Plants, phytochemicals, and natural practices in complementary and alternative system of medicine for treatment of central nervous system disorders

ABSTRACT

Complementary and alternative system of medicine has been at the center of drug discovery for different CNS disorders. Medicinal plants have been in use in healthcare settings and have interestingly fostered the leads for drug development aimed at treating various diseases such as CND disorders, malaria, mycetoma, and inflammation. Electroacupuncture (EA) has the ability to protect prolonged restraint stress, attenuate depressions, and manage few CNS disorders. Bacopa monnieri, Rhodiola rosea, Centella asiatica, Cannabis sativa, Curcuma longa, Cyperus rotundus, Morinda citrifolia, and Withania somnifera are among the most common plants used for treating CNS disorder. Bioactive compounds such as valtrate, curcumin, cannabinoids, apomorphine, pergolide, benzatropine, β-asarone, α-Asarone have been used to treat various CNS disorders, such as addiction, insomnia, depression, Alzheimer’s disease, epilepsy, vitiligo, Parkinson’s disease. These complementary and alternative system of medicines have promising lead in the quest to develop more drugs for CNS disorders.

KEYWORDS:

• Complementary and alternative medicine
• central nervous system disorders
• drug development for CNS disorders
• medicinal plants
• bioactive compounds

Introduction

Complementary and alternative medicine (CAM) has been known as practices which intend to accomplish the healing effect of medicines; however, it may lack biological credibility, as it is usually not scientifically tested, cannot be tested, or has not been proven to be effective. Complementary medicine (CM), CAM, holistic medicine, and integrative medicine or integrated medicine (IM) are among several rebranding which describe same phenomenon^[1]. A typical traditional medical practice can become CAM when it is used in a way that is not in accordance with its original settings with no suitable scientific evidence and explanation. One of the most important goals of medical research is to translate the findings of basic research into beneficial medical developments. In neuropharmacology, it needs understanding the mechanism of disease and the effect of drugs and other compounds on neuronal functions.^[2]

The central nervous system (CNS) is part of the nervous system (NS) made up of mostly the spinal cord and brain. The central nervous system incorporates received information, then influences and coordinates the activities of all body parts. The central nervous system also includes the optic nerve, the retina, as well as olfactory epithelium and the olfactory nerves as part of the central nervous system, directly synapsing on the tissues of brain with no intermediate ganglia.^[3–5]

The discovery of drugs for the treatment of CNS disorders has faced some setbacks. Nervous system (NS) is vital to human body. In spite of the remarkable progress in knowledge of the CNS functions and structure, discovery of novel drugs along with their development for several central nervous system disorders have been challenging.^[2,6,7] Consequently, drug discoveries for CNS treatment and related development program have been experienced eliminations and cutbacks for decades. Complementary and alternative medicine has played a significant role in filling these gaps. CAM has guided the development of some drugs for the treatment of central nervous system (CNS) disorders. This often results in novel or enhanced treatment for CNS disease. In general, it has been noted that CNS drugs record higher rates of failure than their counterparts, clinically and preclinically; in certain areas like neurodegenerative diseases, there has been 100% rate of clinical failures for disease-modifying treatment.^[2] Alternative medicine has played a major role to fill this gap in many parts of the world.

Complementary and alternative medicine makes use of theories, practices, and products perceived or believed by people who make use of them to have healing effects; however, their efficacy has not been fully established using scientifically based approaches, or their practices and theories have no recognized part in biomedicine, or their practices and theories are contradicted directly with scientific evidence or biomedical principles.^[1,8,9] Medicine (biomedicine), as a part of medical sciences, makes use of principles of biophysics, biology, molecular theory, physiology, clinical practice, as well as other natural sciences, with scientific methodology to establish drug effectiveness. In contrast, alternative practices/products do not originate from making use of established scientific methods/principles, but often based on tradition, hearsay, pseudoscience, etc.^[8,9]

Complementary and alternative medicines include various health-care therapies, products, and practices. One of the most notable CAM is the use of medicinal plants (herbs) and their bioactive components. Medicinal plants have been used as complementary and alternative therapies for the treatment of various diseases, including CNS disorders.^[10–12] Medicinal plants have been in use in health-care settings and have interestingly fostered the leads for drug development aimed at treating various diseases such as CND disorders, malaria, mycetoma, inflammation, etc. Bacopa monnieri, Centella asiatica, Curcuma longa, Cyperus rotundus, Morinda citrifolia, and Withania somnifera are among the most common plants used for treating CNS disorder.^[12] Many medicinal plants have been studied and found to contain important compounds and substances, which may be further explored to assess their beneficial use in the management of disorders such as CNS disorders.^[13–15]

This study intends to stimulate interest in studies and applications of various complementary and alternative system of medicine, such as plants, bioactive compounds, acupuncture, etc., as leading potentials for functional and structural novel development of active drugs for treatment of CNS disorders. Table 1 summarizes major medicinal plants commonly used for treating specific CNS disorders. The central nervous system is a sophisticated and very complex, and its disorders are characteristically treated aiming at critical multiple or single targets. Traditional healers, who make use of CAM such as herbs, focus on distinct types of disease appropriate with their experiences and knowledge, instead of using a specified single biomarker targeted therapeutic measure as commonly used in medicine. Complementary and alternative medicine has been used along with functional medicinal treatments in a way that enhances the treatment effects.^[62] Acupuncture which usually involves body piercing using needles to affect the flow of energy may has been thought to complement or increase the effectiveness of science-based medicines when jointly used.^[63,64] This alternative therapy has been noted in cancer therapy^[65–68] Complementary and alternative medicine has been widely recognized.^[69–72]

Table 1. Herbs effective against CNS Disorder.

Plant species	Study evidence	CNS Disorder	Parts used	References
Achyranthes aspera L.	Attenuate epilepsy, Anticonvulsant	Epilepsy, paralysis	Whole plant	^[Citation16,Citation17]
Acorus calamus L.	Increase cognitive function	Paralysis, heat stroke, epilepsy,	Rhizome, leaves	^[Citation18,Citation19]
Aerva lanata (L.) Juss.	No recorded experiment	Headache	Whole plant	^[Citation20]
Alocasia macrorrhizos	No recorded experiment	Mental disorder	Petiole	^[Citation21]
Alstonia scholaris (L.) R.Br.	anti-dopaminergic (schizophrenia)	Nervous debility	Bark	^[Citation22]
Amaranthus viridis L.	No recorded experiment	Epilepsy	Leaves	^[Citation23]
Andrographis paniculata (Burm.f.) Wall	Increase cognitive function	Vertigo	Leaves	^[Citation24,Citation25]
Areca catechu L.	Alzheimer’s disease Antidepressant	Heat stroke	Fruit	^[Citation26,Citation27]
Asparagus racemosus Willd.	Enhances memory, improves cognition, amnesia	Mental disorder, memory loss, epilepsy, nervous debility,	Root	^[Citation28,Citation29]
Begonia silhetensis	No recorded experiment	Headache	Leaves	^[Citation30]
Borassus flabellifer L.	No recorded experiment	Epilepsy	Fruit	^[Citation31]
Calotropis gigantea (L.)	Alzheimer’s disease and Parkinson’s disease	Paralysis	Shoot	^[Citation32]
Cannabis sativa L.	Neurodegenerative disease, Alzheimer’s disease	Schizophrenia	Leaves	^[Citation33,Citation34]
Carissa carandas L.	Anticonvulsant	Insanity, headache	Fruit	^[Citation35,Citation36]
Centella asiatica (L.) Urb.	Alzheimer’s disease, Parkinson’s disease	Memory loss, insanity, mental disorder,	Leaves	^[Citation37,Citation38]
Colocasia esculenta	Nerve tonic	Nervous system disorder	Whole plant	^[Citation39]
Curcuma longa L.	Reduce memory loss, Parkinson’s disease	Memory loss	Rhizome	^[Citation31]
Cyanthillium patulum H.Rob.	No recorded experiment	Vertigo	Leaves, root, flower	^[Citation40,Citation41]
Cyathula prostrata Blume	Antinociceptive	Epilepsy, headache	Leaves, root	^[Citation42,Citation43]
Diplazium esculentum (Retz.) Sw	Cholinesterase and NADH oxidase inhibition	Headache, paralysis, epilepsy	Leaves	^[Citation44]
Dracaena spicata Roxb.	No recorded experiment	Paralysis	Leaves	^[Citation36]
Eclipta prostrata L.	Nootropic and anxiolytic activity	Brain tonic, vertigo	Leaves, root	^[Citation40]
Enhydra fluctuans Lour	CNS depressant	Nervous system disorder	Whole plant	^[Citation45,Citation46]
Foeniculum vulgare Mill	Enhances cognitive function and memory	Nervous debility, headache	Fruit, seed	^[Citation47,Citation48]
Hemidesmus indicus	Anticholinesterase activity	Mental disorder, heat stroke, nervous debility	Leaves, root	^[Citation49]
Hoya parasitica Wall.	No recorded experiment	Paralysis	Leaves	^[Citation40]
Justicia gendarussa Burm.f.	No recorded experiment	Paralysis	leaves	^[Citation31]
Magnifera sylvatica Roxb	No recorded experiment	Headache	Young shoot	^[Citation50]
Marsdenia tenacissima Moon	No recorded experiment	Paralysis	Leaves	^[Citation30,Citation32,Citation35,Citation36]
Phoenix sylvestris (L.)	CNS depressant	Nervous debility	Root, Fruit	^[Citation51]
Pothos scandens L.	No recorded experiment	Migraine, vertigo	Leaves	^[Citation40]
Rauvolfia serpentina Benth.	Acetylcholinesterase inhibition	Epilepsy, schizophrenia, insanity, vertigo	Leaves, root	^[Citation52]
Schefflera roxburghii Gamble	No recorded experiment	Insomnia	Leaves	^[Citation53]
Semecarpus anacardium L.f.	Neuroprotective	Nervous debility	Fruit	^[Citation40]
Staurogyne argentea Wall.	No recorded experiment	Mental disorder	leaves	^[Citation30]
Synedrella nodiflora	Antipsychotic properties	Vertigo	Leaves, stem	^[Citation54]
Tabernaemontana divaricata (L.)	Alzheimer’s disease	Paralysis, epilepsy	Leaves, root, flower	^[Citation55–57]
Thevetia peruviana (Pers.) K.Schum	Anti-acetylcholinesterase	Schizophrenia	Bark, seed	^[Citation58]
Trevesia palmata Vis.	No recorded experiment	Paralysis	Leaves, fruit, root	^[Citation53]
Typhonium trilobatum (L.) Schott	No recorded experiment	Mental disorder, nervous debility	Whole plant	^[Citation45]
Xanthosoma violaceum	Antinociceptive	Alzheimer’s disease	Tuber	^[Citation59,Citation60]
Zingiber zerumbet (L.)	No recorded experiment	Paralysis	Rhizome	^[Citation61]

Action mechanisms of some complementary and alternative medicine in treating disorders of central nervous system

The disorders of CNS are complicated, difficult, and usually require high cost for basic research and clinical therapies because of the mechanisms which are puzzling and most times unknown. Treating central nervous system disorders requires systematic targeted drugs which can pass via brain barriers to targeted precise receptors. Thus far, such systematic targeted drugs usually exhibit severe side effects. Recently, CAM has been vastly recommended and recognized as therapeutic by notable world health bodies, including FAO and WHO. Basic research, medicinal exploration, drug development, and clinical trials of complementary and alternative medicine have significantly increased due to increasing knowledge, awareness, and gradual development.^[7,73]

Complementary and alternative medicine has been at the center of drug discovery for different disorders of CNS. Addiction to cocaine is one of the major health, social, and economic challenges in developed nations which influence many people. The development of novel drugs for the treatment of cocaine dependence is urgently required, although a few trials are already in their early stages. Cocaine is known to mostly bind to re-uptake transporters of dopamine, leading to pleasurable addiction. The species Rhodiola rosea L. is among the popular CAM that have anti-stress, anti-depressive, anxiolytic, and adaptogenic properties. Rhodiola rosea can decrease the withdrawal symptoms of morphine and nicotine. Rhodiola rosea has the capacity to potentiate cocaine-induced hyperactivities.^[7] It also reduced the expression and acquisition of conditioned place preference induced by cocaine. It is conclusive to state that R. rosea is effective in reducing cocaine rewarding properties, however, not in reinstatement associated with cocaine. Epileptic rats have been used to study the antiepileptic effects of and rhynchophylline and Uncaria rhynchophylla,^[7,73] by injecting kainic acid (KA) in rats induced with Sprague-Dawley seizures. Pretreatment with rhynchophylline and Uncaria rhynchophylla can reliably ameliorate seizures occurring simultaneously with reduced mitogen-activated protein kinase (MAPK) c-Jun amino-terminal kinase phosphorylation (JNKp) signal pathways in hippocampus and cerebral cortex.^[7] TNF-α, IL-6, and IL-1β were reported not to be altered, meaning that rhynchophylline and Uncaria rhynchophylla therapeutic effects depend on activation of c-Jun amino-terminal kinase phosphorylation during seizure processes induced by kainic acid.

Guo et al.^[74] and Guo et al.^[75] showed that electroacupuncture (EA) has the ability to protect rat from prolonged restraint stress. Additionally, TGF-β, IL-6, andIL-1β were potentiated in rats with chronic restraint stress; it can be ameliorated by electroacupuncture pre-treatment. It was reported that electroacupuncture can ameliorate depressions accompanied by the alteration of TGF-β, IL-6, and IL-1β in hippocampal CA3 regions. Valtrate, a bioactive compound from Valeriana jatamansi Jones, has been used for treating several mood disorders and can simultaneously reduce depression and corticosterone levels in the serum of rats.^[7] Valtrate has shown anxiolytic effects in behavioral model via hypothalamus-pituitary-adrenal axis (HPA axis). The mechanisms discussed here implied that electroacupuncture and herbal medicine could activate similar mechanisms for the treatment of CNS disorders, including epilepsy and depression.

Lee et al.^[76] analyzed concurrent use of hypnotic drugs and Chinese herbal medicine therapies among Taiwanese adults with insomnia symptoms in a population-based study. They reported that 83.6% of the insomnia sufferers made use of hypnotic drugs. Suan-Zao-Ren-Tang and Jia-Wei-Xiao-Yao-San were continuously used and co-administered along with hypnotic drugs.^[76] They showed that the hip fracture hazard ratio for users of hypnotic drugs who also made use of herbal medicine was below that of those who used only hypnotic drugs. Their result is vital for clinical practices for reducing hip fractures. Additionally, their results are useful for quality of life and health of those with symptoms of insomnia. Complementary and alternative system of medicine has broad categories and mechanisms for treating several CNS disorders, symptoms, and diseases such as addiction, insomnia, depression, epilepsy, vitiligo, etc., with evidence-based medicines from the rudiments which often start with initial observation and basic research up to the expected outcomes which are usually clinical results and patients recovery.

Types of complementary and alternative medicine in use

Complementary and alternative medicines include different health-care therapies, products, and practices, which are diverse in methodologies, applications, and foundations. CAM practices are usually classified based on the types of beliefs they are founded or based on their cultural origins.^[8] The methodologies may integrate or rely on traditional medicines and practices of a folk knowledge, culture, new concepts of disease and health, pseudoscience, belief in supernatural energies, etc.^[8] Each culture usually has its own unique belief or traditional-based health practices developed recently or hundreds, thousands, or even millions of years. Figure 1 shows some of the common CAM used in the management of CNS-related complications.

Figure 1. Complementary and alternative system of medicine in CNS disorders; (a) Acupuncture (b) Chiropractic (c) Achyranthes aspera (d) Enhydra fluctuans Lour.

Belief systems with no scientific base

Complementary and alternative medicines, including the use of homeopathy or naturopathy instead of conventional medicine (see Table 2), are usually based on belief systems which are not often backed by scientific evidence.

Table 2. Use of homeopathy and naturopathy in complementary and alternative medicine.

CAM belief	Description	Overview	Suggested mechanisms	References
Homeopathy	Homeopathy is an alternative system of treating diseases such as CND disorders using small quantities of substances that produce the observed symptoms in larger amounts	Established prior to knowledge of basic chemistry such as molecules and atoms, which indicates that repetitive dilution as done in homeopathy gives only water.	Founded on the belief that any substance which causes symptom of any disease in healthy population also cures such symptom in sick individuals.	^[Citation77,Citation78]
Naturopathy	Naturopathy is an alternative medical therapy which avoids surgery and drugs and lays emphasis on using physical means (electrical treatment, massage) and natural remedies (such as sunshine, heat, water, air) to treat illnesses such as CNS disorders	Conflicts with standard of evidence-based medicines.	It is believed that the body heals itself with supernatural energy which guides body bioprocesses.	^[Citation79–81]

Traditional systems and supernatural energies

Complementary and alternative system of medicine could rely on practices of traditional medicine, e.g. traditional medicine in Africa, Ayurveda in India, traditional Chinese medicine, etc., to treat some diseases such as CNS disorders, infections, etc. Few beneficial uses of traditional medicine have been studied and recommended in the context of ordinary medicine, although the basic belief is rarely backed by scientific evidence. Traditional medicines are regarded as alternatives when used in other places beyond their home regions; or when rationally expected that the practitioner or patient knows they may not work; or when used in place of or along with recognized functional treatment. In many parts of the world, there are beliefs in supernatural energy existence which are not detected by physical science or beliefs in activities of physics energies. Table 3 shows the traditional system in CAM against CNS disorders. Plants such as Verbena officinalis, sweetgrass, cedar, sage, tobacco, etc., have been used in supernatural energies in many parts of the world for the healing of one CNS disorder or the other. These medicinal plants are used for the treatment of several disorders and are also used in many ceremonies.

Table 3. Traditional systems and supernatural energy used in complementary and alternative medicine for treatment of diseases like CNS disorders.

Traditional systems and supernatural energies	Complications	Perceived healing claims	References
Ayurveda	There are some safety concerns on the use of Ayurveda, with some studies results showing about 20% of Ayurvedic Indian-manufactured patent medicines had unsafe and toxic amounts of heavy metals including arsenic, mercury, and lead. In 2015, a US study of users reported high lead levels in blood in 40% of study group. Other concerns exist such as using herbs that contain toxic compounds and insufficient quality control and safety measures in facilities used for Ayurvedic medicines	Ayurveda, an Indian traditional medicine, has belief in three elemental substances (the doshas) existence, called Kapha, Pitta, and Vata, and maintains that the doshas balance results in health, whilst doshas imbalance causes disease, which can be balanced and adjusted with the use of traditional herbs, heavy metals, and minerals. Ayurveda emphasizes using plant-based treatments and medicines, with few products of animal, and added minerals, such as lead, arsenic, sulfur, and copper sulfate	^[Citation82–87]
Traditional Chinese medicine	The practices rely on the belief in supernatural energy known as qi, considerations of Chinese numerology and Chinese Astrology, traditional herbs usage and using other in Chinese substances; has an inaccurate model of physiology and anatomy of internal organs.	Traditional beliefs and practices from China, along with the adjustments made by the Communist party constitute traditional Chinese medicine. Practices include dietary therapy, qigong (exercise), massage (Tui na), acupuncture, herbal medicine, etc.	^[Citation88,Citation89]
Traditional CAM in Africa	In Africa, traditional systems of healing heavily rely on herbs which are usually giving to sick people (with CNS disorders), pregnant women, nursing mothers, etc., with little or no scientific backed prescription. This exposes the individuals to risks of high doses, including exposures to toxic substances in these plants	The belief is mostly based on the claims that diseases have natural remedies, and that natural products such plants are loaded with panacea for different diseases.	^[Citation90,Citation91]
Reiki	No established reliable scientific evidence	The palms of the practitioners are placed on patients close to Chakras, which they believe are the centres of supernatural energies on the basis that the supernatural energies transfer from the palms of the practitioners to heal the patients.	^[Citation92]
Chiropractic	Chiropractic is based on the belief that spine manipulation has effects on supernatural vital energy flow and as a result affects disease and health. Vertebral subluxation is pseudoscientific practice	Used for treatment of vertebral subluxations through spinal manipulations, which are believed to pressure the nerves	^[Citation93–95]
Biofield therapy	There are scepticisms over lack of scientific-based and empirical evidence of existence of fields of putative energy which form the basis of these therapies	Aimed at influencing energy fields which it believes penetrate and surround the body.	^[Citation96]
Bioelectromagnetic therapy	Emphasizes the use of magnets in defying physics laws to influence disease and health	Make use of known electromagnetic fields, including direct-current fields, alternating-current, or pulsed fields in manner not consistent with conventional practices	^[Citation96]

Use of herbs and other substances

Natural materials such as plants and plant-based compounds have been used for functional, therapeutic, medicinal, and prophylactic applications against various illnesses.^[97–99] Complementary and alternative medicine (CAM) practices make use of natural substances such as foods, herbs, minerals, fungal and animal products, megavitamins, and non-vitamin supplements, including using them in the practices of traditional medicine which may integrate other CAM or non-CAM methods^[96,100,101] for the treatment of diseases, including CNS disorders (see Table 1 for herbs commonly used in treating CNS disorders). Typical examples include the therapeutic claims for ginseng, flaxseed oil, echinacea, Moringa oliefera extracts, glucosamine, Omega-3 fatty acid, fish oil, and nonvitamin supplements. Herbal medicines, also known as phytotherapy, comprise not only usage of plants and their products but could also include using mineral and animal products often in combination with plants. Herbal medicine is part of the major branches of CAM with commercial success, and includes elixirs, powders, and tablets, which are usually available in the form of nutritional supplements. Some herbal medicines have demonstrated to have efficacy in the treatment of diseases such as CNS disorders (see Table 1), which often rely on the bioactive compounds present in them. Bioactive compounds have been described and studied in many natural products for various reasons and can be tapped for exploration against CNS-related diseases.^[102–105] Little regulation exists regarding the safety and standards of herbal medicines. Caution should be taken, as many natural products also contain toxic substances and even allergens.^[106]

Efficacy of complementary and alternative medicine

Some scientists maintain a firm opinion that CAM therapies do not have the sufficient requisite scientific-based validations, and as a result, their efficacy could not be ascertained.^[107] Additionally, most claims about the efficacies of CAM have either been controversial or exist with little or no established scientific evidence, as studies on them are often methodologically flawed and of low quality. Differences in standardization and product quality, selective publication bias, and certain companies that make unproven claims question the efficacies of isolated instances where CAM therapeutic evidence exists,^[108] including the treatment of health complications such as malaria, CNS disorders, viral diseases, etc. Someone not diagnosed using medicine with scientific basis may not have in the first instance had true disease identified as a category of alternative disease.^[109] Just like conventional drugs, medicines, interventions, and therapies, it may be hard to assess CAM efficacy using clinical trials. This often require high degree of expertise, awareness, and knowledge of CAM and its components. When an effectively established treatment for any health condition is available already, the Helsinki Declaration proclaims that suppressing the treatment is not ethical. Using treatment of standard-of-care along with CAM technique under testing could give difficult-to-interpret or confounded results.^{[65,110–113]} Overall, establishing the efficacy of some CAM used in the treatment of CNS disorders has been challenging, with few recorded successes. However, the use of CAM in the treatment of illnesses such as CNS disorders has been known to be effective in traditional and modern medicines. Several experiments have validated most of these claims (see Table 1 and 5.3).

Novel approaches in treatment of central nervous system disorders using complementary and alternative medicines

The NS touches every parts of the body, including the skin. Earliest charts of Chinese acupuncture are among the CAM approaches that indicate all the nerves are linked and jointly work to promote health and healthy living.^[73] The connection takes place via the brain, spine, and brain stems. Acupuncture is clearly analgesic through inhibiting potential cation channels of transient receptor in the skin.^[114] The chemokines role in pain has gradually been understood. Chemokines promote pains in skins and also activate ascending neural pathways which regulate the production of chemokines in nerves all over the body.^[115] Chronic pains are body experience which can influence the whole body.

Herbal medicine usage has been in place for thousands of years. Our forefathers partly survived using herbal medicines in treatment of diseases, including CNS disorders. The effectiveness of the herbal medicines largely lies on their constituent bioactive compounds and nutrients. In traditional settings, community and family supports are critical to health-care, such as health care for depression, anxiety, and mood.^[116] Religious practices have also been known to play significant roles in health management. Medical marijuana came into the limelight partly because of ganja use in religious rituals in India. The cautious choice of Cannabis sativa CNS active strains by ancient practitioners led to the use of marijuana in medicine today. Cannabis has received wide approval as psychoactive drug for medical and recreational purposes. The main psychoactive, bioactive compound in cannabis is tetrahydrocannabinol, one of the at least 483 known compounds in cannabis, including over 65 cannabinoids. Cannabidiol is also inclusive. Cannabidiol lotion are smoothly rubbed on cheeks for quick relieving of anxiety.^[117]

Herbs (sometimes called medicinal plants) are composite mixtures of bioactive plant materials that jointly work to promote health. Over the past 20,000 decades, the evolution of our bodies has stretched to make use of these herbal mixtures, usually as CAM and alternative therapy, or as medicines. Medicinal plants play a significant role in drug discovery for the treatment of various diseases, including CNS disorders, cardiovascular diseases, infection, etc. Some bioactive materials may enhance the other materials bioavailability.^[73] Some bioactive compounds could synergize or potentiate the actions of other bioactive constituents.^[118,119] The search for single bioactive compounds in herbal medicine has resulted in the production of several drugs currently in use for the treatment of CNS disorders. Using complex herbal medicines could be significant for CNS complications which single bioactive compounds and modern medicines cannot treat effectively, including chronic pain and headaches.

Our body system is the most powerful medicine naturally available to us. In one way or the other, the human body has its unique way of recovering from illness, especially when there are sufficient nutrients, healthy lifestyle, and normal functioning of the body system (Awuchi et al., 2020a,b^[120]; b). Drugs just assist the body to heal by itself. This explains the reason why so-called miraculous healings have been largely believed, as our bodies heal themselves.^[121] The body heals itself when it is in balance, including balanced nutrition with little or no toxins, as well as healthy lifestyle and regular exercise.^[122] Regular exercise on daily basis is critical in achieving this balance. Balance involves ensuring our body is always in shape and strong, without being underweight, overweight, or obese. The heart, most important body part, requires moderate endurance exercise. Myokines produced by muscles during exercise help maintain healthy body.

Currently, standard health-care practices have not recorded huge rapid progress as was the case in the past. For most individuals, health quality has significantly reduced due to cardiovascular diseases, type 2 diabetes mellitus, obesity, depression, and similar diseases.^[123–126] Health-care providers have been giving several reasons for their patients’ lifestyle diseases.^[125,126] It is high time we learned from traditional healers who maintain that a healthy lifestyle involving living and eating natural foods is vital to having good health.

Traditional medicines and medicinal plants as novel drugs for treatment of CNS disorders

Around one in every nine human deaths has been associated with CNS disorder globally, and at least 28% live with one form of disability or the other at some stage of their lives, as a result of nervous system disorder.^[127] Depression has been considered as one of the most causes of disability, which are more frequent globally than other CNS disorders. Top 20 leading causes of disabilities also include illicit drug use, Asperger syndrome, autism, schizophrenia, anxiety disorders, and dementias including Alzheimer’s disease.^[128] In traditional medicine, medicinal plants are used in treating several disorders such as CNS disorders for decades, as they are affordable and almost readily available. Recent traditional and complementary medicine (T&CM) global survey indicates that substantial progress has been made in the past decade.^[129]

In both developed and developing nations, traditional and complementary medicines are currently used by a significant percentage of the populations. In Europe, at least 100 million people currently make use of traditional and complementary medicines. Consequently, in Europe one in every five people make regular use of traditional and complementary medicines, and also prefer health care that includes traditional and complementary medicine.^[130] There is clear evidence of several more users of T&CM in Africa, North America, Australia, and Asia.^[131]

Traditional medicines have been one of the vehicles for drug discovery and could serve as sources of new supplements, phytomedicines, and bioactive compounds for the treatment of CNS disorders. Valproic acid, lisdexamfetamine, galanthamine, and apomorphine are currently used first-line drugs for treatment of epilepsy, attention-deficit/hyperactivity disorder, Alzheimer’s disease, and Parkinson’s disease, respectively. The bioactive compounds are originally obtained from Valeriana officinalis L., Ephedra sinica Stapf., Galanthus nivalis L., and Papaver somniferum L, respectively. For long, may regulatory authorities such as the FDA have approved some plant-based drugs, including apomorphine (obtained from morphine in plants such as P. somniferum), melevodopa (obtained from levodopa in plants such as Mucuna pruriens), pergolide (obtained from ergot alkaloids in plants such as Claviceps purpurea), carbidopa (obtained from levodopa in plants such as M. pruriens), and benzatropine (from atropine in plants such as Atropa belladonna) for the treatment of Parkinson’s disease. By 2013, reports indicated that the FDA approved at least 307 natural products and their derivatives from plants, marine organisms, fungi, and bacteria, making up to 21% of new chemical substances with approval.^[132]

The most common medicinal plants used in treating CNS disorders include Withania somnifera, Bacopa monnieri, Scoparia dulcis, Tabernaemontana divaricate, Coccinia grandis, Aegle marmelos, Stephania japonica, Centella asiatica, and Asparagus racemosus. Cyperus rotundus, Moringa oleifera, Morinda citrifolia, Curcuma longa, Achyranthes aspera, and Abroma augusta are also widely used in the management of CNS disorders.^[12,133] All these plant species have shown notable therapeutic properties against CNS disorders in various studies (see Table 1). The available scientific-based study evidence for Musa sapientum, Hemidesmus indicus, Euphorbia neriifolia, Datura metel, Curcuma longa, Curcuma aromatica, Convolvulus pluricaulis, Coccinia grandis, Clitoria ternatea, Centella asiatica, Bryophyllum pinnatum, Bacopa monnieri, Aegle marmelos, Achyranthes aspera, and Asparagus racemosus support CAM and T&CM claims. Additionally, pharmacological studies or trials are yet to be done for some medicinal plants used traditionally in treatment of various CNS disorders, including Bauhinia acuminata, Lygodium altum, Plumbago rosea, Solena amplexicaulis, and Typhonium trilobatum.^[12,134] To cure nervous debility, mental disorder and insanity, epilepsy, paralysis, vitiligo, etc., are among regularly mentioned indications of CNS disorders. Most scientific-based study evidence has been made available for activities against some CNS disorders such as memory loss, mental disorder and insanity, and Alzheimer’s disease. Many other plants have been characterized, and this study recommends them for further study to explore their efficacies against disorders related to the central nervous system.^[135–141]

EVIDENCE-BASED MEDICINAL PLANTS and THEIR BIOACTIVE COMPOUNDS EFFECTIVE AGAINST CNS DISORDERS

Several plant-based natural substances have been claimed to be effective against almost all CNS disorders. Table 4 shows plant-derived bioactive compounds, which have already been studied and shown as effective candidates for drug development against CNS disorders. Some of the plants, including Withania somnifera, Morinda citrifolia, Cyperus rotundus, Curcuma longa, Bacopa monnieri, Centella asiatica, etc., are discussed in this section of the study, with more focus on their efficacies against CNS disorders. The major reason for giving detailed discussion on these plant species and their bioactive compounds is to draw attention to the large potentials of CAM in the form of traditional and complementary medicinal as leading candidates in for treating CNS disorders, from commercial and medicinal perspectives.

Table 4. Bioactive compounds effective against CNS disorders.

Bioactive compounds	Plant derived	CNS disorder	Action mechanisms	References
β-asarone, α-Asarone	Acorus calamus	Memory loss, Alzheimer’s disease	Acetylcholiesterase inhibitor	^[Citation142]
Cubebin	Piper cubeba	Alzheimer’s disease, Cognitive dysfunction	Acetylcholiesterase inhibitor	^[Citation143]
Hydroxychavicol	Piper betel	Cognitive dysfunction, Alzheimer’s disease	Attenuate cytokines and both β- and γ-secretase	^[Citation144]
Δ^9-Tetrahydrocannabinol	Cannabis sativa	Huntington’s disease	Attenuates huntingtin aggregate and motor coordination deficit	^[Citation145]
terpinen-4-ol, α-Cyperone	Cyperus rotundus	Brain inflammation	Destabilization of fibers of microtubule	^[Citation146,Citation147]
3,5,6,7,8,3′,4′-Heptamethoxyflavone	Citrus grandis	Alzheimer’s disease, memory disorders	Induce CREB and ERK1/2 activation in cultured neurons	^[Citation148]
Apigenin, baicalein, baicalin, hispidulin, oroxylin A, chrysin	Oroxylum indicum	Nerve tissue development disorder	Induce neuronal differentiation	^[Citation149]
Costunolide	Costus speciosus	Neuroinflammatory diseases	Inhibit activation of MAPKinase and NFkappaB	^[Citation150]
Blumpenes A, B, C, and D	Blumea balsamifera	Alzheimer’s disease	Inhibition of NO	^[Citation151]
Δ^9-Tetrahydrocannabinol	Cannabis sativa L.	Alzheimer’s disease	β-amyloid Inhibition	^[Citation152]
Acteoside	Clerodendrum infortunatum	Cognitive deficit, Alzheimer’s disease	β-amyloid Inhibition	^[Citation153]
Thymoquinone	Nigella sativa	Alzheimer’s disease	β-amyloid Inhibition	^[Citation154]
Bacopaside X, bacopasaponin C, bacopaside II, bacoside A3	Bacopa monniera	Memory loss, Alzheimer’s disease	Inhibition of β-amyloid (Aβ); also inhibits fibrillation	^[Citation155]
Piperodione	Piper retrofractum	Alzheimer’s disease, neurodegenerative diseases	potentiation of nerve growth factor (NGF)	^[Citation156]
Curcumin, bis- demethoxycurcumin, demethoxycurcumin	Curcuma longa	Parkinson’s disease, Neuroinflammation and memory impairment	Prevent mitochondrial dysfunction and apoptosis, and acute neuroinflammation	^[Citation157,Citation158]
Sitoindoside X, sitoindoside IX, sitoindoside VIII, sitoindoside VII, withanoside IV, withaferin A, withanone, Withanolide A	Withania somnifera	Alzheimer’s disease	Prevent loss of synapses, dendrites, and axons; neuroprotection, improve enzymes with antioxidant properties	^[Citation159,Citation160]
Asiatic acid	Centella asiatica	Parkinson’s disease	Prevent neuronal cells loss induced by MPTP/p	^[Citation161]
Δ^9-Tetrahydrocannabinol	Cannabis sativa	Parkinson’s disease	Prevent neuronal damage	(Lastres-Becker et al., 2011)
Cannabidiol	Cannabis sativa	Parkinson’s disease	Prevent neuronal damage	(Lastres-Becker et al., 2011)
Seasmol	Solanum indicum	Multiple sclerosis, Alzheimer’s disease	Protect breakdown of blood–brain barrier	^[Citation162]
Cannabidiol	Cannabis sativa	Alzheimer’s disease	Reduces neuroinflammation induced by β-amyloid	^[Citation163]
Thymoquinone	Nigella sativa	Parkinson’s disease	Retrieved dopaminergic neurons	^[Citation164]
β-santalol, α-Santalol	Santalum album	Anxiety	Sedation	^[Citation165]
Ursolic acid stearoyl glucoside	Lantana camara	Anxiety	Not known yet	^[Citation166]
α-cyperone	Cyperus rotundus	Result in inflammation reduction that can benefit the inflammatory diseases treatment, including Alzheimer’s disease.	Ability to interact with tubulin and is also microtubule polymerization destabilizing agent	^[Citation146]

Curcuma longa, a perennial rhizomatous medicinal plant, belongs to the family of Zingiberaceae; it is used as herb and spice in many parts of the world. Curcuma longa and its bioactive constituents have been linked to cure for various illnesses, including CNS disorders. In addition to protecting memory loss, Curcuma longa contributes to several potential medicinal uses due to its bioactive constituents such as curcuminoids, which are suitable for drug development. Curcumin, a bright yellow natural bioactive compound isolated from Curcuma longa, especially its rhizome, has shown in vivo and in vitro neuropharmacological properties against memory impairment, neuro-inflammation, and various biomarkers of Parkinson’s disease and Alzheimer’s disease.^[157,158] Curcumin has undergone clinical evaluation against few CNS disorders. Rainey-Smith et al.^[167] initially stated curcumin has a low efficiency against symptoms of dementia. But, recently developed novel formulations of curcumin (Theracurmin and Longvida) guarantee higher bioavailability, in combination with adequate chronic and acute activities for the two curcumin formulations, at all doses, including low doses (80 to 180 mg per day).^[168] Burns et al.^[169] carried out a study and reported a remarkable improvement in Déjérine-Sottas disease patient trials, where administration of curcumin was done in two escalating doses (2500 and 1500 mg per day) for 12 months. In another study, curcumin was found to reduce levels of salivary cortisol, TNFα, IL-1β, and increase plasma Brain-Derived Neurotropic factor (BDNF), in group treated with curcumin.^[170] Lopresti et al.^[171] found substantial rise in urinary molecular markers leptin, baseline plasma endothelin-1, substance P, and thromboxane B2, all of which can be associated with curcumin antidepressant action mechanism. In a systematic review, Costa et al.^[172] concluded that shared supplementation using curcuma longa reverses behavioral and neurotoxic damage in Alzheimer’s Disease. In another study, Reddy et al.^[173] evaluated the protective effects of curcumin against amyloid β induced synaptic and mitochondrial toxicities in Alzheimer’s disease, and reported that curcumin can protect against Alzheimer’s disease. Subedi and Gaire^[174] also reported the cellular and molecular mechanisms of curcumin’s neuroprotective effects in cerebral Ischemia.

Cyperus rotundus is an obnoxious weed and a perennial herb commonly found in some parts of the world, mostly in tropics and subtropics. Cyperus rotundus is traditionally used for treating epilepsy and paralysis some countries such as India and Bangladesh.^[175] Study has shown potentials of C. rotundus in enhancing cognition and memory. Cyperus rotundus rhizomes have anticonvulsant activities, anti-AChE activities, prevents pyramidal cell loss, and prevents memory loss.^[176,177] In electrophysiological and behavioral studies, Nóbrega et al.^[147] reported that terpinen-4-ol in Cyperus rotundus essential oil has high effectiveness against convulsion. Additionally, Azimi et al.^[146] found that α-cyperone in C. rotundus has the ability to interact with tubulin and is also microtubule polymerization destabilizing agent. The interactions result in inflammation reduction that can benefit inflammatory disease treatment, including Alzheimer’s disease.

Bacopa monnieri is a small medicinal plant from the family of Plantaginaceae. Bacopa monnieri is used for sharpening cognitive functions and has been recognized as a constituent in several Ayurvedic preparations. Bacopa monnieri is consumed traditionally as leafy vegetable because of its known health benefits.^[178,179] Scientific-based studies have shown B. monnieri potent activities on regulating reactive oxygen species, monoamine modulation and potentiation, increased cerebral blood flows, reduction of β-amyloid, activation of choline acetyltransferase, inhibition of acetylcholinesterase (AChE), and neuroprotection.^[180] Bacopa monnieri has triterpenoid saponins known as bacosides. Out of 12 bacosides analogs, bacoside A has been considered the most potent and most studied Bacopa monnieri component, which in addition includes bacopasaponin C, bacopaside II, bacoside A3, and bacopaside X (a bacosaponin C jujubogenin isomer).^[181] Bacoside A has been shown to have significant inhibitory effects against the toxicity of β-amyloid, reduced receptors of GABA associated with epilepsy, enhanced cognitive and memory functions, and fibrillation.^[182,183] Bacoside A was also shown to increase activities of glutathione reductase, glutathione peroxidase, catalase, and superoxide dismutase.^[155,183] Neale et al.^[184] conducted human trials review which made comparison of the nootropic effects of Panax ginseng and Bacopa monnieri nutraceuticals with a synthetic eugeroic drug called modafinil; in their comparative review, Bacopa monnieri showed largest effects and most consistent of all the three preparations tested.

Withania somnifera, also known as gooseberry, winter cherry, Indian ginseng, or ashwagandha, is a plant in the nightshade or Solanaceae family used in CAM for treatment of diseases, including CNS disorders. Of at least 23 Withania species, Withania somnifera is mostly valuable in traditional and complementary medicine. Different uses of Withania somnifera such as treating CNS disorders (e.g., memory loss, nervous tension, senile debility, and tonic) indicate its ethnopharmacological significance. Studies have shown its several activities against CNS disorders, especially anti-convulsant effects, anti-Alzheimer’s activities, nootropic activities, anti-Parkinson’s activities, anti-depression activities, anti-anxiety activities, neuroprotective activities, and neuritic regeneration activities.^{[159,185–188]} The root is most commonly used part, and the bioactive compounds obtained from the root have shown effectiveness against CNS disorders. Withanoside IV and Withanolide A, which are steroidal lactones, diminished β-amyloid protein which enables the treatment of Alzheimer’s disease.^[189,190] An in vivo study reported that the glyco-withanolides improved the levels of activities of several enzymes with antioxidant activities in the striatum and frontal cortex of rats, which could be significant for the treatment of Alzheimer’s disease.^[191]

Centella asiatica, also called Asiatic pennywort or Indian pennywort, is a herbaceous perennial plant which belongs to the flowering plants of Apiaceae family. It has kidney-shaped leaves, which are used in many traditional and complementary medicine such as Ayurvedic medicine for several centuries. Centella asiatica is applied as revitalizing medicinal plant to strengthen memory and function of nerves. In vivo, Centella asiatica leaves aqueous extracts contribute to enhanced memory and learning processes by the modulation of noradrenaline, 5-hydroxytryptamine, and dopamine systems in the brains of rats,^[192] suggesting that polar compounds, such as asiatic acid in the leaves of Centella asiatica, could improve cognitive functions through the influence on systems of neurotransmitter in the central nervous system. Further studies showed that the triterpenoid (asiatic acid) from Centella asiatica upregulates ADAM10 and downregulates β-secretase (BACE1) in primary cortical neurons of rat,^[193] prevents induced neurotoxicities in aged rats,^[194] diminishes cognitive deficiencies in mice induced by glutamate, and protects cells of SH-SY5Y against apoptosis induced by glutamate, all of which relate to possible routes in treatment of Alzheimer’s disease.^[195] Centella asiatica asiatic acid provided effective neuroprotection in chronic Parkinson’s disease through dopaminergic neuron activation.^[161] Orhan et al.^[196] demonstrated that butyryl cholinesterase inhibitory properties of Chinese Centella asiatica is less strong compared to that of South Asian Centella asiatica.

Morinda citrifolia is a tree in the coffee family, Rubiaceae, that bears fruit; it is commonly found in South Asia^[197] and Australia, as well as some other parts of the world where it is sparingly distributed. Every part of Morinda citrifolia have been reported to have several pharmacological activities, especially the fruit, which has long been used as a diet in tropical regions.^[198] In the European Union, fruit juice of Morinda citrifolia has been recommended as a novel food since 2002.^[199] Studies indicated that fruit juice of Morinda citrifolia has preventive properties against cerebral ischemic neuronal impairment on mice.^[200] Muto et al.^[201] showed that the fruit juice has protective effects on mice brains from cognitive dysfunction induced by stress, mostly decreasing the density of blood vessel resulting from stress. Administering ethyl acetate extracts of fruit juice of Morinda citrifolia increased antioxidant-enzyme, dopamine, and serotonin levels in serum in mice with cognitive dysfunction induced by beta-amyloid.^[202] The fruit ethanol extracts enhanced brain blood flow and memory and reduced acetylcholinesterase activities, oxidative stress, in mice.^[203] These factors have been implicated in many CNS disorders.^[203,204] Behavioral studies showed that administering the fruits methanolic extract reduced the negative impacts of alcohol and heroin dependence.^[205] Figure 2 provides images of some of the commonly used medicinal plants in the treatment of CNS disorders.

Figure 2. Common medicinal plants effective against CNS disorders; (a) Curcuma longa (b) Cyperus rotundus (c) Bacopa monnieri (d) Withania somnifera (e) Centella asiatica (f) Morinda citrifolia (g) Piper cubeba (h) Cannabis sativa.

Many other natural materials, including flavonoids, nobiletin, cocoa, and fisetin, have been shown to exert important therapeutic actions against several altered states of the nervous system.^[206–208] Terpenoids and carotenoids, including astragaulus, are other important natural compounds shown to be effective for the treatment of neuronal disorders, astragaulus obtained from the Astragalus membranaceus, and other similar important compounds present many neuroprotective properties.^[209,210] Nayak et al.^[211] reported the effects of Mucuna pruriens extract on histopathological and biochemical features in ischemia using rat model. Similarly, Neta et al.^[212] also reported the effects of Mucuna pruriens (L.) against Parkinson’s Disease.

Methods of application of complementary and alternative medicine

There are many methods used in the application of complementary and alternative medicine in many countries across the globe. Some of these include practices such as acupuncture, massage, drinking tea (e.g., green tea), tai chi, consumption of prepared plant extracts, etc.^[213,214] Naturopathy, Homeopathy, Oriental/Chinese medicine, topical application, functional herbal therapy, etc., are used in many countries in Africa, Asia, Europe, and the Americas. Fjær et al.^[215] conducted a study on the use of CAM in Europe and reported that most commonly used methods of application of CAM include mind-body medicine (such as relaxation, spiritual, and meditative techniques); whole medical systems (such as acupuncture); body-based and manipulative practices (such as osteopathy, chiropractics, and massage); biologically based systems (such as vitamins, plants, phytochemical/plant extracts, and other natural products), and energy medicine.

Future prospects

There is a need for more studies focused on further exploring more complementary and alternative system of medicines for the treatment of CNS disorders, including anxiety, addiction, insomnia, depression, Alzheimer’s disease, epilepsy, vitiligo, Parkinson’s disease, among others. Most of the CAM therapies such as acupuncture, medicinal plants, bioactive compounds, chiropractic, bioelectromagnetic therapy, etc., need more scientific-based studies to firmly establish their use in developing drugs for CNS disorders. In addition, most of the medicinal plants used in treating CNS disorders have not received sufficient scientific attention. More studies need to be done to discover the phytoconstituents, including bioactive compounds, responsible for their healing effects for potential application in drug discoveries, scientific recognition, and clinical application.

Conclusion

Complementary and alternative system of medicine could rely on practices of traditional medicine, e.g. traditional medicine in Africa, Ayurveda in India, traditional Chinese medicine, etc., to treat some diseases such as CNS disorders, infections, etc. Complementary and alternative system of medicine has been at the center of drug discovery for different CNS disorders. Medicinal plants have been in use in health-care settings and have interestingly fostered the leads for drug development aimed at treating various diseases such CND disorders, malaria, mycetoma, inflammation, etc. Electroacupuncture (EA) has the ability to protect prolonged restraint stress, attenuate depressions, and manage few CNS disorders. Bacopa monnieri, Centella asiatica, Rhodiola rosea, Cannabis sativa, Curcuma longa, Cyperus rotundus, Morinda citrifolia, Withania somnifera, etc., are among the most common plants used for treating CNS disorder. Bioactive compounds such as Valtrate, curcumin, cannabinoids, apomorphine, pergolide, benzatropine, β-asarone, α-Asarone, etc., have been used to treat various CNS disorders, such as addiction, insomnia, depression, Alzheimer’s disease, epilepsy, vitiligo, Parkinson’s disease, etc. Complementary and alternative system of medicines have promising lead in the quest to develop more drugs for CNS disorders.

Acknowledgments

The Author is thankful to Kampala International University, Kampala, for providing the facilities used for this study.

Disclosure statement

No potential conflict of interest was reported by the author.

Data availability statement

Additional data will be made available on request