Literature search strategy

This review provides a comprehensive narrative synthesis of the current evidence on cannabinoid therapeutics. We performed a comprehensive search of PubMed, Scopus, and Google Scholar, updated through June 2025, to identify relevant peer-reviewed articles. To maximize coverage, the search was supplemented by hand-searching the reference lists of selected articles and relevant reviews (Table 1). The search strategy was informed by MeSH and relevant keywords derived from the study aim, including “Cannabis sativa,” “cannabinoids,” “tetrahydrocannabinol,” “cannabidiol,” “endocannabinoid system,” “clinical trials,” “regulatory frameworks,” “formulations,” and “health systems integration,” which were adapted for each database. Boolean operators (AND/OR) and truncations were used to refine the search results.

Inclusion and exclusion criteria

We included peer-reviewed studies published in English, with no date limits, but placed greater emphasis on recent studies to ensure currency, while seminal and historically important publications were included where necessary to provide foundational context. Eligible articles addressed at least one of the following: molecular mechanisms, preclinical findings, clinical applications, safety, formulations and delivery systems, regulatory frameworks, or equity and health system integration related to cannabinoids. We excluded non-English publications and conference abstracts lacking sufficient data, and duplicate records.

Study selection

Titles and abstracts were screened for relevance, followed by a full-text assessment. Only studies directly relevant to the scope of this review were included. The reference lists of key articles were screened to identify additional eligible publications (Table 1).

Data extraction and thematic analysis

From each eligible study, we extracted bibliographic details and key methodological and outcome information and organized the evidence into predefined domains aligned with the review objectives. A narrative, thematic synthesis grouped findings under: (1) phytochemistry and molecular mechanisms, including the ECS, therapeutic mechanisms, and advances in epigenetics/molecular targeting; (2) preclinical evidence; (3) clinical applications in neurological and psychiatric disorders, pain and inflammation, oncology and palliative care, gastrointestinal/dermatological and other emerging uses, and special populations; (4) formulations, delivery systems, and bioavailability; (5) safety, toxicology, and risk management; (6) regulatory landscape and policy challenges; (7) integration into health systems and equity considerations; and (8) future directions. Heterogeneity in study designs and outcomes precluded meta-analysis; therefore, the results were narratively summarized within and across themes.

Narrative synthesis

The findings from the included literature were synthesized into an integrated narrative rather than a quantitative meta-analysis. The thematic structure enabled the integration of molecular, clinical, regulatory, and equity perspectives, providing a holistic overview of cannabinoid therapeutics in the 21st century.

Phytochemistry and molecular mechanism

Cannabinoids derived from Cannabis sativa possess a wide range of pharmacological properties that extend well beyond their psychoactive effects. These activities are primarily mediated by major phytocannabinoids, including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabigerol (CBG), which interact not only with the ECS but also with multiple molecular targets involved in neurological, immunological, and metabolic regulation [17]. To date, more than 120 phytocannabinoids have been identified in Cannabis sativa, with THC, CBD, and CBG emerging as the most extensively studied compounds due to their significant therapeutic potential across a variety of clinical conditions [18]. Advances in molecular pharmacology, epigenetics, and proteomics have repositioned cannabinoids as multifaceted therapeutic agents with potential roles in neuroprotection, pain management, inflammation, and immunomodulation [19]. Cannabis sativa produces more than 120 phytocannabinoids, most of which are synthesized as acidic precursors, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabigerolic acid (CBGA). Under conditions of heating or prolonged storage and exposure to environmental factors, these acidic cannabinoids gradually undergo decarboxylation to yield the pharmacologically active neutral forms THC, CBD, and CBG [10, 20]. CBGA is particularly important as the universal biochemical precursor of THCA, CBDA, and cannabichromene acid (CBCA), and is therefore commonly referred to as the “mother cannabinoid” [21]. Upon decarboxylation, CBGA gives rise to the neutral cannabinoid CBG; however, the enzymatic synthesis of THCA, CBDA, and CBCA occurs from CBGA rather than CBG [22].

Each cannabinoid exhibits distinct pharmacodynamic properties. THC acts as a partial agonist of the CB1 and CB2 receptors, modulating cyclic adenosine monophosphate (cAMP) signaling and neurotransmitter release. While CB1 activation is primarily responsible for its psychotropic effects, CB2 activation underpins its immunomodulatory actions, positioning THC as a dual agent in neurological and peripheral disorders [23]. In contrast, CBD is non-intoxicating and interacts with multiple receptor systems, including G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid type 1 (TRPV1), PPAR-γ, and serotonin receptors, conferring broad therapeutic potential in conditions such as epilepsy, anxiety, and inflammation [24].

CBG demonstrates partial agonism at CB2 receptors, low affinity to CB1, and additional effects through receptor heteromers, with emerging evidence supporting its neuroprotective and gastrointestinal benefits [25]. Recent studies have indicated that cannabinoids influence epigenetic regulation, ion channel dynamics, and mitochondrial function, revealing mechanisms that surpass traditional receptor-ligand interactions. These findings suggest that cannabinoids may exert long-term effects on cellular resilience and metabolic reprogramming, thereby offering new opportunities for precision therapeutics in diseases where classical receptor pharmacology provides only a partial explanation of the clinical effects [26–28]. Beyond the major cannabinoids, minor compounds such as tetrahydrocannabivarin (THCV), cannabichromene (CBC), and cannabinol (CBN) have received increasing attention. Together with terpenes and other phytochemicals, these constituents may contribute to the so-called “entourage effect”, whereby interactions among multiple compounds enhance or modulate therapeutic efficacy [29, 30]. However, despite compelling preclinical findings, the entourage hypothesis remains controversial. While some experimental studies support synergistic interactions [31], evidence from controlled pharmacological and clinical studies has been inconsistent. Recent reviews have highlighted the limited direct clinical evidence supporting the concept and have questioned whether the observed effects reflect true pharmacological synergy or merely additive actions of individual constituents [32, 33]. Notably, rigorous dose-response and receptor-based studies have failed to demonstrate consistent supra-additive synergy in most pain and inflammation models, with current evidence generally favoring additive or modulatory interactions rather than genuine synergy [34, 35]. Distinguishing true pharmacological synergy from additive effects will require further mechanistic and translational investigations.

ECS and therapeutic mechanisms

Building upon the fundamental components of the ECS described above, cannabinoid therapeutics exert their effects through a complex network of receptor-dependent and receptor-independent pathways. In addition to classical CBRs, cannabinoids interact with transient receptor potential channels, GPR55, and nuclear receptors, underscoring the broad physiological influence of endocannabinoid signaling [30, 36, 37]. Collectively, these pathways integrate central, immune, and metabolic processes and contribute to the maintenance of physiological homeostasis. Collectively, the ECS integrates central, immune, and metabolic pathways to maintain homeostasis, making it an attractive therapeutic target for various diseases (Figure 1).

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Figure 1. Comprehensive overview of the endocannabinoid system. Created in BioRender. Ahmed, M. M. (2026) https://BioRender.com/ivtjxje.

Cannabinoids exert therapeutic effects through multilayered molecular mechanisms

Neuroprotection: Both THC and CBD have been shown to reduce oxidative stress, mitochondrial dysfunction, and excitotoxicity in preclinical models, thereby conferring neuroprotective effects relevant to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases [38, 39]. However, robust human evidence demonstrating disease-modifying effects in these conditions remains lacking.

Anti-inflammatory actions: CB2 activation suppresses pro-inflammatory cytokine release, whereas CBD modulates nuclear factor kappa B (NF-κB) and inflammasome pathways [40].

Analgesia: CB1 activation reduces neurotransmitter release in nociceptive circuits, whereas TRPV1 and GPR55 contribute to peripheral pain modulation [29].

Immunomodulation: Cannabinoids influence immune tolerance and immune cell activity, including T-cell responses and macrophage function, with implications for autoimmune disorders and cancer immunology [41]. In addition to these primary pathways, cannabinoids interact with dopaminergic, serotonergic, and glutamatergic systems, contributing to their effects on mood, cognition, and reward. For instance, CBD’s partial agonism at serotonin 5-HT1A receptors underlies its anxiolytic properties [42], whereas THC’s interaction with dopaminergic circuits provides insight into both its therapeutic potential and its association with psychosis in susceptible individuals [43].

Advances in epigenetics and molecular targeting

Cannabinoids exert profound epigenetic influences, extending their role beyond receptor binding to the regulation of gene expression (Figure 2). Experimental evidence indicates that cannabinoids modulate DNA methylation, histone acetylation, and non-coding RNA expression, thereby reshaping cellular function. For example, THC exposure alters gene networks involved in synaptic plasticity and psychiatric vulnerability [44], whereas CBD demonstrates potential as an epigenetic modulator, influencing chromatin remodeling and the transcription of anti-inflammatory genes. These findings suggest that cannabinoids not only relieve symptoms but also modify the molecular landscape that drives the disease processes [45]. Beyond epigenetics, proteomic studies have uncovered extensive cannabinoid-induced modulation of neuronal and immune proteins, offering insights into its neuroprotective and immunoregulatory effects [46]. Proteomic mapping highlights altered pathways in oxidative stress, mitochondrial function, and cytokine signalling, which may explain the efficacy of cannabinoids in disorders such as neurodegeneration, chronic pain, and autoimmune diseases. The integration of multi-omics approaches, including transcriptomics, metabolomics, and single-cell sequencing, further refines our understanding of how cannabinoids orchestrate cross-level molecular changes. This systems-level perspective is pivotal for advancing precision medicine strategies, in which cannabinoid formulations can be tailored to an individual’s genetic, epigenetic, and proteomic profile [47, 48].

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Figure 2. Cannabinoids: molecular mechanisms and therapeutic potential. Created in BioRender. Ahmed, M. M. (2026) https://BioRender.com/zzn5n6e.

At the molecular signalling level, cannabinoids modulate key intracellular pathways, such as NF-κB, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and cAMP response element-binding protein (CREB), thereby influencing apoptosis, inflammation, and neuroplasticity. CBD’s regulation of the NF-κB axis, for example, underscores its potential to mitigate chronic inflammatory states, whereas THC’s modulation of CREB-dependent transcription may help explain its dual effects on cognition and mood. Cross-talk with dopaminergic, serotonergic, and glutamatergic systems further broadens their therapeutic scope, linking molecular signalling to behavioural outcomes relevant to psychiatric and neurological conditions [49]. Despite these advances, there are significant challenges. Standardizing cannabinoid formulations, clarifying dose-response relationships, and ensuring safety across diverse populations are essential prerequisites for clinical adoption. Emerging tools, such as CRISPR-based epigenome editing, high-resolution metabolomics, and AI-driven omics integration, hold promise for resolving these uncertainties and advancing precision cannabinoid therapeutics [31, 50].

Preclinical evidence

Preclinical research has been instrumental in clarifying the pharmacological effects of cannabis, providing mechanistic insights, validating molecular targets, and generating proof-of-concept data for its therapeutic applications. Much of this progress has come from in vitro experiments and animal models, which have elucidated the role of the ECS, comprising CBRs, endogenous ligands, and metabolic enzymes, as a central regulator of pain, inflammation, neurodegeneration, mood, and immune responses [14, 23]. Despite these promising findings, translating these results into clinical practice remains challenging because of interspecies differences, disease complexity, and model heterogeneity, which limit their direct applicability to humans. In oncology research, preclinical studies have shown that THC, CBD, and CBG possess anticancer properties, including the induction of apoptosis, inhibition of angiogenesis, and suppression of metastasis in glioma, breast cancer, and colorectal cancer models [51]. In psychiatric research, CB1 activation has been associated with fear extinction and reduced anxiety-like behaviours in mouse models of post-traumatic stress disorder (PTSD), providing compelling support for cannabinoids as potential adjunctive therapies for trauma-related conditions [52].

Preclinical cannabinoid research has also provided valuable mechanistic insights and identified novel therapeutic targets for conditions such as pain, neurodegeneration, epilepsy, cancer, and psychiatric disorders. However, major translational challenges persist, including significant interspecies differences in ECS distribution, which limit the direct applicability of animal findings to humans [53]. Many animal studies use supratherapeutic dosing, raising concerns about the relevance of the observed effects in clinical settings. Additionally, the limited validity of disease models, reproducibility issues, and frequent discrepancies between preclinical and clinical outcomes further hinder the translation to effective human therapies [54]. To address these limitations, there is an urgent need for improved translational frameworks, such as multi-omics profiling, human-derived organoid models, and refined animal systems that better mimic human diseases. Expanding research beyond THC and CBD to include minor cannabinoids, such as THCV, CBN, and CBC compounds, with emerging roles in appetite regulation, sleep modulation, and anti-inflammatory activity, may also enhance therapeutic discovery and clinical relevance [55].

Clinical applications and evidence

Neurological and psychiatric disorders

Cannabinoid-based interventions have shown varied clinical efficacy across neurological disorders, with the most substantial evidence in treatment-resistant epilepsy, particularly in syndromes such as Dravet and Lennox-Gastaut syndromes [56]. Randomized controlled trials of CBD have demonstrated significant seizure reduction and improved quality of life in different populations [57–59]. Evidence remains limited or inconclusive for Parkinson’s disease, Huntington’s disease, autism spectrum disorders (ASD), and Tourette syndrome (Figure 3). Small trials and open-label studies suggest possible improvements in tremor, rigidity, or behavioural symptoms; however, methodological limitations prevent firm conclusions [57, 58]. Cannabinoids have been approved in Canada and Europe (e.g., Sativex^®) for symptom relief in multiple sclerosis, especially spasticity and neuropathic pain. However, trials have produced mixed results, with modest efficacy and varying tolerability [57, 60, 61]. Human trials for Alzheimer’s disease are lacking. Preclinical studies suggest that cannabinoids may reduce tau hyperphosphorylation and beta-amyloid accumulation, offering a neuroprotective role, although clinical, and mitigate oxidative stress, thereby preserving neuronal integrity and synaptic function [62]. In animal models of Alzheimer’s disease, cannabinoid treatment has also been associated with improvements in learning, memory, and behavioural outcomes, supporting the hypothesis that modulation of the ECS may influence disease progression [63]. However, these encouraging findings have yet to be validated in adequately powered clinical trials, and further translational research is required before cannabinoids can be incorporated into evidence-based management strategies for Alzheimer’s disease.

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Figure 3. Cannabinoid efficacy ranges from established evidence to inconclusive evidence applications. Created in BioRender. Ahmed, M. M. (2026) https://BioRender.com/c1h8fi2.

CBD’s analgesic effect in neurological conditions, such as migraine and neuropathic pain, is presumed to result from the modulation of serotonin and dopamine pathways. However, the trials remain small and often lack placebo control, with current evidence categorized as preliminary [64].

Although several studies have linked positive psychiatric treatment outcomes to the use of cannabinoids, a systematic review including over 80 studies, including randomized controlled trials, concluded that evidence proving that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, PTSD, or psychosis remains scarce or low [65]. These findings are consistent with those of a more clinically focused systematic review [66]. The main challenges for broader clinical use include legal and regulatory barriers, concerns about long-term safety (especially in children), and the psychoactive effects of certain cannabinoids, such as THC [67]. Consequently, epilepsy remains the only neurological or psychiatric condition for which cannabinoids have achieved regulatory approval and have been incorporated into clinical guidelines [68]. Further high-quality clinical trials are needed to determine the efficacy and safety of cannabis-based therapeutics in other neurological and psychiatric disorders [67].

Formulations, delivery systems, and bioavailability

The clinical success of cannabinoid therapeutics in the 21st century depends not only on understanding the molecular mechanisms but also on designing formulations and delivery systems that maximize bioavailability, safety, and patient adherence. Owing to their high lipophilicity, poor water solubility, and extensive first-pass metabolism, cannabinoids such as THC and CBD present challenges in achieving consistent dosing. Recent developments in oral, sublingual, inhaled, transdermal, and nanotechnology-based delivery strategies offer novel pathways to overcome these obstacles [103]. Oral administration remains the most common route because of its convenience; however, cannabinoids exhibit low and variable bioavailability because of intestinal degradation and extensive first-pass metabolism [104]. In the fasted state, oral CBD bioavailability is approximately 6–20%, although high-fat meals may increase systemic exposure by two- to four-fold [105]. Sublingual administration, as in tinctures and sprays, provides more rapid absorption and avoids significant hepatic metabolism, although inter-individual variability persists. Inhaled delivery (via smoking or vaporization) achieves the fastest onset (within minutes) and relatively high bioavailability (10–35%), making it suitable for acute symptom management, such as breakthrough pain or nausea [106]. Despite these pharmacokinetic advantages, respiratory safety remains an important consideration. The outbreak of e-cigarette or vaping-associated lung injury (EVALI) highlighted the risks associated with unregulated vaping products, particularly THC-containing formulations adulterated with vitamin E acetate and other contaminants [107]. These events underscore the importance of stringent manufacturing standards, quality control, and post-marketing surveillance to ensure the safety of inhaled cannabinoid products. Transdermal patches and gels provide controlled and sustained cannabinoid release while bypassing gastrointestinal metabolism. This route offers the advantages of steady plasma levels, improved adherence, and reduced psychoactive peaks [108]. However, the lipophilic nature of cannabinoids poses challenges for skin permeation, often necessitating enhancers or lipid-based formulations [109].

Nanotechnology-based systems, including nanoemulsions, liposomes, solid lipid nanoparticles, and polymeric nanocarriers, have emerged as promising strategies for enhancing cannabinoid solubility, stability, and targeted delivery [103]. For example, nanoemulsified CBD beverages show improved absorption compared to oil-based formulations. Lipid-based carriers, such as self-emulsifying drug delivery systems and micelles, enhance gastrointestinal uptake by promoting lymphatic transport, thereby bypassing first-pass metabolism [110]. These technologies hold promise for developing consistent oral formulations suitable for regulatory approval. Despite technological advances, patient adherence remains influenced by palatability, onset of action, dosing convenience, and psychoactive side effects of the drug. For instance, oral oils may have an undesirable taste or delayed effects, while inhaled forms carry a social stigma. The variability in cannabis plant chemotypes further complicates standardization, making regulatory harmonization essential for safe prescribing practices [111]. Importantly, cost and accessibility also shape adherence, as advanced nanoformulations may remain unavailable in low-resource settings. Next-generation delivery systems must integrate precision medicine principles by tailoring formulations to individual patient needs, metabolic profiles, and disease states [112]. Emerging bioinspired technologies, including dissolving microneedle platforms [113], provide additional opportunities for sustained drug release and improved tissue penetration. Recently, biomimetic “tree thorn-inspired” hyaluronic acid-based microneedles have demonstrated effective tissue delivery and prolonged therapeutic activity [114], highlighting the broader potential of advanced transdermal systems that could be adapted for cannabinoid therapeutics.

Safety, toxicology, and risk management

Recent regulatory changes and increasing cannabis potency have renewed concerns regarding its safety profile, particularly regarding the adverse effects of THC. High-THC formulations, whether through acute or chronic exposure, are associated with impaired cognition, reduced academic and occupational performance, and an elevated risk of accidents [115]. Psychiatric risks, including psychosis, schizophrenia, mood and anxiety disorders, and suicidality, have also been associated with cannabis exposure [116]. THC primarily acts through CB1 and CB2 receptors, influencing neurotransmission, pain regulation, and cardiovascular, gastrointestinal, and hepatic functions [67]. Both THC and CBD undergo hepatic metabolism via cytochrome P450 enzymes, particularly CYP3A4 and CYP2C9, making them prone to significant drug–drug interactions. For example, the co-administration of CYP3A4 inhibitors, such as ketoconazole or macrolide antibiotics, can nearly double plasma cannabinoid concentrations, amplifying psychoactive effects and increasing the risk of hepatotoxicity and sedation [117].

Cannabinoids are contraindicated in patients with severe psychiatric, cardiovascular, renal, or hepatic disorders because of the heightened risk of toxicity. Furthermore, pharmacodynamic interactions with CNS depressants and sympathomimetics may cause additive or synergistic adverse effects [118]. Chronic THC exposure induces tolerance and withdrawal symptoms, such as irritability, insomnia, and appetite loss, lasting 2 to 6 days [119], and long-term use is strongly associated with cannabis use disorder, cognitive impairment, and psychiatric comorbidities [120]. While THC is the principal psychoactive constituent driving dependence risk, CBD is non-intoxicating and may attenuate some of THC’s psychotropic effects, although the evidence remains inconclusive. Both compounds can cause dizziness and fatigue, with THC exerting stronger effects on cognition and psychomotor performance than CBD. For medical purposes, oral formulations are preferred to avoid the harmful by-products of combustion [121]. In addition, interindividual variability driven by genetic polymorphisms in cytochrome P450 enzymes appears to significantly influence susceptibility to adverse effects, highlighting the need for personalized approaches to cannabinoid risk management [122].

Regulatory landscape and policy challenges

The global regulatory framework for cannabinoid therapeutics remains fragmented, complex, and rapidly evolving. Countries such as the United States, Canada, Germany, and Australia have established structured medical cannabis programs, whereas many regions in Africa and parts of Europe continue to operate under restrictive or evolving policies [123–125]. Historically, cannabis was classified as a Schedule I substance under the United States Controlled Substances Act because of its perceived high abuse potential and lack of accepted medical use [126]. This designation created substantial barriers to research, including restricted access to study-grade cannabis, complex Drug Enforcement Administration (DEA) registration procedures, and stringent Food and Drug Administration (FDA) Investigational New Drug (IND) requirements [127]. However, significant regulatory changes have occurred in recent years. In 2026, federal authorities reclassified FDA-approved marijuana-containing products and marijuana regulated under state medical programs to Schedule III, representing an important milestone in reducing research barriers and facilitating access to cannabinoid-based therapies [128]. Furthermore, legislative reforms, including the Cannabidiol and Marijuana Research Expansion Act, have sought to expand scientific investigation, although considerable variability and regulatory inconsistencies persist across states [129].

The European Medicines Agency (EMA) and member states of the European Union (EU) have adopted diverse regulatory approaches. Germany has implemented one of the most comprehensive frameworks, incorporating both medical and recreational cannabis through pharmacies, social clubs, and telemedicine services [130]. In contrast, France has adopted a more cautious approach, with access to medical cannabis maintained through a tightly regulated national programme during its transition toward a permanent regulatory framework [131]. Canada and Australia maintain comprehensive national medical cannabis programs, with Canada also legalizing recreational cannabis use [132, 133]. Recent post-legalization experiences further highlight the evolving nature of cannabinoid regulation and the importance of continuous policy evaluation. In Canada, population-based studies have reported increasing numbers of cannabis-related emergency department visits, hospitalizations, and cannabis use disorder presentations in the years following legalization, reinforcing the need for sustained public health surveillance and ongoing monitoring of health outcomes as regulatory frameworks continue to evolve [134]. Similarly, Germany’s 2024 Cannabis Act, which removed medical cannabis from narcotics legislation and expanded access through prescription-based pathways, represents a major regulatory shift aimed at improving patient access and facilitating research. However, these experiences also emphasize the importance of maintaining robust regulatory oversight, quality assurance, and evidence-based prescribing practices. Collectively, these developments demonstrate that expanded access to cannabinoid-based therapies must be accompanied by effective governance frameworks and continuous assessment of long-term public health outcomes [135]. In Africa, policy development remains relatively nascent. South Africa permits limited medical cannabis use, whereas several other countries focus predominantly on export-oriented cultivation, thereby creating challenges for domestic access, healthcare integration, and research collaboration [124, 136].

Clinical research continues to face substantial obstacles. Cannabis contains more than 100 cannabinoids and numerous terpenes, complicating product standardization, dose optimization, and quality assurance. Designing placebo-controlled trials is particularly challenging because many products are already commercially available through dispensaries and medical programs [137]. Until recently, U.S. researchers were limited to a single DEA-approved cannabis source, restricting the diversity of formulations available for investigation, although subsequent DEA reforms have sought to broaden supply channels [138]. Quality control and Good Manufacturing Practice (GMP) compliance present additional challenges. Implementation of GMP standards requires considerable investment in infrastructure, personnel training, and Standard Operating Procedures, while inconsistent regulatory enforcement across jurisdictions contributes to variability in product safety, composition, and efficacy [139]. Without rigorous oversight, patients may be exposed to contaminants, inaccurate labelling, or inconsistent cannabinoid concentrations [140, 141].

Ethical and legal complexities further complicate the clinical deployment of cannabinoid therapeutics. Many physicians lack formal education and training in cannabinoid pharmacology and therapeutics, contributing to reluctance in recommending or prescribing these products despite increasing patient demand [142]. Although recent regulatory reforms have expanded access, evolving federal and state frameworks continue to create legal ambiguities regarding prescribing practices, dispensing, reimbursement, and physician liability. Additional concerns include paediatric use, psychiatric risks, long-term safety, and obtaining informed consent among vulnerable populations [143]. Finally, stigma associated with historical criminalization and racialized drug policies continues to influence public perception, policy development, and equitable access to cannabinoid-based therapies [144]. Greater international harmonization of regulatory standards, enhanced physician education, and robust pharmacovigilance systems will be essential to support the safe and evidence-based integration of cannabinoid therapeutics into mainstream clinical practice [145].

An emerging challenge involves the rapid proliferation of semi-synthetic and hemp-derived cannabinoids, including Δ8-THC, hexahydrocannabinol (HHC), and related analogues. These compounds have gained popularity because of perceived legal loopholes and widespread online availability, yet their pharmacological profiles, safety, and long-term health effects remain incompletely characterized [146]. The inconsistent regulation of these products across jurisdictions has created additional challenges for quality control, consumer safety, and public health surveillance, highlighting the need for harmonized regulatory frameworks and more rigorous toxicological evaluation [147].

Integration into health systems and equity considerations

The integration of cannabinoid therapeutics into health systems presents both opportunities and challenges, requiring a balance between scientific evidence, regulatory oversight, and social equity in their use. Safe and effective incorporation depends on robust policy frameworks, standardized formulations, and rigorous quality control. However, regulatory fragmentation, limited physician training, and uneven legal acceptance hinder its consistent implementation [148]. Equity must be embedded holistically throughout the process of developing and applying clinical guidelines, starting at the priority-setting stage and involving individuals with lived health inequities. An early definition of disadvantaged populations is essential for evidence appraisal, subgroup analyses, and implementation strategies. Structured equity approaches remain valuable for efficient, evidence-based, and transparent development [149, 150]. However, limitations in the evidence base, such as poor reporting of sociodemographic factors, scarce subgroup analyses, and epidemiological gaps, highlight the knowledge gaps that must be addressed to ensure equitable access. Ensuring affordability, cultural acceptability, harm reduction, patient education, and surveillance of benefits and risks are key to maximizing the therapeutic value of cannabinoids while minimizing unintended harms and promoting fair distribution of benefits across all populations [137].

Future directions

The future of cannabinoid therapeutics lies at the intersection of advanced technology, precision medicine, and robust public health frameworks (Figure 4). AI and real-world evidence (RWE) platforms are transforming drug discovery and evaluation by identifying therapeutic targets, optimizing formulations, and simulating patient responses, thereby enabling more precise and personalized treatment strategies [151, 152]. AI-driven tools can accelerate data extraction from the expansion of cannabis literature, guide the design of targeted strains, and enhance adherence through digital cannabis platforms [153]. Complementing this, RWE studies using electronic health records and registries provide critical insights into safety and effectiveness beyond the controlled settings of clinical trials, addressing gaps in generalizability and informing regulatory decision-making [154, 155]. Future research should also incorporate pharmacoeconomic evaluations and health technology assessments to determine the cost-effectiveness of cannabinoid-based medicines relative to standard therapies. Although favourable economic outcomes have been reported for selected indications, such as refractory epilepsy and multiple sclerosis-related spasticity, the available evidence remains limited and heterogeneous [156, 157]. Robust real-world studies will therefore be essential to inform reimbursement decisions and support equitable implementation across diverse healthcare systems [158]. Precision cannabinoid medicine, encompassing individualized dosing and pharmacogenomics, will play a pivotal role in addressing variability in patient responses. Genetic polymorphisms within the ECS and drug-metabolizing enzymes influence pharmacodynamics and pharmacokinetics, offering opportunities to tailor therapies to optimize efficacy and minimize adverse effects [159, 160]. Integrating genetic data with patient history, environmental exposures, and lifestyle factors can advance individualized dosing regimens, particularly for complex conditions such as cancer-related pain [161]. Multi-omics approaches, including genomics, proteomics, metabolomics, and lipidomics, promise to uncover biomarkers and therapeutic targets by elucidating cannabinoid interactions at the system level [162]. Such integration may refine cancer therapies by clarifying the mechanisms of apoptosis, angiogenesis, and metastasis inhibition [163], while also advancing the understanding of neuroprotective effects in neurodegenerative diseases [67]. Conferences and collaborative initiatives, such as the Cannabis Clinical Outcomes Research Conference, are vital for disseminating these findings and fostering interdisciplinary engagement [154].

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Figure 4. Future directions for the clinical integration of cannabinoid therapeutics. Created in BioRender. Ahmed, M. M. (2026) https://BioRender.com/mj1zvbs.

Finally, public health surveillance and safety monitoring are central to ensuring the responsible integration of cannabinoid therapeutics. Despite the increasing use of medical cannabis, knowledge gaps persist regarding optimal formulations, dosages, and long-term safety [164]. Adverse effects, including cognitive impairment, fatigue, and drug interactions, underscore the importance of standardized post-marketing surveillance [121, 165]. Real-world registries have emerged as valuable tools for addressing these gaps by capturing longitudinal data on treatment effectiveness, adverse events, quality of life, and patient-reported outcomes. For example, the UK Medical Cannabis Registry has provided important RWE across a range of clinical indications, demonstrating improvements in health-related quality of life while facilitating ongoing assessment of safety and tolerability [166]. As regulatory frameworks evolve, particularly following cannabis rescheduling, surveillance systems must be harmonized internationally to safeguard patients and support therapeutic innovation [167]. Together, these future directions of AI integration, precision dosing, multi-omics discovery, and robust safety monitoring offer a roadmap for advancing cannabinoid therapeutics into safe, effective, and equitable medical practice [163].