Faculty of Pharmaceutical Sciences, Motherhood University, Roorkee, Haridwar, India 247661
A customary Indian concoction produced from the foliage of Cannabis sativa, bhang has been traditionally employed in Ayurveda for its mind-altering and medicinal benefits. Contemporary scientific discoveries have affirmed numerous ancestral uses by uncovering that the plant-based cannabinoids in bhang—chiefly delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—act as strong influencers of the body’s endocannabinoid regulatory network. These compounds exhibit a broad spectrum of pharmacological actions by interacting with multiple molecular targets, including CB1 and CB2 receptors, TRP channels, serotonin (5-HT1A) receptors, GABA-A receptors, and PPAR-? nuclear receptors. This polypharmacology underlies their potential for treating complex disorders such as chronic pain, systemic inflammation, anxiety, and depression. Moreover, the “entourage effect”—a synergistic interaction among cannabinoids, terpenes, and flavonoids—further enhances the therapeutic efficacy and safety of whole-plant formulations like bhang. This review integrates traditional Ayurvedic insights with modern pharmacological evidence, emphasizing the multi-target mechanisms of cannabinoids and their implications in integrative medicine. It also discusses current challenges, including regulatory barriers, variability in formulation, and the need for clinical standardization. By exploring both the molecular and clinical landscape, this paper advocates for the repositioning of bhang-based therapies within evidence-based healthcare systems.
Bhang, a traditional Indian preparation derived primarily from the leaves of Cannabis sativa, has long been embedded in the cultural, spiritual, and medicinal practices of India, particularly within the Ayurvedic system of medicine. Historically, bhang has been revered not only for its psychoactive effects but also for its therapeutic applications, where it was classified as a medhya rasayana (nootropic agent) and vrishya (aphrodisiac), signifying its use in enhancing cognitive functions, memory, and reproductive health [1]. In various classical texts and folk traditions, bhang has been employed for the management of pain, anxiety, insomnia, digestive disturbances, and inflammatory disorders. Modern science has gradually shifted attention from the whole plant preparation towards isolating and studying specific phytochemicals—chiefly phytocannabinoids—that mediate these traditional effects. Phytocannabinoids, unique to Cannabis sativa, interact with the body’s endocannabinoid system (ECS), a sophisticated neuromodulatory network composed of G-protein coupled cannabinoid receptors (CB1, predominantly in the central neural system, and CB2, largely in peripheral immune tissues), endogenous lipid-based ligands (such as anandamide & 2-arachidonoylglycerol), and enzymes that regulate their synthesis & deprivation (e.g., FAAH and MAGL) [2]. The ECS plays a central role in maintaining homeostasis across various physiological domains, including nociception, mood regulation, appetite, immune function, neuroprotection, and stress responses.
Figure1. Cannabis Sativa Tree and Seeds
Phyto cannabinoids from bhang, especially Δ?-tetrahydrocannabinol (THC) and cannabidiol (CBD), demonstrate a remarkable polypharmacology profile. THC, the primary psychoactive constituent, primarily produces its effects by partially activating CB1 receptors, resulting in characteristic alterations in mood, perception, and cognition [3]. However, it also exhibits anti-inflammatory and pain-relieving properties via modulation of both CB1 and CB2 receptors, and through secondary interactions with other molecular targets [4]. CBD, on the other hand, is non-intoxicating and acts through various mechanisms, including negative allosteric modulation of CB1 receptors, inhibition of FAAH (resulting in elevated anandamide levels), activation of 5-HT1A serotonin receptors, and agonism at transient receptor potential (TRP) channels, such as TRPV1 (5). Furthermore, CBD and other minor cannabinoids like cannabigerol (CBG) and cannabichromene (CBC) have been shown to engage nuclear receptors like PPAR-γ, which modulate inflammatory and oxidative stress pathways implicated in neurodegenerative and metabolic diseases (6).
The polypharmacology nature of cannabinoids allows them to modulate multiple interconnected signaling cascades simultaneously, making them particularly suitable for addressing complex, multifactorial disorders, including nerve-related pain, brain inflammation, seizures, mood disturbances, and depressive illnesses, where single-target therapies often fall short (7). Importantly, the entourage effect—where cannabinoids, terpenoids, and flavonoids in the plant matrix act synergistically—further enhances the therapeutic potential of whole-plant formulations like bhang, compared to isolated compounds alone (8). This synergism may contribute to better efficacy and a broader therapeutic window. Modern analytical studies of bhang have confirmed the presence of not just major cannabinoids like THC & CBD, but also numerous minor cannabinoids, terpenes (such as myrcene, limonene, and β-caryophyllene), and flavonoids (including cannflavin A), all of which contribute to its pharmacological complexity (9).
Therefore, integrating traditional Ayurvedic knowledge with contemporary pharmacological insights highlights the relevance of bhang and its phytoconstituents in modern integrative medicine. As the understanding of cannabinoid pharmacodynamics expands, it reinforces the therapeutic promise of bhang-derived compounds, not only as symptom-targeted interventions but as holistic, multi-target agents for the management of pain, inflammation, mood disorders, and beyond(10).
Major Cannabinoids Identified in Bhang:
|
Compound |
Abbreviation |
Pharmacological Actions |
Molecular Targets |
|
Δ?-Tetrahydrocannabinol |
THC |
Psychoactive, analgesic, anti-inflammatory |
CB1, CB2, TRPV1, GPR55 |
|
Cannabidiol |
CBD |
Non-psychoactive, anxiolytic, neuroprotective, anti-epileptic |
5-HT1A, TRPV1, GABA-A, PPARγ |
|
Cannabigerol |
CBG |
Antidepressant, antibacterial, anti-inflammatory |
α2-adrenoceptor, 5-HT1A, TRPV1 |
|
Cannabinol |
CBN |
Sedative, anticonvulsant |
CB2, TRPV2 |
|
Cannabichromene |
CBC |
Anti-inflammatory, neurogenic |
TRPA1, TRPV1 |
Key cannabinoids present in bhang consist of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC), each contributing distinct pharmacological actions through diverse molecular targets. THC, the principal psychoactive constituent, is recognized for its analgesic, anti-inflammatory, and neurobehavioral effects, mediated predominantly via partial agonism at cannabinoid receptors CB1 and CB2, along with interactions at transient receptor potential vanilloid 1 (TRPV1) channels and G protein-coupled receptor 55 (GPR55) (11). In contrast, CBD is non-psychoactive and exhibits anxiolytic, neuroprotective, anti-epileptic, and anti-inflammatory effects through multiple mechanisms, including agonism at serotonin 5-HT1A receptors, modulation of TRPV1, positive allosteric modulation of GABA-A receptors, and activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) (12). CBG, often referred to as the precursor or "mother cannabinoid," demonstrates antidepressant, antibacterial, and anti-inflammatory activities, with its actions linked to modulation of α2-adrenoceptors, 5-HT1A receptors, and TRPV1 channels (13). CBN, a mildly psychoactive degradation product of THC, possesses sedative and anticonvulsant properties, primarily through CB2 and TRPV2 receptor engagement (14). Meanwhile, CBC has been reported to promote neurogenesis and exert anti-inflammatory effects, largely via TRPA1 and TRPV1 channel activation (15). The phytocannabinoid composition of bhang is influenced by multiple factors, including the plant part utilized (e.g., leaves versus flowers), environmental growing conditions, and extraction methodologies. Leaf-based bhang preparations, which are traditional in Indian practices, generally contain lower THC concentrations compared to resinous or flower-based cannabis products, making them potentially more suitable for therapeutic applications where minimal psychoactivity is desired (16). An important pharmacological concept associated with these compounds is the “entourage effect”—a spectacle where cannabinoids, terpenoids, and flavonoids act synergistically to produce enhanced therapeutic effects and mitigate adverse events (17). This synergy supports the rationale for using whole-plant or broad-spectrum extracts rather than isolated cannabinoids, as they may provide superior efficacy and tolerability in clinical contexts (18).
Molecular Targets and Mechanisms of Action
Cannabinoids exert their pharmacological effects through a complex interplay of receptors, enzymes, and signaling pathways, reflecting their polypharmacological nature.
Endocannabinoid System (ECS)
The internal cannabimimetic network, often referred to as the ECS, is an ancient biochemical communication system vital for maintaining bodily stability across multiple physiological domains. This system comprises specialized docking proteins—referred to here as RC1 and RC2—that interact with naturally formed fatty-based bio-signals such as neuroester-X and glycinolipid-Y. Enzymes like lipid-cleaving hydrolase (LCH) and mono-fat degrader enzyme (MFDE) are responsible for producing and dismantling these messengers. RC1 receptors are dominantly found in regions associated with cognition and coordination, such as the frontal neural hub, memory center, motor loop nucleus, and balance lobe (20). These receptors mediate the psychotropic influence of major plant-derived compounds and contribute to sensory filtering, emotion regulation, voluntary movement, recollection, and appetite stimulation. In contrast, RC2 receptors are prevalent within defensive cell clusters and peripheral body systems, where they oversee immune signaling, cellular movement, and inflammation moderation. This positions them as pivotal targets for immune-calming and anti-inflammatory actions of botanical agents (21).
In addition to engaging with the primary cannabinoid receptors RC1 and RC2, cannabis-derived compounds also influence a variety of alternative cellular binding sites, enhancing their broad therapeutic potential. Among these are thermo-sensitive ion channels like TPX1 and TPX2, which play key roles in detecting pain and thermal stimuli. They also act on mood-related neurotransmitter systems, such as the serotonin-linked SR1A receptor, which is associated with anti-anxiety and mood-lifting actions. Furthermore, these compounds interact with gene-regulating proteins like metabolic response controller delta (MRCD), a nuclear factor involved in controlling inflammation and oxidative stress which modulate inflammation and oxidative stress; and GABA-A receptors, where cannabidiol (CBD) acts as a positive allosteric modulator, enhancing inhibitory neurotransmission (22). The simultaneous engagement of these diverse molecular targets underpins the polypharmacology of cannabinoids. It supports their use in managing complex, multifactorial conditions such as chronic pain, neurodegenerative diseases, anxiety, and mood disorders. Furthermore, the combined action of cannabinoids with terpenoids and flavonoids in whole-plant preparations, often referred to as the “entourage effect,” enhances their efficacy and safety profile compared to isolated compounds (23).
Non-Cannabinoid Receptors and Targets
In addition to acting on classical cannabinoid receptors, cannabinoids and related phytochemicals exert significant effects through several non-cannabinoid receptors and molecular targets, contributing to their broad therapeutic profile. One such target is the thermosensitive vanilloid-type channel 1 (TPV1), an ion-permeable gateway that lacks strict selectivity for specific cations implicated in nociception, thermoregulation, and neurogenic inflammation. Activation or modulation of TRPV1 by cannabinoids such as cannabidiol (CBD) and cannabigerol (CBG) helps mediate analgesic and anti-inflammatory effects (24). The 5-HT1A serotonin receptor, another key site of cannabinoid action, is involved in the regulation of anxiety, stress responses, and mood. CBD, in particular, acts as an agonist at this receptor, supporting its anxiolytic and antidepressant properties (25). The GABA-A receptor, which governs inhibitory neurotransmission in the central nervous system, is positively modulated by CBD, enhancing GABAergic tone and contributing to its calming and anti-seizure effects (26). Another important molecular target is Metabolic regulator gamma (MRG), a genomic-level receptor, governs the transcription of genes involved in immune response, redox balance, and fat processing. Stimulation of MRG by cannabinoids such as CBD and certain terpenes underpins their neuroprotective, anti-inflammatory, and metabolic effects (27). The widespread distribution of these targets across various tissues and organ systems explains the multi-system pharmacology of cannabinoids, which enables their potential use in managing complex disorders that simultaneously involve pain, mood dysregulation, and chronic inflammation.
Table 1 Pharmacological Targets of Cannabinoids in CNS and Inflammation
|
Target / Receptor |
Role in Physiology / Pathology |
Cannabinoid Action |
Therapeutic Significance |
|
TRPV1 (Transient Receptor Potential Vanilloid 1) |
Mediates nociception, neurogenic inflammation, thermoregulation |
Activation / modulation by CBD, CBG |
Analgesia, anti-inflammatory, neuroprotective effects |
|
5-HT1A (Serotonin Receptor Subtype 1A) |
Regulates mood, anxiety, and stress responses |
Agonism by CBD |
Anxiolytic, antidepressant properties |
|
GABA-A (Gamma-Aminobutyric Acid Type A) |
Controls inhibitory neurotransmission in CNS |
Positive allosteric modulation by CBD |
Anxiolytic, sedative, anticonvulsant actions |
|
Gamma-type lipid-responsive transcription factor (PPAR-γ) |
Regulates inflammation, oxidative stress, lipid metabolism |
Activation by CBD, certain terpenes |
Anti-inflammatory, neuroprotective, metabolic regulatory roles |
Cannabinoids in Pain Management
Cannabinoid-based compounds are gaining recognition as effective alternatives for addressing persistent pain disorders, especially in scenarios where standard painkillers like anti-inflammatory medications and narcotic agents prove insufficient or cause adverse effects, demonstrate limited efficacy, or unacceptable side effects. In neuropathic pain, activation of CB1 receptors reduces nociceptive transmission at both spinal and supraspinal levels, modulating pain perception centrally (28). In inflammatory pain, CB2 receptor engagement modulates immune cell activity, suppresses cytokine release, and attenuates peripheral inflammation (29). Additionally, cannabinoids such as CBD and CBG contribute to TRPV1 desensitization, reducing pain sensitivity through modulation of this key nociceptive ion channel (30). Both preclinical and clinical studies indicate that cannabinoids may offer pain relief comparable to that of opioids but with a superior safety profile, marked by a lower risk of dependence, tolerance development, and respiratory depression (31).
Anti-Inflammatory Effects
Cannabinoid compounds produce anti-inflammatory outcomes by influencing various stages of the inflammatory process. They block the stimulation of NF-κB, which results in decreased expression of inflammation-related proteins like COX-2 and iNOS (32). Moreover, these compounds reduce the synthesis of pro-inflammatory cytokines—including TNF-α, IL-1β, and IL-6—thus mitigating the overall inflammatory response in various disease models (33). Furthermore, activation of PPAR-γ by cannabinoids results in transcriptional repression of inflammatory genes, offering a nuclear-level mechanism for anti-inflammatory activity. These actions collectively contribute to the therapeutic potential of cannabinoids in inflammatory conditions such as arthritis, inflammatory bowel disease (IBD), and neuroinflammation.
Modulation of Mood and Anxiety
The anxiolytic and antidepressant effects of cannabinoids are mediated through diverse receptor systems and signaling pathways. CBD’s agonism at 5-HT1A receptors resembles the action of selective serotonin reuptake inhibitors (SSRIs), providing a mechanistic basis for its anxiolytic and antidepressant potential (34). The enhancement of GABAergic tone through modulation of GABA-A receptors further promotes relaxation and stress resilience (35). In addition, CB1 receptor activation contributes to hippocampal neurogenesis, a process implicated in mood regulation and cognitive function recovery in depression (36). Cannabinoids help regulate the neuroendocrine stress system, known as the hypothalamic-pituitary-adrenal (HPA) axis, by lowering its overactivation in stress-related scenarios—a critical contributor to the development of anxiety and mood disturbances. These actions underline their therapeutic promise in addressing mental health conditions like post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and clinical depression (MDD).
Synergistic Mechanisms and the Entourage Effect
A distinctive feature of cannabis-based therapies is the entourage effect, whereby the therapeutic impact of cannabinoids is enhanced through their synergistic interaction with other plant constituents, including terpenes and flavonoids. Terpenes such as myrcene and limonene have been shown to modulate blood-brain barrier permeability and receptor binding affinity, potentially augmenting cannabinoid bioavailability and efficacy (37). Flavonoids in bhang, including cannflavins, provide additional antioxidant and anti-inflammatory effects that complement the actions of cannabinoids. This synergism not only broadens the therapeutic window but also helps mitigate adverse effects, thereby favoring the use of whole-plant extracts like traditional bhang over isolated cannabinoid formulations in integrative medicine.
Figure 3. Cannabinoid Therapeutic Effects: Mechanisms in Pain, Inflammation, Mood, and Synergy
Challenges and Future Directions
Although cannabinoids and whole-plant preparations such as bhang hold considerable therapeutic promise, their widespread clinical integration faces significant challenges. One of the primary obstacles is the legal and regulatory complexity surrounding cannabis and cannabinoid-based medicines, which varies widely across different countries and often impedes research, development, and clinical application (38). In addition, there is a lack of dose standardization and product consistency, as natural cannabis preparations can vary considerably in their cannabinoid, terpene, and flavonoid content depending on cultivation conditions, plant part used, and extraction method. This variability complicates efforts to ensure reproducible therapeutic outcomes and safety profiles (39). The psychoactivity of THC also poses a barrier, limiting its acceptance for broader medical use, particularly in vulnerable populations where cognitive or psychomotor impairment is undesirable. Furthermore, while preclinical and early-phase clinical studies support the analgesic, anti-inflammatory, and anxiolytic potential of cannabinoids, there remains an urgent need for large-scale, randomized Rigorous clinical studies are essential to confirm the therapeutic effectiveness and safety of cannabinoids in well-defined conditions like nerve-related pain, widespread anxiety disorders, and severe depressive illnesses(40).
Looking ahead, future research and development in cannabinoid therapeutics will likely focus on several strategic directions. The development of non-psychoactive formulations, including those rich in cannabidiol (CBD) or minor cannabinoids with negligible intoxicating effects, aims to maximize therapeutic benefits while minimizing adverse central effects. Advances in artificial intelligence (AI) and in silico modeling offer opportunities to predict cannabinoid-receptor interactions, optimize compound design, and identify novel polypharmacological profiles. Such approaches may accelerate drug discovery and reduce reliance on animal models. Additionally, cannabinoids are increasingly being considered for inclusion within integrative medicine frameworks, where they can complement existing pharmacotherapies and lifestyle interventions to provide holistic management of complex, multifactorial disorders. These future directions highlight the potential for cannabinoids, including traditional preparations like bhang, to evolve into evidence-based tools within modern healthcare systems.
CONCLUSION
Cannabinoids derived from bhang exemplify the potential of multi-target agents in addressing complex and multifactorial conditions such as chronic pain, systemic inflammation, and mood disorders. By interacting with a wide array of molecular targets—including cannabinoid receptors, TRP channels, serotonin receptors, GABA-A receptors, and nuclear receptors such as PPAR-γ—these compounds offer a robust scientific rationale that supports and enriches the traditional Ayurvedic uses of bhang. Their polypharmacological profile not only enhances therapeutic efficacy but also provides opportunities for integrative approaches in modern medicine. However, realizing the full clinical potential of cannabinoids will require sustained research efforts focusing on the development of standardized, non-psychoactive formulations, elucidation of deeper mechanistic pathways, and rigorous clinical validation through well-designed randomized controlled trials. Such efforts will be critical to translating the rich heritage of bhang into safe, effective, and globally accepted therapeutics for contemporary healthcare challenges.
REFERENCES
Harsh Agarwal, Sakshi Khanka, Sanjay Kumar Verma, Cannabinoids as Multi-Target Agents: Exploring Bhang in Pain, Inflammation, and Mood Disorders, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 7, 2609-2619. https://doi.org/10.5281/zenodo.16096779
10.5281/zenodo.16096779
