Some medicinal plants, their constituents, effects and probable mechanisms of action.
Substantial number of studies has been conducted to find alternatives or treatments for psychosis. Psychosis represents a variety of mental disorders characterized by the presence of delusions, hallucinations and grossly disorganized thinking in a clear sensorium. Psychosis is burdensome and difficult to treat given the inability of the typical and atypical antipsychotics to adequately manage it, accompanied by numerous disturbing adverse effects. Therefore, many with chronic mental health problems justifiably feel disappointed by the apparent ineffectiveness of conventional treatment and naturally search for a more holistic approach to treatment and alternative medicines having less or no side-effects. Plants are rich in secondary metabolites which have the ability to interact with the Central nervous system (CNS) to produce effects that can be beneficial for the management of psychosis, these phytochemicals are believed to have minimal adverse effects. A review of some of the medicinal plants used as antipsychotics, indicated that many medicinal plants possess antipsychotic effects that can improve the treatment of psychosis. Apparently, further studies are necessary in order to isolate the active constituents, ascertain their molecular mechanisms and safety, and also to test them in clinical studies for the development of new pharmacotherapies for psychosis.
- Medicinal plants
- Molecular mechanisms
- Secondary metabolites
The term “psychosis” denotes a variety of mental disorders: the presence of delusions, various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory, and grossly disorganized thinking in a clear sensorium. Schizophrenia is an enduring, disabling psychiatric illness affecting about 1% of the population globally. It is characterized by various symptoms classified into positive, negative and cognitive) [1, 2].
Plants provide the essential nutrients and remedy needed by humans, they are healthier compared to animal diets. Over time much benefits have been derived from medicinal plants due to their rich natural phytochemicals that interact favorably with the human body and neurotransmitters to produce effects that are beneficial to man. In this chapter we will look at some medicinal plant used in the pharmacotherapy of psychosis.
2. Management of psychosis
Psychosis is an immense social and economic problem, but the management of psychosis remains insufficient. Basically typical and atypical antipsychotics are used for the treatment of schizophrenia, the typical antipsychotics such as chlorpromazine and haloperidol are only effective in the treatment of positive symptoms, and are accompanied by disturbing adverse effects such as extrapyramidal side-effects , the atypical antipsychotic drugs such as risperidone and olanzapine provide some beneficial effects on negative symptoms and cognitive deficits , but they are inadequate and mild. Prolonged use also results in increased oxidative load  which could lead to cardiovascular disorders, diabetes, and agranulocytosis seen with clozapine, they also cause moderate to severe weight gain [2, 6, 7, 8]. The use of medicinal plants as complementary remedies for the treatment of psychosis have become necessary because of their characteristically high chemical diversity, biochemical specificity, and several other properties that make them favorable lead structures for the treatment of various disorders, including psychosis , for example,
Medicinal plants are either used as an alternative or in addition to orthodox medicine , users search for a more holistic approach to treatment, others expect that alternative medicines have less or no side-effects, and many with chronic mental health problems justifiably feel disappointed by the apparent ineffectiveness of conventional treatment .
3. Review of relevant pathophysiology
Neuropsychiatric Disorders may occur as a result of a number of factors such as genetic predisposition, lifestyle factors such as substance abuse and recently diet is also believed to be a factor  due to certain observations that associated incidence of psychotic episodes in neuropsychiatric diseases with poor dietary patterns, such as a lower intake of omega-3 fatty acids, vegetables, fibers, fruits, vitamins and minerals , all these are substances that can be obtained naturally supporting the use of natural products in psychosis especially because of the high antioxidant content of these natural products, since oxidative stress is implicated in psychosis.
4. Secondary metabolites in medicinal plants for psychosis
The discovery of effective plant-based medicinal plants for the treatment of psychosis is constrained by a need to conclusively identify relevant active constituents and understand synergies within them and an inability to sufficiently standardize replicable extracts.
A large number of natural phytochemicals are claimed to have beneficial effects on the adequate functioning of the human brain . Essentially, metabolites produce effects on human brain function probably due to the connection between plant, mammalian biochemistry and molecular functioning. Principally, as a result of the numerous molecular signaling pathways that are conserved between taxa and their role in the synthesis of secondary metabolite . Secondly the effects might be based on the similarities between the prevalent natural herbivores of plants and the nervous systems of humans. Therefore, the phytochemicals whose synthesis has been retained by a process of natural selection and on the basis of their ability to interact with the CNS of herbivorous or symbiotic insects will also interact with the human CNS system via the same mechanisms . Some of the significance of secondary metabolites involve general protective roles (such as antioxidant, ultra violet (UV) light-absorbing, free radical-scavenging and antiproliferative agents) and preservation the plant against microorganisms such as bacteria, fungi, and viruses. More intricate actions involve dictating or modifying the plant’s relationship with more complex organisms [23, 24, 25]. This is achieved primarily by their role of feeding deterrence, consequently, many phytochemicals are bitter and/or toxic to potential herbivores, with this toxicity often extending to direct interactions with the herbivore’s central and peripheral nervous systems  identified extracts and constituents from 85 individual medicinal plants that have potential efficacy for treating psychiatric disorder. Accordingly, secondary metabolites often act as agonists or antagonists of neurotransmitter systems [25, 27] or form structural analogs of endogenous hormones .
Secondary metabolites can be subdivided into many distinct groups base on their chemical structure and synthetic pathways, furthermore, these groups can be broadly categorized in terms of the nature of their ecological roles and also their eventual effects and comparative toxicity in the consuming animal. The phytochemicals are herewith, discussed base on the chemical nature of their alleged active components. The largest and most widespread of phytochemical groups are the alkaloids, phenolic compounds and terpenes.
Alkaloids are a structurally diverse group of over 12,000 cyclic nitrogen-containing compounds that are found in over 20% of plant species . The use of alkaloids for medicinal purposes dates as far back as the Stone Age .
The alkaloids are known to be the common poisons, neurotoxins, and traditional psychedelics for example atropine, scopolamine, and hyoscyamine, from
Gentianine is a major alkaloid extracted from
4.2 Phenolic compounds
Phenolic compounds are universally found across the plant kingdom, with approximately 10,000 structures identified to date. Phenolics are synthesized from precursors produced by the phenylpropanoid pathway with the exception of a few notable compounds. Structurally, they share at least one aromatic hydrocarbon ring with one or more hydroxyl groups attached .
Phenolic compounds comprise of simple low-molecular weight compounds, such as the coumarins, simple phenylpropanoids, and benzoic acid derivatives, to more complex structures such as flavanoids, tannins and stilbenes . These compounds play an important role in CNS functioning by interacting directly with neurotransmitter systems. In in vivo models, phenolics enhance cognition through antagonistic gamma-aminobutyric acid (GABA) receptor binding, with resultant cholinergic upregulation and exert antidepressant effects via monoamine oxidase inhibition in the brain, sedative, anxiolytic and antipsychotic effects by binding to GABA receptors, [36, 37, 38]. Flavonoids are widely distributed throughout the plant kingdom. They are constituents of medicinal plants used as herbal medicines in traditional medical practice, and are now considered valuable therapeutic agents in modern medicines [39, 40]. Many studies have reported that flavones modulate neurotransmission through enhancement of GABA activity in the central nervous system; which led to the hypothesis that they could exert tranquilizing effects in behavioral hyperactivity such as schizophrenia [41, 42]. Undeniably, a number of evidences have implicated the role of altered GABAergic transmission in the pathophysiology of schizophrenia [43, 44]. Morin a flavonoid isolated from plants was found to exhibit antipsychotic effects .
Tannins are a group of plant secondary metabolites that have the ability to tan or convert animal skin into leather. These compounds are classified as being water soluble phenolics with the ability to precipitate alkaloids, gelatins, and other proteins. High tannin concentrations are found in nearly every part of many plants, such as in the bark, wood, leaves, fruit, roots, plant galls, and seed. Tannins may exert their biological effects in two different ways: as unabsorbables, these are usually complex structures with binding properties which may produce local effects in the gastrointestinal tract (antioxidant, radical scavenging, antimicrobial, antiviral, antimutagenic, and antinutrient effects), or as absorbable, these are usually low molecular weight structures which are easily absorbed, and produce systemic effects in various organs . Gallic acid, a gallotanin found in many plants was reported to demonstrate anti-schizophrenic activity primarily due to its antioxidant and anti-inflammatory effects . A novel tannin composition effective in treating mental diseases such as acute or chronic schizophrenia, was isolated from Rhubarb (Rhe; Rhi zoma) a kind of crude drug known from the past and has been frequently used as a Japanese-Chinese medicine .
Saponins are naturally occurring, but functionally and structurally diverse phytochemicals that are broadly distributed in plants. They are a complex and chemically varied group of compounds consisting of triterpenoid or steroidal glycones linked to oligosaccharide moieties. Although there is a scarce documentation on the antipsychotic potential of saponin, polygalasaponins, a saponin isolated from
Terpenes are a diverse group of more than 30,000 lipid-soluble compounds. Their structure includes 1 or more 5-carbon isoprene units, Terpenoids are classified base on the number of isoprene units they contain; isoprene, which itself is synthesized and released by plants, comprises 1 unit and is classified as a hemiterpene; monoterpenes incorporate 2 isoprene units, sesquiterpenes incorporate 3 units, diterpenes comprise 4 units, sesterpenes include 5 units, triterpenes incorporate 6 units, and tetraterpenes 8 units . Some of the recognized antipsychotic terpenoids are myrcene, beta-caryophyllene and limonene. However, these terpenoids do not only have antipsychotic properties but possess anti-depressant effects due to the suppression and activation of the cannabinoid receptor 2 .
5. Review of medicinal plants for psychosis
Many medicinal plants are in use both in developed and developing countries for the treatment of psychosis, some of these plants have been studied for their antipsychotic properties whereas most of these plants have no scientific backings for their efficacy. Literature search of the PUBMED and Sciencedirect journals have documented a number of plants studied for their antipsychotic properties in laboratory animals, however, most of the studies carried out are preliminary, and the need for further studies to isolate the active constituents, determine the mechanism of action and conduct clinical trials to verify their efficacy and safety is necessary. Table 1 gave a list of some of the reviewed antipsychotic plants, their constituents and probable mechanism of action.
|Plant name||Parts used||Constituents and effects||Probable mechanism of action||Author|
|Roots||The root extract of ||The possible mechanism of action of ||Kumbol, et al. |
|Leaves||The essential oil was extracted from the leaves of ||The possible mechanism of action might be due to antioxidant effects as well as enhancing NMDA neurotransmission.||de Araújoa et al. |
|Leaves||Mechanism of action may be attributed to dopamine antagonism in the frontal cortical regions of the brain.||Jash & Chowdary. |
|Whole plant||Triterpenoid, saponins, and bacosides are considered to be the major constituents in the plant. ||The antipsychotic properties may be related to its normalization of dopamine and serotonergic neurotransmission and reduction of acetylcholinesterase activity.||Chatterjee et al. |
|Leaf Juice||Yadav et al. |
|Leaves||Cannabidiol one of the major constituent of ||The possible mechanism of ||Zuardi et al. |
|Leaves||The antipsychotic properties are possibly mediated via the GABAergic neurotransmission as well as blockade of dopamine D-2 receptors||Taıwe et al. |
|Bulb||alkaloids, saponins and tannins were found to be some of the major constituents of ||The possible mechanism of action of Crinum giganteum may be limited to dopamine D1 antagonism.||Amos et al. |
|Whole plant||The major constituent in ||The possible mechanism of action may be due to dopamine receptor antagonism||Amoateng et al. |
|Ber-ries||Embelin was isolated from Embelia ribes and found to be responsible for the antipsychotic effect of the plant. Embelin reversed apomorphine induced stereotypic behavior, confirming its antipsychotic potential.||Embelin action may be due dopamine antagonism and decreased level of neurotransmitters such as dopamine, serotonin and noradrenaline as well as antioxidant effects.||Durg et al. |
|The effect of the extract amphetamine-induced stereotyped behavior in mice suggest anti-dopaminergic actions on the limbic system||Amos et al. |
Studies have shown that
|The probable mechanism of action of ||Arowona et al. |
|Roots||Triterpenes has been identified in |
Findings revealed the antipsychotic effects of
|The probable mechanism of action of ||de Sousa & de Almeida. |
|Fruits||scopoletin, rutin and quercetin are the major constituents of ||The probable mechanism of antipsychotic effect of ||Pandy et al. |
|Root bark||Saponins are present in abundance in the extract and might contribute in part for the observed CNS effects. The extract demonstrated antipsychotic effects by attenuating apomorphine induced stereotypic behavior||The effect of the extract against apomorphine is suggestive of possible interference with central dopaminergic neurotransmission.||Amos et al. |
|Stem bark||The probable mechanism of action might be due to dopamine D1 and D2 antagonism.||Amos, et al. |
|Leaves||The Probable mechanism of action include antioxidant action and enhancement of NMDA neurotransmission as well as neuroprotection.||Sharma et al. |
|Leaves||The plant’s major compound is ginseng which is known to possess numerous pharmacological effects. ||The antipsychotic properties may be related to its normalization of dopamine and serotonergic neurotransmission and reduction of acetylcholinesterase activity.||Chatterjee et al |
|Fruits||alstonine an indole alkaloid isolated from ||Alstonine indirectly modulates DA receptors, specifically by modulating DA uptake, it also decreases glutamate uptake in acute hippocampal slices. Alstonine also increases serotonergic transmission and increases intraneuronal dopamine catabolism.||Linck et al. [34, 35]|
|Fruits||The antipsychotic activity may be mediated through augmentation of GABA at the GABAA–benzodiazepine receptor complex pathway, or inhibition of dopamine neurotransmission at dopamine D1/D2 receptors||Oyemitan et al. |
|Roots||polygalasaponin molecular mechanism of action is dopamine (D2) and serotonin (5HT2) receptor antagonism||Chung et al. |
|Leaves||11-demethoxyreserpiline, 10- demethoxyreserpiline, α-yohimbine and reserpiline are alkaloids isolated from the leaves of ||The mechanism of action of the plant is due to the blockade of dopamine (D2) and serotonin (5HT2) receptor.||Gupta et al. |
|The extracts of ||The probable antipsychotic mechanism of ||Coors et al. |
|The antipsychotic effect of ||Rao et al. |
|Root Bark||Securinega virosa has been described as “cure all” in Africa traditional medicine because of its use widely in the treatment of many illnesses. The plant contains saponins, flavonoids, alkaloids and tannins, and was found to possess antipsycotic activity||The probable mechanism of action may be due to dopamine D1 and D2 antagonism.||Magaji et al. |
|Leaves||The antipsychotic mechanism of ||Ayoka et al. |
|Leaves||Gentianine is a major alkaloid isolated from ||It probable mechanism of action might be due to dopamine antagonism.||Bhattacharya et al. |
|The extract of the whole plant has demonstrated anticonvulsant, sedative, in vitro antioxidant and free radical scavenging properties as well as antinociceptive properties in acute and neuropathic pain. ||The probably mechanism of the antipsychotic properties of ||Amoateng et al. |
|Leaves and roots||The plant contains Flavonoids, saponins and tannins in abundance which may be responsible in part for the observed activities. ||Ior et al. |
|The mechanism of action of ||Guptaa et al. |
6. Efficacy of natural plants in the treatment of psychosis
Many medicinal plants studied for psychosis were found to have efficacy against the positive, negative and cognitive deficit of schizophrenia in laboratory animals, without the disturbing adverse effects seen with conventional antipsychotic drugs. Even those that are thought to act on the dopamine receptors had minimal or no cataleptic tendencies. The tendency for these plants to ameliorate the negative symptoms in schizophrenia, and in some cases also improve psychotic symptoms, may be owing to the ability of most plants to generally exert anti-inflammatory effects  and given that inflammation is a risk factor in most neuropsychiatric disorders including schizophrenia . Oxidative stress is also a major factor in psychosis, plants contain diverse constituents which exhibit antioxidant, and neuroprotective effects useful in ameliorating psychotic symptoms .
Large number of schizophrenic patients fail to respond adequately to the initial antipsychotic drug treatment necessitating the addition of natural antipsychotic plants to their treatment regimen. As recently reviewed by Hoenders et al.  the inclusion of traditional medicine or Ayurvedic herbs to antipsychotics, generally improve the psychopathology of the disease, however, more studies are needed to conclusively support this finding.
7. Molecular mechanisms of antipsychotic action of medicinal plants
Many medicinal plants have been studied for their antipsychotic properties and several mechanisms of action have been proposed for their actions. A number of these plants were believed to act in a similar manner as orthodox medicines but in most cases without the disturbing adverse effects. Table 1 gave a summary of the probable antipsychotic mechanism of action of the medicinal plants. Various animal models are used to investigate the antipsychotic properties of medicinal plants, some of these models help to determine whether these plants have typical or atypical antipsychotic like effects.
Dopaminergic deregulation, hypofunction of NMDA receptors and GABAergic activity, diminished cholinergic firing, neuroinflammation and increased oxidative stress has been demonstrated to play a pathophysiological role in schizophrenia .
The dopamine and amphetamine animal models are basically used to study the typical antipsychotic effects of drugs, their action are similar to the conventional antipsychotics such as haloperidol, chlorpromazine, fluphenazine and thioridazine. The stereotypic behavior observed in animals following the administration of apomorphine a dopaminergic agonist, are attributed to stimulation of D1 and D2 receptors [74, 75]. Mesolimbic and nigrostriatal dopaminergic pathways play key roles in the mediation of locomotor activity and stereotyped behavior. Animal models used for assessing antipsychotic drugs are established on the neurochemical hypothesis of schizophrenia, which involve largely the neurotransmitters dopamine and glutamate . The antagonism of dopamine D2 receptors in the mesolimbic-mesocortical system is thought to be the basis of the therapeutic actions of the antipsychotic drugs, especially those active against hallucinations and delusions . The dopamine-based models usually employ apomorphine, a direct agonist, or amphetamine, a drug that increases the release of this neurotransmitter and blocks its re-uptake.
The term atypical refers to the reduced propensity of the of an agent to cause undesirable motor side effects, but it is also used to describe agents with a different pharmacological profile from the typical antipsychotics; several of these newer antipsychotics improve the negative as well as the positive symptoms . The atypical antipsychotics are categorized base on their pharmacological properties. These include serotonin–dopamine antagonists, multi-acting receptor- Targeted antipsychotics, and dopamine partial agonists. . Examples include clozapine, quetiapine, risperidone, amisulpride, sertindole, zotepine and aripiprazole. The dopamine dysregulation with hyperfunction of the mesolimbic dopamine system was the original tenet theory underlying the basis of schizophrenia  and the earliest animal models were established on the basis of pharmacological manipulation in an endeavor to simulate this feature , which respond to agents that affect primarily the dopaminergic system, but does not demonstrate the negative or cognitive symptoms seen in schizophrenia . In contrast, a widely used animal model of schizophrenia involves the acute or repeated administration of sub-anesthetic doses of ketamine . In rodents, N-methyl-Daspartic acid receptor (NMDAR) blockade induces hyperactivity, stereotypy, deficits in prepulse inhibition , social interaction and memory (Becker and Grecksch ), which models the positive, negative and cognitive symptoms of schizophrenia, respectively . Furthermore, studies have revealed that reactive oxygen species have a significant role in the pathogenesis of many illnesses, particularly neurological and psychiatric illnesses.  Oxidative stress may be a common pathogenic mechanism underlying many major psychiatric disorders as the brain is relatively susceptible to oxidative damage . Previous study confirmed that oxidative stress damage occurs in patients with schizophrenia and one possible therapeutic solution is to use antioxidants . Reports from some of the medicinal plants studied that delineate some of the animal models used and their molecular mechanism of action are highlighted.
Morinda citrifoliaLinn (Rubiaceae)
Securinega virosa(Roxb ex. Willd) Baill
Picralima nitidaStampf Th. et H. Dur.
Crassocephalum bauchiense(Hutch.) Milne-Redh
Alpinia zerumbet(Pers.) Burtt. et Smith
Albizia zygia(DC.) J.F. Macbr. (Leguminosae)
Plants have been the mainstay for the treatment of diseases all over the world before the development of conventional medicines. The interest in the therapeutic uses of plants have been revived due to obvious reasons such as their safety, availability, and affordability as well as their efficacy. Research on medicinal plant have provided evidences for their use, and further studies in order to isolate the active constituents and also to test them in clinical studies is important for the development of new pharmacotherapies for psychosis.
The authors acknowledge all sources, and are grateful to the authors/editors of all the articles, journals, and books from where the literature for this article has been reviewed.
Conflict of interest
The authors declare no conflict of interest.