This review (2017) discusses bioactive compounds containing the indole moiety (half/part of a molecule) from plants that can potentially serve as antidepressive medication due to its relation to serotonin.
Depression is the most common illness observed in the elderly, adults, and children. Antidepressants prescribed are usually synthetic drugs and these can sometimes cause a wide range of unpleasant side effects. Current research is focussed on natural products from plants as they are a rich source of potent new drug leads. Besides Hypericum perforatum (St. John’s wort), the plants studied include Passiflora incarnata L. (passion flower), Mitragyna speciosa (kratom), Piper methysticum G. Forst (kava) and Valeriana officinalis L. Harman, harmol, harmine, harmalol and harmaline are indole alkaloids isolated from P. incarnata, while mitragynine is isolated from M. speciosa. The structure of isolated compounds from P. methysticum G. Forst and V. officinalis L. contains an indole moiety. The indole moiety is related to the neurotransmitter serotonin which is widely implicated for brain function and cognition as the endogenous receptor agonist. An imbalance in serotonin levels may influence mood in a way that leads to depression. The moiety is present in a number of antidepressants already on the market. Hence, the objective of this review is to discuss bioactive compounds containing the indole moiety from plants that can serve as potent antidepressants.
Depression is a highly prevalent global disorder characterised by low mood, anhedonia, cognitive symptoms and disturbances of sleep and appetite. Neurotransmitter imbalances—most notably of serotonin, but also norepinephrine and dopamine—are described as major contributors to depressive states, and current pharmacotherapy typically targets these systems. Synthetic antidepressants such as tricyclic antidepressants and selective serotonin reuptake inhibitors are widely used, but adverse effects and variable efficacy have encouraged interest in plant-derived therapies. Ghosh and colleagues set out to review plant-derived indole alkaloids and related indole-containing phytochemicals as potential leads for antidepressant drug development. The paper aims to collate evidence on specific plants and isolated compounds that exhibit central nervous system activity, to discuss structure–activity relationships that link indole chemistry to serotonergic and other neuroreceptor actions, and to identify gaps where further phytochemical and pharmacological characterisation is needed.
This work is presented as a mini review compiled through bibliographic searches of scientific journals and literature identified via the Web of Science electronic database. The extracted text indicates a narrative synthesis of chemical structures and reported pharmacological activities rather than a formal systematic review. The paper does not provide explicit details about search dates, inclusion and exclusion criteria, study selection procedures, or formal quality/risk-of-bias assessment. Consequently, the review appears to be a selective, literature-based overview that integrates phytochemical descriptions, reported in vitro and in vivo pharmacology, and examples of clinical data where available. Where experimental models are discussed, the authors draw on reported in vitro receptor and enzyme studies, in vivo animal behavioural models (for example mouse models of behavioural despair), and the limited human clinical trial data available for some botanicals (notably kava). Structure–activity and molecular docking observations are summarised from prior pharmacological and medicinal chemistry studies cited in the literature.
The review highlights four plants of particular relevance: Passiflora incarnata (passion flower), Mitragyna speciosa (kratom), Piper methysticum (kava) and Valeriana officinalis (valerian). Two of these—P. incarnata and M. speciosa—contain characterised indole alkaloids, while kava and valerian contain compounds with indole-like features or other indole-containing substructures that may be pharmacologically relevant. Passiflora incarnata: The authors report isolation of several indole alkaloids from passion flower, including harman, harmol, harmine, harmalol and harmaline. Pharmacologically, P. incarnata extracts have been reported to exhibit a benzodiazepine-like profile and to act via GABAergic mechanisms, consistent with their traditional use as sedatives and anxiolytics. Mitragyna speciosa: Mitragynine is identified as the major indole alkaloid in kratom, with related alkaloids speciogynine, paynantheine and speciociliatine. The review cites animal studies in which aqueous or alkaloidal extracts produced antidepressant-like effects in behavioural despair paradigms. One study noted mitragynine’s influence on the hypothalamic–pituitary–adrenal (HPA) axis, suggesting a neuroendocrine component to its actions. Piper methysticum (kava): Active constituents are primarily lipophilic kavalactones (at least seven identified), including dihydromethysticin; these compounds interact with multiple neurotransmitter systems (dopaminergic, serotonergic, GABAergic, glutamatergic), inhibit monoamine oxidase B (MAO-B) in some reports, and act on ion channels. The authors report that lipid-soluble extracts retain most pharmacological activity versus aqueous extracts. Importantly, double-blind placebo-controlled human trials have demonstrated anxiolytic effects of kavalactones, improved sleep quality, and no detrimental effects on mental or motor function—supporting kava as a potential benzodiazepine alternative for anxiety and related symptoms. Valeriana officinalis: Valerenic acid and valepotriates are described as principal active constituents used in sedative preparations. Valepotriates are chemically unstable (thermolabile, acid- and base-sensitive). Mechanistically, valerian preparations are reported to interact with the GABAergic system—via inhibition of GABA transaminase, modulation of GABA receptors/benzodiazepine binding sites, and interference with GABA uptake—supporting anxiolytic and hypnotic effects and potential usefulness during benzodiazepine withdrawal. Experimental models and evidence base: The authors note that most studies reviewed were in vivo animal investigations, fewer were in vitro, and only kava had undergone clinical trials among the plants discussed. Reported pharmacological outcomes vary between preparations and geographic sources, reflecting variation in secondary metabolite profiles. Indole scaffold and medicinal chemistry: The paper provides a chemical and pharmacological rationale for interest in indole alkaloids. Indoles are bicyclic systems (a six‑membered benzene fused to a five‑membered nitrogen-containing pyrrole) that share structural similarity with serotonin, enabling interactions with serotonin receptors (5‑HT families) and other G protein–coupled receptors. The authors discuss structure–activity relationship (SAR) observations: the indole NH and π-electron density contribute to receptor interactions (hydrogen bonding, π–π and cation–π interactions), though some studies indicate the NH is not absolutely required for activity at certain receptors (for example some 5‑HT2 responses). Examples from medicinal chemistry include bioisosteric modification (benzofurans, benzothiophenes, azaindoles) used to modulate solubility, receptor affinity and oral bioavailability; molecular docking studies suggest 2‑phenyl‑indole scaffolds can occupy conserved and non‑conserved receptor subpockets, explaining selectivity differences. The review also highlights that many marketed drugs contain indole substructures and that plant-derived indole alkaloids (and derivatives such as reserpine, vinblastine) have long pharmacological histories. Limitations in the evidence: Across the cited studies, the active constituent(s) responsible for antidepressant effects are often unresolved; crude or semi‑purified extracts predominate, and biochemical variability tied to geography, climate and plant nutrition undermines reproducibility. The authors also note that much of the reliable pharmacological evidence comes from synthetic indole analogues rather than from fully characterised natural products.
Ghosh and colleagues interpret the assembled evidence as supportive of plants as a valuable source of indole-containing lead structures for antidepressant drug discovery. They argue the structural similarity between the indole scaffold and endogenous serotonin provides a plausible mechanistic basis for neurological activity, and that indole chemistry has yielded numerous pharmacologically important molecules. The review emphasises several constraints that temper enthusiasm. Many plant studies use crude extracts and do not isolate or identify the single active principle, producing heterogeneous and sometimes non‑reproducible results. Geographic and ecological variation alters secondary metabolite content, complicating generalisation of findings. Chemical instability of certain constituents (for example valepotriates) and the synthetic inaccessibility of some complex natural indole alkaloids are further obstacles. The authors also acknowledge that relatively few clinical trials exist for the botanicals discussed, with most pharmacological data originating from in vivo animal models or in vitro receptor studies. On the basis of these limitations, the authors recommend targeted phytochemical work (isolation and structural characterisation), metabolomics studies to map active metabolite profiles, and rigorous in vitro and in vivo pharmacological testing to define dose–response relationships and mechanisms. They also highlight the value of medicinal chemistry to derive bioisosteres and more drug‑like analogues when natural compounds are unstable or not synthetically tractable. Overall, the investigators present plant indole alkaloids as promising but underexplored leads that require more systematic pharmacological and chemical development before clinical application.
The review concludes that most plant remedies investigated for psychiatric effects remain crude or semi‑purified and that observed in vitro and in vivo results are inconsistent across regions and preparations. Ghosh and colleagues advocate for concerted efforts to isolate active principles, perform phytochemical identification and metabolomics, and carry out thorough in vitro and in vivo evaluations. They note that while synthetic indole alkaloids have already proven useful in medicine, many naturally occurring indole alkaloids remain difficult to synthesise and under‑studied. In sum, the authors regard plant-derived indole alkaloids as a reservoir of valuable starting points for future antidepressant development and encourage further research to realise this potential.
According to the World Health Organization, depression affects an estimated 350 million people worldwide. Patients with depression indicate symptoms of anxiety disorders and accompanied with an inability to experience pleasure and interest, loss of concentration, selfdoubt, social anxiety, sleep and appetite disorder. The main factors that cause depression are chemicals or hormones imbalance in the brain. The main hormone associated with depression is serotonin. Other hormones are norepinephrine and dopamine. These hormones are necessary for normal brain function and to control feelings. The destruction of these hormones may cause chemical imbalance in the brain resulting in depression. Depression can be treated depending on its severity, by psychotherapy or medication. Antidepressants are the main types of medication used to treat depression. There are many different types of antidepressant drugs available, and they differ only in the way they act on the brain, their cost, and their side effects profile. In the first line treatment, most patients are either prescribed a tricyclic antidepressant (TCA) or a selective serotonin reuptake Inhibitor (SSRI;. The drugs that are commonly used for anxiety treatments are benzodiazepines. Although there are many antidepressant drugs in the market used to treat depression, the after effects of using these drugs are of great concern). An alternative therapy of depression is the use of herbal medicines. The use of herbal extracts is gaining wider acceptance among the medical profession and by patients. The majority of herbal remedies utilized for the treatment of depression are crude or semipurified extracts. There is scarcity in reports on research involving the active principle capable of inducing activity on the central nervous system (CNS). A review byincludes information of only on psychoanaleptic, psycholeptic, and psychodysleptic effects. A recent review bydiscussed the structure-activity relationship of the antidepressant effects of flavonoids isolated from natural and synthetic sources. Synthetic indole alkaloids, their activity, and potential use in medicine have already been reviewed in several articles. However, no review paper has been published correlating plant indole alkaloids isolated with antidepressant activity. This review provides information on the potential of natural indole alkaloids for the treatment of neurological disorder, structure-activity relationship studies, and extent these to other bioactive metabolites as potential antidepressant drug leads from the perspective of chemical structure. It is compiled through bibliographic investigation of scientific journals and relevant literature identified through Web of Science electronic databases.
This review article deals with plants possessing activity on the CNS. Although many types of plants fall into this category, we will highlight only plants which exhibit antidepressant properties. Two plants that contain indole alkaloids are Passiflora incarnata L. (passion flower) and Mitragyna speciosa (Korth.) Havil (kratom), while the other two plants that did not show the presence of indole alkaloids are Piper methysticum G. Forst (kava) and Valeriana officinalis L., deserve special attention. Chemical structure of isolated compounds from these plants can be used as the basis for the development of new drugs. Passiflora incarnata and other species such as P. alata Curtis, P. coerulea L. and P. edulis Sims are widely used as sedative in traditional medicine in most European countries and in America. The structure of benzodiazepines drugs consists of a benzene ring fused to a diazepine system comprising a seven-membered heterocyclic moiety with two nitrogen atoms in positions 1 and 2 of the ring. Indole alkaloids isolated from P. incarnata namely harman, harmol, harmine, harmalol and harmaline consist of a benzene ring fused to a five membered heterocycle containing one nitrogen atom. Several studies have indicated that P. incarnata has a pharmacological profile similar to benzodiazepines and acts through gamma-aminobutyric acid (GABA) receptors. The leaves of M. speciosa have been used as a traditional medicine to treat diarrhea, diabetes and to improve blood circulation. Mitragynine is the major indole alkaloid present in M. speciosa with its analogs, speciogynine, paynantheine and speciociliatine. Two studies conducted on aqueous extract and alkaloidal extract of M. speciosa induced antidepressant-like effect on mouse models of behavioral despair. A study conducted byon mitragynine shows the effect of antidepressants in animal behavioral model of depression through the interaction with the hypothalamicpituitary-adrenal (HPA) axis in the neuroendocrine system. Piper methysticum G. Forst is consumed as a drink called kava which induces a pleasant mental state toward feeling cheerful while reducing fatigue and anxiety. The study shows that most of the pharmacological activities are retained from the lipid-soluble extract compared to aqueous extract. The lipid-soluble extract contains at least seven pyrones, known as kavalactone. Kavalactones generally interacts with the dopaminergic, serotonin, gamma aminobutyric acid (GABA), glutamatergic neurotransmissions, prevents monoamine oxidase B (MOB) and also provide a variety of effects on ion channels. Dihydromethysticin is one of the six major kavalactones found in the kava plant. The structure of dihydromethysticin comprises an arylethylene-α-pyrone bound to an indole-like moiety comprising two oxygens instead of nitrogens. It contributes toward anxiolytic activity and act as antidepressant drugs. Double-blind placebo-controlled studies demonstrated that kavalactones effect anxiolytic activities without depressing mental and motor functions and improves the quality of sleep. Kavalactones is an alternative to replace the usage of benzodiazepines in depression therapy. Valeriana officinalis L., also known as valerian is widely used by many countries as a sedative, anticonvulsant, for hypnotic effects, and anxiolytic activity. Valerenic acid and valepotriates have been reported as active ingredients in pharmaceutical preparations and valerian commercial crude extracts have recorded use in many countries. Valepotriates which comprise triesters of polyhydroxycyclopenta-(c)-pyrans with the carboxylic acids: acetic, valeric, isovaleric, α-isovaleroxy-isovaleric, β-methylvaleric, β-acetoxy-isovaleric, β-hydroxyisovaleric and β-acetoxy-β-methylvaleric acid, are used as sedatives. Valepotriates are unstable, thermolabile and decompose rapidly under acidic or alkaline conditions in water, as well as in alcoholic solutions. Valepotriates are useful in improving animal and human conditions during benzodiazepine withdrawals. Although there are a variety of different chemical constituents, the mechanism of action is reported as interaction of valerian with the GABA system in the brain through inhibition of GABA transaminase, the interaction with the GABA receptor/benzodiazepine and interference in uptake and intake recruitment of GABA in synaptosomes. Various models have been utilized to investigate antidepressant effects of plants. Pharmacodynamic models include in vitro, in vivo and clinical models were utilized to assess the effects (Table). A majority of the selected plants species reviewed were studied at in vivo level, a few study in vitro and only kava had undergone clinical trials. In all of the cases, more research needs to be carried out to establish the active compounds, most effective dose and to determine whether this varies between different types of depressions.
Indole alkaloids have a bicyclic structure, consisting of a sixmembered benzene ring fused to a five-membered nitrogencontaining pyrrole ring. This pyrrole ring with nitrogen atom gives rise to the basic properties of indole alkaloids that make them particularly pharmacologically active (El-Sayed and Verpoorte, 2007). Indole alkaloids are widely distributed in plants belonging to the families Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae. Important indole alkaloids which have been isolated from plants include the antihypertensive drug, reserpine from Rauvolfia serpentinaand the powerful antitumor drugs, vinblastine and vincristine from Catharanthus roseus (El-Sayed and Verpoorte, 2007). Studies on the effectiveness of indole alkaloids in treating depression is not new and has been conducted since 1952, but currently very little attention has been given by the scientific community to the benefits of the therapeutic usefulness of plants endowed with antidepressant properties. Indole alkaloids are often associated with the function of G-protein receptors, in particular for neuronal signal transmission through receptors for serotonin (5-HT/hydroxytryptamine). Apart from the hydrogen donor via free N-H, the presence of π-electrons density contributes to the highest occupied molecular orbital (HOMO) energy of the planar indole skeleton. This allows interaction with nucleobases, in particular protonated atom as well as target proteins. The chemical structure of the neurotransmitter serotonin is based on electron-rich aromatic indole ring. The presence of nitrogen atom in indole ring is to maintain the aromatic system and makes binding N-H acidic rather than nitrogen basic. The indole ring is able to form hydrogen bonds through the N-H moiety and π-π stacking or cation-π interactions, via the aromatic moiety. Hydrophobicity of indole rings is almost the same as the phenyl subunit and less hydrophobic than the classic isosteric benzothiophene and benzofuran ring. The N-H indole group play a decisive role in the interaction with target bioreceptor while synthesized benzothiophene and benzofuran derivatives show moderate to limited affinity for the target bioreceptor. Reserpine is one of the examples of indole alkaloids isolated during the last 60 years which show sedative action on the CNS. Incidentally, two chemicals, viz., tryptamine and serotonin found in the brain are also indole alkaloid derivatives. At present the active constituents from plant extracts responsible for the antidepressant effect is still unclear. Thus we try to identify a few important chemical structures isolated from plant extracts exhibiting antidepressant activities and ascertain the skeleton pattern similarity that might contribute to antidepressant activity. Early attempts have been made to identify structural similarities between serotonin and indole alkaloids. The most distinct similarity consists of six membered heterocyclic rings fused to five membered rings. The difference is the presence of a nitrogen atom or distribution of π electrons (Figure). Through a structure activity relationship studyreported that the variation in activity of different types of molecules suggest that the receptor is very sensitive to the nature of the tryptamine. Other chemical compounds that are successfully isolated from antidepressant plants are mentioned in this review paper because they are maybe specific agonists with particular substitution patterns that able to selectively activate a subset of effectors. This phenomenon is now known as functional selectivity. Serotonin, is widely used in brain function and cognition as endogenous receptor agonist. Serotonin exerts its functions through seven families of receptors (5-HT1-5-HT7) which are members of the G-protein coupled receptor family. A number of compounds bearing the indole moiety have been described to own affinity toward different serotonin receptors. The structural similarity of indole alkaloids (exogenous agonists) to endogenous neurotransmitters like serotonin has led investigators to predict the potential neurological activity of these molecules. Schematic of processes associated with neurotransmission of exogenous agonists is described in Figure. The indole ring is also known as bioisosteres and has similar chemical and physical as biological molecules. This similarity is used in the development of the prototype drug that aims to improve pharmacological activity and optimize the pharmacokinetic profile. In another study of pharmacological assessment of benzofurans and thienopyrrole led to bioisosteric molecules that possess dimethyltryptaminelike activity. Early work with benzo[b]thiophenes and 3indenalkylamines demonstrated that for compounds lacking ring substituents, the ability to act as agonists in the rat fundus was about the same as tryptamines. The results revealed the indole NH was not essential to activate the 5-HT2 receptor in the rat fundus. A series of 2-aryl indole NK1 receptor antagonists and their derivatives are good ligands but have low oral bioavailability in rats. In order to increase solubility and absorption, the basic nitrogen was introduced, leading to the analog azaindole and related compounds exhibiting the same NK1 binding affinity with the series of 2-aryl indole NK1 receptor antagonists. Molecular docking of 2 phenyl-indole derived ligands with serotonin 5-HT6 and melanocortin-4 receptors indicate that the privileged scaffold may accommodate depending on the nature conserved subpocket and non-conserved binding pocket. Interactions of non-conserved parts of the binding pocket are responsible for important differences in the molecular recognition by the corresponding target receptor. According to de Sa et al. () common indole alkaloids found in natural sources are tryptophan amino acids in human nutrition and the discovery of plant hormones that have therapeutic effects such as anti-inflammatory, a phosphodiesterase inhibitor, 5-HT receptor agonists and antagonists, cannabinoid receptor agonists and HMG-CoA reductase inhibitors. Indole scaffold has binding pockets and possesses common complementary binding domain to the target receptor, which belongs in a class of GPCRs (G-protein important membrane receptors coupled). Most drugs on the market contain the indole substructure. These include indomethacin, ergotamine, frovatriptan, ondansetron, and tadalafil.
This review found a majority of the plant-based remedies indicated for the treatment of psychiatric ailments were crude or semipurified. The results for in vivo and in vitro varies and were not reproducible because in different biogeographical regions the secondary metabolite content of the plants correlates with availability of nutrients, climate and ecological conditions. In addition the bioactivity of plants might be contributed by a single compound or mixture of compounds. The authors suggest the effort to obtain active principles, phytochemicals identification, and metabolomics study should be conducted with inspections in vitro and in vivo for a better characterization of plant-based drugs. In most cases, the synthesis of indole alkaloids were inspired by the naturally occurring molecules and their similarity to serotonin. The indole alkaloids from plant sources are quite complex compared to synthetic. The importance of synthetic indole alkaloids is already established as the structure is available in various ligand receptors, enzyme inhibitors and modulators bioreceptor. Some of the naturally occuring indole alkaloids cannot be synthesized by currently know methods. In addition, most of the information on the effectiveness of indole alkaloids was reported from synthetic indole alkaloids. As a result the potential of many naturally occuring indole alkaloids as new drug leads for various psychiatric disorders is still untapped. Historically, plant-based compounds have been the source of several of the most successful drug leads or drugs used in medicine. This is indicative that more could lay in store to be discovered. In conclusion, several indole alkaloids have been employed as antidepressants or provide lead structures for its development. Based on our findings, plants contain a reservoir of indole alkaloids which are valuable starting points for the development of future antidepressants.
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