Herbal Medicines: The Double-Edged Sword for Brain—A Narrative Update

Herbal medicines (HMs), also called botanical medicine, phytomedicine, or phytotherapy, refer to herbs, herbal materials, herbal preparations, and finished herbal products that contain parts of plants or other materials as active ingredients. The plant components used in herbal therapy include roots, seeds, stems, berries, leaves, fruits, bark, flowers, or even the whole plants. Some HMs are also prepared from excretory plant products such as gum, resins, and latex.[1] Typically, HMs are available in different forms, such as capsules, powders, infusions, poultices, and essential oils. Archaeologically, the use of HMs dates back to the Paleolithic age, approximately 60,000 years ago. However, written records of their use are evinced for the past 5,000 years.[2] Chinese, Indian, and Arabic are the three most influential traditional medicine systems to improve public health problems.[1] [2]

The use of HMs or products, either by itself or in conjunction with other therapies, to treat medical ailments has achieved tremendous popularity in recent years. Consumer demand for HMs is rising exponentially. One of the prime reasons for increased consumption of HMs is due to their easy availability and cost-effectiveness. Other reasons for this resurgence can possibly be attributed to the side effects of allopathic drugs, lack of concrete curative therapy for several chronic diseases, snowballing antimicrobial resistance, as well as the hefty investment in pharmaceutical research and development.[3] A recent report by World Health Organization (WHO) stated that around 80% of the world's population is estimated to use traditional medicines encompassing ancient practices such as acupuncture, ayurvedic medicine and herbal mixtures, as well as modern medicines.[4]

HMs have been effectively experimented in laboratories for various neurological and non-neurological disease conditions, but with variable success rate in humans. While HMs are often regarded safe, they are not without risks. In this article, we have provided a narrative update on the current role of HMs in different neurological conditions, their mechanism of neuroprotection and neurorestoration, and the potential neurological and non-neurological side effects and complications.

Literature Search

An electronic search was conducted using the following databases from January 2000 to December 2023: PubMed, PubMed Central, Embase, Scopus, and Science Citation Index (Web of Science). Only studies published in the English language were considered. The search used key terms such as “Herbs,” “Phytochemicals,” “India,” “Asia,” “Neuroprotection,” “Neurological diseases,” and “Complications.” The sources included research articles, systematic reviews and meta-analyses, narrative reviews, and editorials. Letters to the editor, commentaries, abstracts only, and unpublished data were excluded.

Neurological Indications and Mechanisms

A good number of phytochemicals with neuroprotective and nootropic properties have been tried experimentally and clinically in various neurological conditions like ischemic brain injury,[5] [6] [7] traumatic brain injury (TBI),[8] [9] subarachnoid hemorrhage,[10] [11] Parkinson's disease,[12] [13] Huntington's disease,[14] [15] Alzheimer's disease,[16] [17] multiple sclerosis,[18] [19] brain tumors,[20] [21] seizure disorders,[22] [23] primary headache disorders,[24] [25] meningitis,[26] [27] neuropsychiatric conditions (anxiety, depression, stress, insomnia),[28] [29] [30] etc. ([Table 1]). Numerous mechanisms mediate their neuroprotective and neurorestorative roles, the prominent ones being antioxidative, anti-inflammatory, and antiapoptotic properties, and their role in immune regulation, hormonal regulation, and modulation of neurotransmitters and ion channels.[31] [32] [33] In addition, a few phytochemicals also possess antiproliferative, antiamyloidogenic, antiviral, and antidiabetic properties.[34] At the molecular level, different neuroprotective mechanisms of phytochemicals include signaling pathways such as hypoxia-inducible factor 1 (HIF-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1); free radical scavenging, reduction of nitric oxide (NO) toxicity and acetylcholine esterase (AChE) activity, decrease of phosphorylated AKT (pAkt) and its downstream targets, downregulation of the aquaporin-4 (AQP-4) and toll-like receptor 4 signal, reduction in malondialdehyde and NO levels, increasing neuronal density in the hippocampus, and inhibition of oxidative stress.[35] [36] It is claimed that these mechanisms stabilize the balance between cerebral blood flow (CBF) and cerebral metabolic rate (CMR) of oxygen consumption, reduce cerebral edema, and restore blood–brain barrier (BBB) integrity, thereby improving neurological outcome ([Fig. 1]).

Fig. 1 Neuroprotective and nootropic mechanisms of phytochemicals. BBB, blood–brain barrier; CBF, cerebral blood flow; CMRO₂, cerebral metabolic rate of oxygen consumption.

Table 1
Phytochemicals with neuroprotective and nootropic properties
Botanical name	Corresponding common name in India	Corresponding major constituents
1. Acorus calamus 2. Allium sativum 3. Aloe barbadensis Miller 4. Bacopa monnieri 5. Cannabis sativa 6. Carthamus tinctorius L. 7. Carum carvi 8. Carum roxburghianum 9. Celastrus paniculatus 10. Centella asiatica 11. Cissampelos pareira 12. Claviceps purpurea 13. Clitoria ternatea 14. Convolvulus pluricaulis 15. Coriandrum sativum 16. Crocus sativus 17. Cuminum cyminum 18. Curcuma longa 19. Desmodium gangeticum 20. Eclipta alba 21. Ginkgo biloba 22. Hypericum perforatum (St. John's wort) 23. Juglans regia 24. Moringa oleifera 25. Mucuna pruriens 26. Nigella sativa 27. Passiflora incarnata 28. Piper longum 29. Piper methysticum 30. Piper nigrum 31. Valeriana jatamansi 32. Withania somnifera 33. Zingiber officinale 34. Artemisia dracunculus [a] 35. Resveratrol[a]	1. Sweet flag/vacha 2. Garlic/lahsun 3. Aloe vera 4. Brahmi 5. Bhang/ganja/charas 6. Safflower/kusum 7. Krishna jeera/black cumin 8. Ajmoda/ajwain 9. Jyotismati 10. Mandukparni/jalbrahmi 11. Patha 12. Ergot 13. Aparajit/kakkattan 14. Shankhpushpi 15. Dhaniya 16. Saffron/kesar 17. Jeera 18. Circumin/turmeric/haldi 19. Shalparni 20. Bringharaj 21. Maidenhair tree 22. Basani/mongulu 23. Walnut 24. Drumstick 25. Kawaanch 26. Kalonji/kaala jeera 27. Krishna kamal 28. Pippali 29. Kava 30. Black pepper/kali mirch 31. Sugandhbala/tagar 32. Indian ginseng/ashwagandha 33 Fresh ginger (adrak)/dry ginger (sonth)	1. β-asarone, α-asarone, eugenol, calamusonol 2. Allicin, flavonoids, terpenes 3. Aloe-emodin, aloin, aloesin, emodin, acemannan 4. Saponins, triterpenoids, betulinic acid, sterols 5. Cannabinoids, terpenoids, flavonoids 6. Quercetin, kaempferol, matairesinol, linoleic acid, sterols 7. Carvone, limonene, quercetin, kaempferol, linoleic acid 8. d-limonene, α-terpinene, and d-piperitone, d-linalool 9. Celastrine, paniculatine, celapagine, celapanine paniculatus, oleic acid 10. Asiaticoside, centelloside, asiatic acid 11. Berberine, hayatine, quercetin, kaempferol, saponins 12. Ergotamine, ergovaline, ergocristine, ergometrine 13. Quercetin, kaempferol, ternatins 14. Triterpenoids, flavonol, glycosides, steroids 15. Linalool (terpene alcohol), neryl acetate, γ-terpinene, α-pinene 16. Crocin, picrocrocin and safranal 17. Cuminaldehyde, cymene, terpenoids, apigenin, luteolin, ferulic acid, linolenic acid 18. Circumin, turmerone, zingiberene 19. Desmodin, gangetin, quercetin, kaempferol, triterpenoids, saponins 20. Coumestans (wedololactone, demethylwedelolactone), flavonoids, triterpenes 21. Ginkgolides, bilobalide, lactones 22. Hypericin, hyperforin, flavonoids, tannins 23. Alpha-linolenic acid, ellagic acid, quercetin, kaempferol, tannins 24. Flavonoids, alkaloids, phenols, vitamins 25. L-dopa, mucunine, mucunadine, tannins, flavonoids, saponins 26. Thymoquinone, nigellone, α-hederin, carvacrol 27. Apigenin, luteolin, vitexin, passiflorine, saponins, coumarins 28. Piperine, piperlongumine, piperic acid, flavonoids, saponins 29. Kavalactones (kavain, dihydrokavain, yangonin, methysticin), flavokawains, kavapyrones 30. Piperine, piperlongumine, piperic acid, flavonoids, saponins 31. Valerenic acid, isovaleric acid, β-caryophyllene, flavonoids, saponins 32. Withanolides (withanolide A, withanolide D), withanine, withaferins, saponins 33. Gingerol, shogaol, zingerone 34. Estragole, eucalyptol, α-pinene, flavonoids, tannins 35. Piceatannol, pterostilbene

^a Name commonly used in India for these phytochemicals could not be found in the literature.

Factors Contributing to Adverse Health Outcomes with HMs

HMs are often perceived as safe due to their natural origin, but they can have various side effects and complications. Mild to moderate adverse effects include allergic reaction, rash, dermatitis, asthma, dry mouth, headache, dizziness, agitation, seizure, fatigue, sinus arrythmia, gastrointestinal upset, muscle spasm, muscle weakness, sleep disorder, dyselectrolytemia, nausea, vomiting, loss of appetite, etc. Severe side effects like life-threatening anaphylactic reaction, coagulopathy, life-threatening arrythmia, organ toxicity (hepatotoxicity, nephrotoxicity, cardiotoxicity, neurotoxicity, etc.), carcinoma, cardiac arrest, and even death have been reported.[36] [37] [38] [39] The causes of HM-induced side effects can be multifactorial and can occur during the preparation phase or consumption phase or both.[40] [41] [42] [43] [44] [45]

Preparation phase: Inappropriate process of extract preparation, unsuitable storage conditions, contamination with heavy metals, microbial contamination, radioactive contamination, cross-contamination, product substitution, adulteration, inconsistent quality testing and control, etc.
Consumption phase: Direct toxic effects of active constituents or metabolites, unregulated administration, imprecise dosing, herb–drug interactions, interindividual variability (age, diet, preexisting clinical status, genetic polymorphism, polypharmacy), etc.

Neurological Adverse Effects

Numerous neurological adverse effects of HMs, such as cerebral edema, cerebral arteritis, convulsions, delirium, encephalopathy, mood disturbances, hallucinations, psychosis, paresthesia, and cerebrovascular accidents, have been described in the literature. These neurological adverse effects can result from several mechanisms (as described above); however, the predominant ones include direct neurotoxicity, interaction with neurotransmitter systems, and herb–drug interactions.[37] [38] [39] [40] [46] Also, there is growing evidence that few HMs contain potentially harmful levels of heavy metals like mercury, arsenic, and lead, all of which contribute to neurotoxicity.[47] [48] Illegal drug usage for recreational purposes could be another factor for HM-induced neurotoxicity ([Table 2]). These effects can vary based on the dosage, duration of use, route of exposure, individual susceptibility, and the specific herbal preparation used.[42] [43] [44] [45] Damage to the central nervous system (CNS) or peripheral nervous system (PNS) may be subtle initially and may not be detected unless specific behavioral tests for coordination, memory, and learning are performed. This enigmatic type of toxicity is a feature of many types of HMs, where low doses of herbal toxins may be ingested over a long period of time.[49]

Table 2
Neurological and non-neurological adverse effects of neuroprotective and nootropic phytochemicals, including herb–drug interactions
Botanical name	Neurological adverse effects	Non-neurological adverse effects	Potential drug interactions
Atropa belladonna	Confusions, hallucinations, delirium	Antimuscarinic effects leading to palpitations, flushing, and mydriasis	Anticholinergics (benztropine, trihexyphenidyl), TCAs, antipsychotics (clozapine, olanzapine), and muscle relaxants (cyclobenzaprine)
Cannabis sativa	Delusions, hallucinations, dizziness, and impaired judgment	Tachycardia and dry mouth	CNS depressants, antidepressants (SSRIs, TCAs), anticoagulants and antiplatelets, antiepileptics, antihypertensives, and antidiabetics
Claviceps purpurea	Headache, hallucination, and seizures	Hypertension, nausea, vomiting, gangrene, and abortion	Beta-blockers, CCBs, triptans, serotonergic drugs (SSRIs, SNRIs, and MAOIs), macrolide antibiotics (e.g., erythromycin, clarithromycin), and CYP3A4 inhibitors (grapefruit juice)
Ephedra sinica (ma huang)	Headache, agitation, psychomimetic effects, delirium, and convulsions	Hypertension, tachycardia, palpitations, nausea, and vomiting	Other CNS stimulants, beta-blockers, MAO inhibitors, phenothiazines, and theophylline
Ginkgo biloba	Headache, dizziness, seizures, and bleeding (intracerebral hemorrhage, subarachnoid hemorrhage)	Gastrointestinal upset, nausea, and diarrhea	Anticoagulants and antiplatelets, NSAIDs, and MAO inhibitors
Hypericum perforatum	Dizziness, headaches, agitation, restlessness, and insomnia or vivid dreams	Nausea, dry mouth, photosensitivity, and serotonin syndrome (when combined with other serotonergic agents)	SSRIs, triptans, anticoagulants, antiepileptics, oral contraceptives, HIV PIs, and NNRTIs
Mucuna pruriens	Dyskinesia, dizziness, and psychomimetic effects	Nausea, vomiting, abdominal bloating, and orthostatic hypotension	Antiparkinsonian drugs (levodopa, carbidopa), serotonergic drugs (SSRIs, SNRIs, and MAOIs), CNS depressants, and anticoagulants
Passiflora incarnata	Drowsiness, confusions, dizziness, headaches, and ataxia	Nausea, diarrhea, and cardiac dysrhythmia	CNS depressants, antiepileptics, anticoagulants, and antiplatelets
Piper methysticum	Drowsiness, dizziness, headaches, and hallucination, ataxia	Nausea, diarrhea, muscle weakness, dermopathy (dry, scaly skin), and hepatotoxicity	CNS depressants, serotonergic drugs (SSRIs, SNRIs, and MAOIs), and hepatotoxic drugs (acetaminophen, statins), anticoagulants
Valeriana jatamansi	Drowsiness, dizziness, and headaches	Nausea, vomiting, diarrhea, and hypotension (exaggerated response in those taking antihypertensive medications)	CNS depressants, antidepressants, antihistamines (diphenhydramine, cetirizine), and anticonvulsants (pregabalin, gabapentin)
Withania somnifera	Drowsiness, dizziness, headaches, and mood swings	Nausea, vomiting, diarrhea, and adrenal hypofunction (long term)	Immunosuppressants, sedatives, thyroid hormone medications, and antihypertensive and antidiabetic drugs

Abbreviations: CCBs, calcium channel blockers; CNS, central nervous system; HIV, human immunodeficiency virus; MAOIs, monoamine oxidase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; SNRIs, serotonin and norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

Safety Evaluation

The major hurdle in using HMs either alone or in combination for prophylactic and/or therapeutic purposes is the lack of concrete scientific evidence with regard to their pharmacokinetic and pharmacodynamic profile, human equivalent dose, potential side effects, herb–herb and herb–drug interactions, and possible antidotes. However, the biggest challenge is the accurate identification and authentication of the raw herbal material and also the final marketed products. Traditional methods of authentication include morphological, microscopic, and chemical characterization; nevertheless, in the recent years, several novel and inventive procedures have gained traction. While DNA sequencing may be effectively used to detect pollutants and adulteration, omics has emerged as a useful research tool for prediction and toxicity evaluation.[44] [45] Further, computational models and in silico predictions based on the chemical structure of herbal compounds can further predict toxicity potential.[50] [51] [52] Integrating data from these various approaches ensure a thorough evaluation of the toxicological profile associated with HMs.

Precautionary Measures during Consumption

HMs should be prescribed by a physician and should not be consumed unmonitored (especially by pregnant and lactating mothers). Over-the-counter sale of HMs should be prohibited. Before consuming, the label (dosage, potential side effects, interactions, and contraindications, etc.) and expiry date should be checked for the seal of the regulatory authority. HMs containing heavy metals like mercury, arsenic, and lead should not be used. If an HM is consumed with any other herbal preparation or allopathic medicine, it should be informed to the treating physician. Any noticeable adverse effect should be immediately notified to the physician.[53] [54] [55]

Conclusion

While certain HMs demonstrate potential neuroprotective effects, they are also associated with a range of neurological and non-neurological adverse effects. The diverse phytochemicals present in HMs may exert additive or synergistic actions in vivo, which can enhance or, in some cases, inhibit their therapeutic efficacy. Therefore, it is essential to use HMs cautiously, adhering to recommended dosages and under the supervision of a qualified health care professional. Although evaluating their toxicological potential remains a complex task, ongoing research into species authentication, identification of toxic phytochemicals, elucidation of toxicity mechanisms, and quantification of environmental contaminants in HMs is commendable. Large-scale clinical studies are needed to comprehensively establish the safety profile of HMs, whether used individually or in combination.

Referenzen

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Abbildungen

Fig. 1 Neuroprotective and nootropic mechanisms of phytochemicals. BBB, blood–brain barrier; CBF, cerebral blood flow; CMRO₂, cerebral metabolic rate of oxygen consumption.