 59 Aviles-Montes D, Herrera-Ruiz M, Roman-Ramos R, Jimenez-Ferrer JE, González-Cortazar M, Zamilpa A, Tortoriello J. Pharmacological interaction between galphimine-A, a natural anxiolytic compound and GABAergic drugs. Int J Pharmacol 2015; 11: 944-955
• 60 Santillán-Urquiza MA, Herrera-Ruiz M, Zamilpa A, Jiménez-Ferrer E, Román-Ramos R, Tortoriello J. Pharmacological interaction of Galphimia glauca extract and natural galphimines with ketamine and haloperidol on different behavioral tests. Biomed Pharmacother 2018; 103: 879-888
• 61 Garige BSR, Keshetti S, Vattikuti UMR. In vivo study on depressant effects and muscle coordination activity of Galphimia glauca stem methanol extract. Pharmacognosy Res 2016; 8: 219-225
• 62 Herrera-Arellano A, Jiménez-Ferrer JE, Zamilpa A, Morales-Valdez A, García-Valencia CE, Tortoriello J. Efficacy and tolerability of a standardized herbal product from Galphimia glauca on generalized anxiety disorder. A randomized, double-blind clinical trial controlled with lorazepam. Planta Med 2007; 73: 713-717
• 63 Herrera-Arellano A, Jiménez-Ferrer JE, Zamilpa A, García-Alonso G, Herrera-Alvarez S, Tortoriello J. Therapeutic effectiveness of Galphimia glauca vs. lorazepam in generalized anxiety disorder. A controlled 15-week clinical trial. Planta Med 2012; 78: 1529-1535
• 64 Romero-Cerecero O, Islas-Garduño AL, Zamilpa A, Pérez-García MD, Tortoriello J. Therapeutic effectiveness of Galphimia glauca in young people with social anxiety disorder: a pilot study. Evid Based Complement Alternat Med 2018; 2018: 1716939
• 65 Romero-Cerecero O, Islas-Garduño AL, Zamilpa A, Herrera-Arellano A, Jiménez-Ferrer E, Tortoriello J. Galphimine-B standardized extract versus alprazolam in patients with generalized anxiety disorder: a ten-week, double-blind, randomized clinical trial. Biomed Res Int 2019; 2019: 1037036
• 66 Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 2000; 5: 334-346
• 67 Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R. A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of Withania somnifera . Indian J Psychiatry 2000; 42: 295-301
• 68 Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med 2012; 34: 255-262
• 69 Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: a randomized, double-blind, placebo-controlled study. Medicine (Baltimore) 2019; 98: 17186
• 70 Fuladi S, Emami SA, Mohammadpour AH, Karimani A, Manteghi AA, Sahebkar A. Assessment of Withania somnifera root extract efficacy in patients with generalized anxiety disorder: a randomized double-blind placebo-controlled trial. Curr Clin Pharmacol 2020; 15: 1 DOI: 10.2174/1574884715666200413120413.
• 71 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; 31: 123-129
• 72 Salve J, Pate S, Debnath K, Langade D. Adaptogenic and anxiolytic effects of ashwagandha root extract in healthy adults: a double-blind, randomized, placebo-controlled clinical study. Cureus 2019; 11: 6466
• 73 Langade D, Kanchi S, Salve J, Debnath K, Ambegaokar D. Efficacy and safety of ashwagandha (Withania somnifera) root extract in insomnia and anxiety: a double-blind, randomized, placebo-controlled study. Cureus 2019; 11: 5797
• 74 Kelgane SB, Salve J, Sampara P, Debnath K. Efficacy and tolerability of ashwagandha root extract in the elderly for improvement of general well-being and sleep: a prospective, randomized, double-blind, placebo-controlled study. Cureus 2020; 12: 7083
• 75 Deshpande A, Irani N, Balkrishnan R, Benny IR. A randomized, double blind, placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults. Sleep Med 2020; 72: 28-36
• 76 Langade D, Thakare V, Kanchi S, Kelgane S. Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: a double-blind, randomized, parallel-group, placebo-controlled study. J Ethnopharmacol 2021; 264: 113276
• 77 Moradkhani H, Sargsyan E, Bibak H, Naseri B, Sadat-Hosseini M. Melissa officinalis L., a valuable medicine plant: a review. J Med Plant Res 2010; 4: 2753-2759
• 78 Shakeri A, Sahebkar A, Javadi B. Melissa officinalis L.–A review of its traditional uses, phytochemistry and pharmacology. J Ethnopharmacol 2016; 188: 204-228
• 79 Ibarra A, Feuillere N, Roller M, Lesburgere E, Beracochea D. Effects of chronic administration of Melissa officinalis L. extract on anxiety-like reactivity and on circadian and exploratory activities in mice. Phytomedicine 2010; 17: 397-403
• 80 Cases J, Ibarra A, Feuillère N, Roller M, Sukkar SG. Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Med J Nutrition Metab 2011; 4: 211-218
• 81 Haybar H, Javid AZ, Haghighizadeh MH, Valizadeh E, Mohaghegh SM, Mohammadzadeh A. The effects of Melissa officinalis supplementation on depression, anxiety, stress, and sleep disorder in patients with chronic stable angina. Clin Nutr ESPEN 2018; 26: 47-52
• 82 Srivastava JK, Shankar E, Gupta S. Chamomile: a herbal medicine of the past with bright future. Mol Med Rep 2010; 3: 895-901
• 83 Amsterdam JD, Li Y, Soeller I, Rockwell K, Mao JJ, Shults J. A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J Clin Psychopharmacol 2009; 29: 378-382
• 84 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; 23: 1699-1705
• 85 Mao JJ, Xie SX, Keefe JR, Soeller I, Li QS, Amsterdam JD. Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: a randomized clinical trial. Phytomedicine 2016; 23: 1735-1742
• 86 Keefe JR, Guo W, Li QS, Amsterdam JD, Mao JJ. An exploratory study of salivary cortisol changes during chamomile extract therapy of moderate to severe generalized anxiety disorder. J Psychiatr Res 2018; 96: 189-195
• 87 Adib-Hajbaghery M, Mousavi SN. The effects of chamomile extract on sleep quality among elderly people: a clinical trial. Complement Ther Med 2017; 35: 109-114
• 88 Chang SM, Chen CH. Effects of an intervention with drinking chamomile tea on sleep quality and depression in sleep disturbed postnatal women: a randomized controlled trial. J Adv Nurs 2016; 72: 306-315
• 89 Amsterdam JD, Shults J, Soeller I, Mao JJ, Rockwell K, Newberg AB. Chamomile (Matricaria recutita) may provide antidepressant activity in anxious, depressed humans: an exploratory study. Altern Ther Health Med 2012; 18: 44-49
• 90 Kyrou I, Christou A, Panagiotakos D, Stefanaki C, Skenderi K, Katsana K, Tsigos C. Effects of a hops (Humulus lupulus L.) dry extract supplement on self-reported depression, anxiety and stress levels in apparently healthy young adults: a randomized, placebo-controlled, double-blind, crossover pilot study. Hormones (Athens) 2017; 16: 171-180
• 91 Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, De Keukeleire D, Hayrack A. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine 2010; 17: 389-396
• 92 Carmona F, Coneglian FS, Batista PA, Aragon DC, Angelucci MA, Martinez EZ, Pereira AMS. Aloysia polystachya (Griseb.) Moldenke (Verbenaceae) powdered leaves are effective in treating anxiety symptoms: a phase-2, randomized, placebo-controlled clinical trial. J Ethnopharmacol 2019; 242: 112060
• 93 Jana U, Sur TK, Maity LN, Debnath PK, Bhattacharyya D. A clinical study on the management of generalized anxiety disorder with Centella asiatica . Nepal Med Coll J 2010; 12: 8-11
• 94 Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD). J Altern Complement Med 2008; 14: 175-180
• 95 Edwards D, Heufelder A, Zimmermann A. Therapeutic effects and safety of Rhodiola rosea extract WS 1375 in subjects with life-stress symptoms–results of an open-label study. Phytother Res 2012; 26: 1220-1225
• 96 Cropley M, Banks AP, Boyle J. The effects of Rhodiola rosea L. Extract on anxiety, stress, cognition and other mood symptoms. Phytother Res 2015; 29: 1934-1939
• 97 Wolfson P, Hoffmann DL. An investigation into the efficacy of Scutellaria lateriflora in healthy volunteers. Altern Ther Health Med 2003; 9: 74-78
• 98 Hui KM, Huen MS, Wang HY, Zheng H, Sigel E, Baur R, Ren H, Li ZW, Wong JT, Xue H. Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem Pharmacol 2002; 64: 1415-1424
• 99 De Carvalho RS, Duarte FS, de Lima TC. Involvement of GABAergic non-benzodiazepine sites in the anxiolytic-like and sedative effects of the flavonoid baicalein in mice. Behav Brain Res 2011; 221: 75-82
• 100 Firoozabadi A, Kolouri S, Zarshenas MM, Salehi A, Mosavat SH, Dastgheib SA. Efficacy of a freeze-dried aqueous extract of Nepeta menthoides Boiss. & Buhse in the treatment of anxiety in patients with depression: a double-blind, randomized, controlled trial. J Herbal Med 2017; 10: 17-23
• 101 Nematolahi P, Mehrabani M, Karami-Mohajeri S, Dabaghzadeh F. Effects of Rosmarinus officinalis L. on memory performance, anxiety, depression, and sleep quality in university students: a randomized clinical trial. Complement Ther Clin Pract 2018; 30: 24-28
• 102 Kell G, Rao A, Katsikitis M. A randomised placebo controlled clinical trial on the efficacy of Caralluma fimbriata supplement for reducing anxiety and stress in healthy adults over eight weeks. J Affect Disord 2019; 246: 619-626
• 103 Morin CM, Koetter U, Bastien C, Ware JC, Wooten V. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep 2005; 28: 1465-1471
• 104 Koetter U, Schrader E, Käufeler R, Brattström A. A randomized, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from non-organic sleep disorder. Phytother Res 2007; 21: 847-851
• 105 Dimpfel W, Suter A. Sleep improving effects of a single dose administration of a valerian/hops fluid extract–a double blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms. Eur J Med Res 2008; 13: 200-204
• 106 Kennedy DO, Little W, Haskell CF, Scholey AB. Anxiolytic effects of a combination of Melissa officinalis and Valeriana officinalis during laboratory induced stress. Phytother Res 2006; 20: 96-102
• 107 Taavoni S, Nazem Ekbatani N, Haghani H. Valerian/lemon balm use for sleep disorders during menopause. Complement Ther Clin Pract 2013; 19: 193-196
• 108 Abdellah SA, Berlin A, Blondeau C, Guinobert I, Guilbot A, Beck M, Duforez F. A combination of Eschscholtzia californica Cham. and Valeriana officinalis L. extracts for adjustment insomnia: a prospective observational study. J Tradit Complement Med 2019; 10: 116-123
• 109 Wheatley D. Kava and valerian in the treatment of stress-induced insomnia. Phytother Res 2001; 15: 549-551
• 110 Ranjbar M, Firoozabadi A, Salehi A, Ghorbanifar Z, Zarshenas MM, Sadeghniiat-Haghighi K, Rezaeizadeh H. Effects of herbal combination (Melissa officinalis L. and Nepeta menthoides Boiss. & Buhse) on insomnia severity, anxiety and depression in insomniacs: Randomized placebo controlled trial. Integr Med Res 2018; 7: 328-332
• 111 Maroo N, Hazra A, Das T. Efficacy and safety of a polyherbal sedative-hypnotic formulation NSF-3 in primary insomnia in comparison to zolpidem: a randomized controlled trial. Indian J Pharmacol 2013; 45: 34-39
• 112 Meier S, Haschke M, Zahner C, Kruttschnitt E, Drewe J, Liakoni E, Hammann F, Gaab J. Effects of a fixed herbal drug combination (Ze 185) to an experimental acute stress setting in healthy men–an explorative randomized placebo-controlled double-blind study. Phytomedicine 2018; 39: 85-92
• 113 Hanus M, Lafon J, Mathieu M. Double-blind, randomised, placebo-controlled study to evaluate the efficacy and safety of a fixed combination containing two plant extracts (Crataegus oxyacantha and Eschscholtzia californica) and magnesium in mild-to-moderate anxiety disorders. Curr Med Res Opin 2004; 20: 63-71
• 114 Scholey A, Benson S, Gibbs A, Perry N, Sarris J, Murray G. Exploring the effect of Lactium^™ and Zizyphus Complex on sleep quality: a double-blind, randomized placebo-controlled trial. Nutrients 2017; 9: 154
• 115 Cornu C, Remontet L, Noel-Baron F, Nicolas A, Feugier-Favier N, Roy P, Claustrat B, Saadatian-Elahi M, Kassaï B. A dietary supplement to improve the quality of sleep: a randomized placebo controlled trial. BMC Complement Altern Med 2010; 10: 29
• 116 Lemoine P, Bablon JC, da Silva C. A combination of melatonin, vitamin B₆ and medicinal plants in the treatment of mild-to-moderate insomnia: A prospective pilot study. Complement Ther Med 2019; 45: 104-108
• 117 Woronuk G, Demissie Z, Rheault M, Mahmoud S. Biosynthesis and therapeutic properties of Lavandula essential oil constituents. Planta Med 2011; 77: 7-15
• 118 Koulivand PH, Khaleghi Ghadiri M, Gorji A. Lavender and the nervous system. Evid Based Complement Alternat Med 2013; 2013: 681304
• 119 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; 17: 94-99
• 120 Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Dienel A, Schläfke S. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of ʼsubsyndromalʼ anxiety disorder: a randomized, double-blind, placebo controlled trial. Int Clin Psychopharmacol 2010; 25: 277-287
• 121 Uehleke B, Schaper S, Dienel A, Schlaefke S, Stange R. Phase II trial on the effects of Silexan in patients with neurasthenia, post-traumatic stress disorder or somatization disorder. Phytomedicine 2012; 19: 665-671
• 122 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; 17: 859-869
• 123 Kasper S, Anghelescu I, Dienel A. Efficacy of orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep–a randomized, placebo-controlled trial. Eur Neuropsychopharmacol 2015; 25: 1960-1967
• 124 Chien LW, Cheng SL, Liu CF. The effect of lavender aromatherapy on autonomic nervous system in midlife women with insomnia. Evid Based Complement Alternat Med 2012; 2012: 740813
• 125 Karan NB. Influence of lavender oil inhalation on vital signs and anxiety: a randomized clinical trial. Physiol Behav 2019; 211: 112676
• 126 Otaghi M, Qavam S, Norozi S, Borji M, Moradi M. Investigating the effect of lavender essential oil on sleep quality in patients candidates for angiography. Biomed Pharmacol J 2017; 10: 473-478
• 127 Jokar M, Zahraseifi. Baradaranfard F, Khalili M, Bakhtiari S. The effects of lavender aromatherapy on menopausal symptoms: a single-blind placebo-controlled clinical trial. Int J Pham Res 2018; 10: 182-188
• 128 Nasiri Lari Z, Hajimonfarednejad M, Riasatian M, Abolhassanzadeh Z, Iraji A, Vojoud M, Heydari M, Shams M. Efficacy of inhaled Lavandula angustifolia Mill. Essential oil on sleep quality, quality of life and metabolic control in patients with diabetes mellitus type II and insomnia. J Ethnopharmacol 2020; 251: 112560
• 129 Velasco-Rodríguez R, Pérez-Hernández MG, Maturano-Melgoza JA, Hilerio-López ÁG, Monroy-Rojas A, Arana-Gómez B, Vásquez C. The effect of aromatherapy with lavender (Lavandula angustifolia) on serum melatonin levels. Complement Ther Med 2019; 47: 102208
• 130 Ayik C, Özden D. The effects of preoperative aromatherapy massage on anxiety and sleep quality of colorectal surgery patients: a randomized controlled study. Complement Ther Med 2018; 36: 93-99
• 131 Namazi M, Amir Ali Akbari S, Mojab F, Talebi A, Alavi Majd H, Jannesari S. Aromatherapy with Citrus aurantium oil and anxiety during the first stage of labor. Iran Red Crescent Med J 2014; 16: e18371
• 132 Heydari N, Abootalebi M, Jamalimoghadam N, Kasraeian M, Emamghoreishi M, Akbarzadeh M. Investigation of the effect of aromatherapy with Citrus aurantium blossom essential oil on premenstrual syndrome in university students: a clinical trial study. Complement Ther Clin Pract 2018; 32: 1-5
• 133 Pimenta FC, Alves MF, Pimenta MB, Melo SA, de Almeida AA, Leite JR, Pordeus LC, Diniz MF, de Almeida RN. Anxiolytic effect of Citrus aurantium L. on patients with chronic myeloid leukemia. Phytother Res 2016; 30: 613-617
• 134 Moslemi F, Alijaniha F, Naseri M, Kazemnejad A, Charkhkar M, Heidari MR. Citrus aurantium aroma for anxiety in patients with acute coronary syndrome: a double-blind placebo-controlled trial. J Altern Complement Med 2019; 25: 833-839
• 135 Moradi K, Ashtarian H, Danzima NY, Saeedi H, Bijan B, Akbari F, Mohammadi MM. Essential oil from Citrus aurantium alleviates anxiety of patients undergoing coronary angiography: a single-blind, randomized controlled trial. Chin J Integr Med 2021; 27: 177-182
• 136 Arabfirouzjaei Z, Ilali E, Taraghi Z, Mohammadpour RA, Amin K, Habibi E. The effect of Citrus aurantium aroma on sleep quality in the elderly with heart failure. JBUMS 2019; 21: 181-187
• 137 Abdollahi F, Mobadery T. The effect of aromatherapy with bitter orange (Citrus aurantium) extract on anxiety and fatigue in type 2 diabetic patients. Adv Integr Med 2020; 7: 3-7
• 138 Goes TC, Antunes FD, Alves PB, Teixeira-Silva F. Effect of sweet orange aroma on experimental anxiety in humans. J Altern Complement Med 2012; 18: 798-804
• 139 Mirghafourvand M, Mohammad-Alizadeh Charandabi S, Hakimi S, Khodaie L, Galeshi M. Effect of orange peel essential oil on postpartum sleep quality: a randomized controlled clinical trial. Eur J Integr Med 2016; 8: 62-66
• 140 Gnatta JR, Piason PP, Lopes CL, Rogenski NM, Silva MJ. Aromatherapy with ylang for anxiety and self-esteem: a pilot study. Rev Esc Enferm USP 2014; 48: 492-499
• 141 Feyzabadi Z, Jafari F, Kamali SH, Ashayeri H, Badiee Aval S, Esfahani MM, Sadeghpour O. Efficacy of Viola odorata in treatment of chronic insomnia. Iran Red Crescent Med J 2014; 16: e17511
• 142 Feyzabadi Z, Rezaeitalab F, Badiee S, Taghipour A, Moharari F, Soltanifar A, Ahmadpour MR. Efficacy of violet oil, a traditional Iranian formula, in patients with chronic insomnia: a randomized, double-blind, placebo-controlled study. J Ethnopharmacol 2018; 25: 22-28
• 143 Shirzadegan R, Gholami M, Hasanvand S, Birjandi M, Beiranvand A. Effects of geranium aroma on anxiety among patients with acute myocardial infarction: a triple-blind randomized clinical trial. Complement Ther Clin Pract 2017; 29: 201-206
• 144 Afrasiabian F, Mirabzadeh Ardakani M, Rahmani K, Azadi NA, Alemohammad ZB, Bidaki R, Karimi M, Emtiazy M, Hashempur MH. Aloysia citriodora Palau (lemon verbena) for insomnia patients: a randomized, double-blind, placebo-controlled clinical trial of efficacy and safety. Phytother Res 2019; 33: 350-359
• 145 Hatano VY, Torricelli AS, Giassi AC, Coslope LA, Viana MB. Anxiolytic effects of repeated treatment with an essential oil from Lippia alba and (R)-(−)-carvone in the elevated T-maze. Braz J Med Biol Res 2012; 45: 238-243
• 146 Soto-Vásquez MR, Alvarado-García PAA. Anxiolytic-like effect of Lippia alba essential oil: A randomized, placebo-controlled trial. J Complement Med Res 2018; 7: 101-107
• 147 Lee M, Lim S, Song J, Kim M, Hur M. The effects of aromatherapy essential oil inhalation on stress, sleep quality and immunity in healthy adults: randomized controlled trial. Eur J Integr Med 2017; 12: 79-86
• 148 Stevens N, Dorsett J, DaBell A, Eggett DL, Han X, Parker TL. Subjective assessment of the effects of an herbal supplement containing lavender essential oil on sleep quality: a randomized, double-blind, placebo-controlled crossover study. Cogent Medicine 2017; 4: 1380871
• 149 Hur MH, Hong JH, Yeo S. Effects of aromatherapy on stress, fructosamine, fatigue, and sleep quality in prediabetic middle-aged women: a randomised controlled trial. Eur J Integr Med 2019; 31: 100978
• 150 Gürler M, Kızılırmak A, Baser M. The effect of aromatherapy on sleep and quality of life in menopausal women with sleeping problems: a non-randomized, placebo-controlled trial. Complement Med Res 2020; 9: 1-10
• 151 McDonnell B, Newcomb P. Trial of essential oils to improve sleep for patients in cardiac rehabilitation. J Altern Complement Med 2019; 25: 1193-1199
• 152 Hamzeh S, Safari-Faramani R, Khatony A. Effects of aromatherapy with lavender and peppermint essential oils on the sleep quality of cancer patients: a randomized controlled trial. Evid Based Complement Alternat Med 2020; 2020: 7480204
• 153 Polonini H, Mesquita D, Lanine J, Dijkers E, Gkinis S, Raposo NRB, Brandão MAF, Ferreira ADO. Intranasal use of lavender and fennel decreases salivary cortisol levels and improves quality of sleep: a double-blind randomized clinical trial. Eur J Integr Med 2020; 34: 101015
• 154 Kamalifard M, Farshbaf-Khalili A, Namadian M, Ranjbar Y, Herizchi S. Comparison of the effect of lavender and bitter orange on sleep quality in postmenopausal women: a triple-blind, randomized, controlled clinical trial. Women Health 2018; 58: 851-865
• 155 Taherzadeh Z, Khaluyan H, Iranshahy M, Rezaeitalab F, Eshaghi Ghalibaf MH, Javadi B. Evaluation of sedative effects of an intranasal dosage form containing saffron, lettuce seeds and sweet violet in primary chronic insomnia: a randomized, double-dummy, double-blind placebo controlled clinical trial. J Ethnopharmacol 2020; 262: 113116
• 156 Ancoli-Israel S. Sleep and its disorders in aging populations. Sleep Med 2009; 10 (Suppl. 01) S7-S11
• 157 Suh S, Cho N, Zhang J. Sex differences in insomnia: from epidemiology and etiology to intervention. Curr Psychiatry Rep 2018; 20: 69
• 158 Williamson E. Synergy and other interactions in phytomedicines. Phytomedicine 2001; 8: 401-409
• 159 Spinella M. The importance of pharmacological synergy in psychoactive herbal medicines. Altern Med Rev 2002; 7: 130-137
• 160 Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 2009; 16: 97-110
• 161 Wagner H. Synergy research: approaching a new generation of phytopharmaceuticals. Fitoterapia 2011; 82: 34-37
• 162 Bhutani MK, Bishnoi M, Kulkarni SK. Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes. Pharmacol Biochem Behav 2009; 92: 39-43
• 163 Wasowski C, Marder M. Flavonoids as GABA_A receptor ligands: The whole story?. Br J Pharmacol 2011; 163: 234-245
• 164 Campbell EL, Chebib M, Johnston GA. The dietary flavonoids apigenin and (−)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA_A receptors. Biochem Pharmacol 2004; 68: 1631-1638
• 165 Vissiennon C, Nieber K, Kelber O, Butterweck V. Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin–are they prodrugs?. J Nutr Biochem 2012; 23: 733-740
• 166 Aguirre-Hernández E, González-Trujano ME, Terrazas T, Herrera-Santoyo J, Guevara-Fefer P. Anxiolytic and sedative-like effects of flavonoids from Tilia americana var. mexicana: GABAergic and serotonergic participation. Salud Mental 2016; 39: 37-46
• 167 Noguerón-Merino MC, Jiménez-Ferrer E, Román-Ramos R, Zamilpa A, Tortoriello J, Herrera-Ruiz M. Interactions of a standardized flavonoid fraction from Tilia americana with serotoninergic drugs in elevated plus maze. J Ethnopharmacol 2015; 164: 319-327
• 168 Hernández-León A, González-Trujano ME, Fernández-Guasti A. The anxiolytic-like effect of rutin in rats involves GABA_A receptors in the basolateral amygdala. Behav Pharmacol 2017; 28: 303-312
• 169 Carrasco MC, Vallejo JR, Pardo-de-Santayana M, Peral D, Martín MA, Altimiras J. Interactions of Valeriana officinalis L. and Passiflora incarnata L. in a patient treated with lorazepam. Phytother Res 2009; 23: 1795-1796
• 170 Tweddell P, Boyle C. Potential interactions with herbal medications and midazolam. Dent Update 2009; 36: 175-178