Cannabidiol (CBD) and tetrahydrocannabinol (THC): Mechanisms, therapeutic benefits and clinical impact on cancer, mental health and inflammation

Cannabidiol (CBD) and tetrahydrocannabinol (THC) are the two main cannabinoids present in Cannabis sativa. Both compounds interact with the endocannabinoid system (ECS), a network of receptors and chemical signals throughout the body, but produce different pharmacological effects. While THC is psychoactive and has a strong affinity for CB1 receptors, CBD has no psychoactive effects and instead uniquely modulates ECS activity

Context

The potential benefits of cannabis-derived compounds have gained considerable attention in recent years. Around 2900 BC, the ancient Chinese began using an extract from the Cannabis sativa plant, often referred to as cannabis or marijuana, for medicinal purposes. The ancient Chinese used hemp in several ways to treat conditions such as gout, malaria, joint pain and muscle spasms .(2).

Earlier in the 19th century, Western medicine began researching the potential medical benefits of cannabis. Many years of legality problems hindered cannabis research and use due to its psychotropic properties. In the 1960s and 1970s, interest in the recreational use of cannabis grew despite restrictive laws, and scientists were able to identify the psychotropic and medicinal components of cannabis. Access to medical cannabis or cannabinoid-based drugs has expanded thanks to global policies and advances in research .(3)

In India, references to marijuana date back to ancient times. The Atharvaveda (c. 1500-1000 BCE) mentions „bhanga” as one of five sacred plants that relieve anxiety, although there is a debate as to whether the term refers specifically to cannabis or not. The Sushruta Samhita (around 600 BCE) recommends „bhanga” for treating ailments such as phlegm and diarrhea.(4) . During the colonial period, the British government conducted extensive research, culminating in the 1894 report of the Indian Hemp Drugs Commission, which recognized the widespread use of hemp and concluded that moderate consumption was not harmful .(5)

In Africa, cannabis was introduced more than a thousand years ago, probably through trade routes from Asia. In the 19th century, its cultivation and use were introduced in various regions. In South Africa, indigenous communities use cannabis for medicinal and recreational purposes. Use of the plant was so widespread that in 1922. South Africa became one of the first countries to criminalize cannabis, influenced by racial and social factors .(6)

In 2018. Canada formally legalized cannabis for both medical and recreational use, and in early 2021. Mexico did the same. In 2018. The United States passed the U.S. Agriculture Improvement Act of 2018, the U.S. Drug Enforcement Administration no longer classifies cannabis and cannabis-derived products as restricted drugs. In the United States, hemp is classified as marijuana that contains less than 0.3% delta-9-THC. In the United States, as of August 2021, non-medical use of cannabis is permitted in 18 states, and medical use of cannabis is permitted in 37 states and the District of Columbia (DC). CBD and THC have been extensively studied for their roles in pain management, neuroprotection and immune modulation (7).

Australia's approach to cannabis has undergone significant changes. While cannabis has historically been used for recreational and ceremonial purposes, restrictive laws were introduced in the second half of the 20th century due to concerns about health effects. However, there has been a shift toward permissiveness, leading to the legalization of medicinal marijuana in 2016. Beyond that, debates continue over its safety, regulatory oversight and the balance between THC and CBD in prescriptions(8) . The historical background of cannabis is complex and multifaceted, reflecting various cultural, medical and legal activities in different regions and eras.

Mechanism of action

CBD and THC share the same molecular structure, but interact differently with the ECS. The endocannabinoid system (ECS) includes two receptors CB1 and CB2, endogenous ligands (anandamide and 2-AG), and metabolic enzymes(9) . The main difference lies in the psychoactive properties of THC, which can induce euphoria and cognitive changes, while CBD has anti-inflammatory and anti-anxiety effects without intoxication(1) . THC exerts its effects mainly by binding to CB1 receptors, which are highly expressed in the central nervous system. These receptors are found in the hippocampus, frontal cortex, basal ganglia of the brain, hypothalamus, cerebellum and spinal cord. Activation of CB1 receptors inhibits adenylate cyclase, reducing cyclic adenosine monophosphate (cAMP) levels and modulating neurotransmitter release. This causes changes in dopamine, GABA and glutamate signaling, contributing to the psychoactive properties of THC, including euphoria, altered cognitive function and analgesia (9).

Additionally, THC interacts with CB2 receptors in immune cells, exerting anti-inflammatory effects by reducing cytokine production and modulating immune responses. CB2 is found mostly in immune cells, hematopoietic cells and glial cells. CB2 is expressed mainly in the periphery under normal, healthy conditions; under conditions of disease or injury, this regulation occurs in the brain, so CB2 is expressed in the brain under unhealthy conditions. CB1 and CB2 are also widely expressed in the cardiovascular system .(10)

Unlike THC, CBD does not bind strongly to CB1 or CB2 receptors. Instead, it indirectly modulates ECS activity by inhibiting fatty acid amide hydrolase (FAAH), leading to increased levels of anandamide, an endogenous cannabinoid with analgesic and anti-inflammatory properties(11) . CBD also acts as a negative allosteric modulator of CB1, reducing the psychoactive effects of THC by changing the receptor's conformation. In addition to ECS, CBD interacts with other receptor systems, including CBD exhibiting anti-anxiety and antidepressant effects by increasing serotonin transmission through serotonin (5-HT1A) receptors. Involvement in pain perception and inflammation through the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. Regulation of metabolic and neuroinflammatory processes via peroxisome proliferator-activated receptors (PPARs). Regulation of blood pressure, bone density and anti-tumor properties through GPR55 (9).

In summary, while THC and CBD interact with components of the endocannabinoid system, their different affinities and actions at different receptor sites result in different physiological and psychological effects.

Pharmacokinetics of THC and CBD

The metabolism of cannabis depends on the route of ingestion. After oral ingestion, THC travels to the liver, where most of it is metabolized. THC is metabolized to other molecules by CYP2C and CYP3A in the liver. These enzymes convert THC into 11-OH-THC, which is also psychoactive, and then into 11-COOH-THC, which is not psychoactive. More than 65% of marijuana is excreted in the feces, and up to 20% in the urine. The majority of marijuana (80% to 90%) is excreted within 5 days as hydroxylated and carboxylated metabolites. Among the major metabolites, the THC metabolite 11-COOH-THC is the major glucuronide conjugate in urine, while the THC metabolite 11-OH-THC is the predominant form in feces. The remaining THC and both of its metabolites reach the heart and then enter the circulation. THC and 11-OH-THC enter the brain simultaneously (12).

CBD is another chemical of cannabis. CBD enters the body similarly to THC. The pharmacokinetics of CBD are complicated, and the bioavailability of orally administered CBD is low in different species. In general, the most abundant metabolites of CBD are hydroxylated 7-COOH derivatives, which are excreted intact or as glucuronide conjugates. CBD can both inhibit and enhance the activation of target binding sites. Among other things, CBD blocks the activation of the equivalent nucleoside transporter (GPR55) and the TRP subfamily of cation channels (TRPM8, glycine receptors), and increases the activity of serotonin receptor 1A, glycine receptors α1 and α3, and TRPA1.(13).

Absorption of CBD and THC

The absorption of CBD and THC varies widely depending on the route of administration. Oral administration, such as food products or capsules, results in a delayed onset of action due to first-pass metabolism in the liver, leading to bioavailability of about 6-15% for THC and 10-20% for CBD. Inhalation via smoking or vaporization allows cannabinoids to quickly enter the bloodstream through the lungs, reaching maximum plasma concentrations within minutes and bioavailability in the 10-35% range. Topical applications, including creams and transdermal patches, bypass first-pass metabolism but have limited systemic absorption, making them more suitable for topical effects (12).

Elimination of CBD and THC

THC's elimination half-life varies depending on the frequency of use. THC has a half-life of one to two days for infrequent users, but because it accumulates in fatty tissues, chronic users can have extended elimination periods of many weeks. With low renal clearance, CBD is excreted mainly in feces, and has a half-life of 18 to 32 hours after oral ingestion. Long-term retention of cannabis in adipose tissue has implications for pharmacodynamic effects and drug testing (9), (12).

Dosage of CBD and THC

The approximate dose of CBD (cannabidiol) and THC (tetrahydrocannabinol) varies depending on individual factors such as body weight, metabolism, tolerance, method of administration and ailment being treated. Since there is no universal dosage range, scientists and medical professionals suggest gradually increasing the dose to determine the most effective amount while minimizing side effects .(11)

CBD dosage

CBD is well tolerated, and studies suggest doses can range from as little as 10 mg per day for general well-being to several hundred milligrams per day for chronic illness. For stress and anxiety, clinical studies indicate that 300 to 600 mg of CBD per day can provide relief. In contrast, treating pain and inflammation often requires doses of 20 to 200 mg per day, depending on severity. Studies have shown that CBD doses of 25 to 160 mg per day can be beneficial for sleep disorders. For epilepsy, where CBD is used in an FDA-approved drug (Epidiolex), doses typically start at 2.5 mg per kg of body weight and can be increased as needed (15).

THC dosage

THC is psychoactive, and its dosage requires careful titration to balance therapeutic effects with side effects such as sedation, dizziness or increased heart rate. For pain management, THC doses typically range from 2.5 mg to 30 mg per day, with lower doses (2.5-5 mg) preferred for new users (16) . Moreover, cancer patients undergoing chemotherapy have reported relief from nausea and vomiting with doses of 5 to 15 mg of THC daily. Similarly, a dose of 5 to 10 mg of THC before bed is commonly used for sleep disorders. Conditions such as post-traumatic stress disorder (PTSD) and anxiety may require lower doses (1-5 mg THC per day) to avoid exacerbating symptoms, but pain and spasticity associated with multiple sclerosis often require higher doses in the range of 2.5 to 25 mg per day (15)(17).

 

Endocannabinoid deficiency syndrome

According to the theory of Clinical Endocannabinoid Deficiency Syndrome (CEDS), a dysregulated endocannabinoid system can be the cause of many ailments, including fibromyalgia, migraines and irritable bowel syndrome (IBS). The endocannabinoid system (ECS) has a significant impact on the body's homeostasis, pain sensation, immune response and neurological processes. Chronic diseases, which are typically difficult to treat with traditional therapies, can be exacerbated by deficiencies in endocannabinoid signaling(18) . Studies have further shown that people with fibromyalgia exhibit reduced amounts of anandamide, a major endogenous cannabinoid, which may contribute to increased pain sensitivity. Similarly, altered amounts of endocannabinoids in the cerebrospinal fluid have been reported in migraine patients, supporting the concept that ECS disorders play a role in the etiology of migraine (19) . IBS, a disorder characterized by visceral pain and bowel dysfunction, has been linked to endocannabinoid abnormalities, and clinical evidence suggests that cannabinoid-based therapies can improve symptom control (19) . CBD and THC have been explored as potential treatments for CEDS-related disorders. CBD's ability to stimulate endocannabinoid signaling by inhibiting FAAH (fatty acid amide hydrolase), the enzyme that degrades anandamide, may help restore ECS balance and reduce symptoms in affected individuals. THC, through its direct agonist activity at CB1 receptors, has shown efficacy in relieving chronic pain and muscle spasms in patients with fibromyalgia and multiple sclerosis (20) . Moreover, studies have shown that cannabinoid-based therapies can reduce migraine frequency and intensity, supporting the idea that ECS modulation plays a role in headache disorders (18) . Further research is needed to better understand the mechanisms underlying endocannabinoid deficiency and to develop targeted cannabinoid therapies for affected individuals. Large-scale clinical trials are important to determine optimal dosing regimens and assess long-term safety in patients with CEDS-related diseases

CBD and THC in cancer therapy

Cannabinoids elucidate potential in cancer treatment by modulating various steps involved in tumor progression, apoptosis and immune response. THC, through activation of CB1 and CB2 receptors, has been shown to induce apoptosis in cancer cells by activating the mitochondrial pathway, leading to the release of cytochrome c and activation of caspase enzymes. Moreover, THC inhibits angiogenesis, the formation of new blood vessels that supply tumors with nutrients, by further reducing the expression of vascular endothelial growth factor (VEGF)(21) . On the other hand, CBD exhibits anticancer properties through multiple mechanisms independent of CB1 and CB2 receptor activation. It has been observed to inhibit cancer cell proliferation by modulating PPARγ receptors and inducing the production of reactive oxygen species (ROS), which then leads to oxidative stress and apoptosis in cancer cells(22) . Moreover, CBD interferes with cancer cell invasion and metastasis by inhibiting the expression of matrix metalloproteinases (MMPs), enzymes that disrupt the extracellular matrix and facilitate tumor spread. A key advantage of cannabinoids in cancer therapy is their ability to mitigate side effects caused by chemotherapy. Both THC and CBD have shown efficacy in reducing chemotherapy-induced nausea and vomiting (CINV) by binding to serotonin 5-HT3 receptors in the brainstem, which regulate vomiting responses, thereby reducing vomiting and nausea. Cannabinoids have shown promise in managing cancer-related pain by modulating nociceptive pathways and reducing inflammation (22) . Recent evidence also suggests that cannabinoids may modulate the immune system's response to cancer. CBD has been shown to suppress pro-inflammatory cytokines such as TNF-α and IL-6, potentially reducing cancer-promoting inflammation. The study further indicates that cannabinoids may enhance the effectiveness of conventional cancer treatments, such as chemotherapy and radiation therapy, by increasing the sensitivity of cancer cells to these therapies (23) . On the contrary, these promising discoveries and challenges remain in translating cannabinoid-based therapies into clinical practice. Variations in cannabinoid formulations, dosing regimens and patient responses require further large-scale controlled studies to determine optimal therapeutic strategies. Further concerns regarding the psychoactive effects of THC, potential drug interactions and long-term safety profiles require careful consideration in clinical applications (21) . More studies highlight that CBD enhances the efficacy of chemotherapeutic agents. For example, CBD enhances the cytotoxic effects of temozolomide in glioma models by lowering p21, a key cell cycle regulator. Moreover, cannabinoids have shown promise in reducing tumor progression in breast and prostate cancer models by modulating the PI3K/AKT/mTOR signaling pathway (24) . Studies indicate that THC induces apoptosis in glioma cells through CB1/CB2 activation. Meanwhile, CBD exhibits anti-proliferative properties and inhibits cancer cell invasion through up-regulation of tissue inhibitors of metalloproteinases (TIMP-1). Moreover, CBD and THC have been shown to be effective in treating chemotherapy-induced nausea and chronic cancer pain (25).

CBD and THC in mental health

Cannabinoids have gained considerable attention for their therapeutic effects on various disorders related to mental status, such as anxiety, depression, post-traumatic stress disorder (PTSD) and schizophrenia (26).

Anxiety and depression

Modulation of the serotonin (5-HT1A) receptor is the main way CBD exhibits anti-anxiety and antidepressant effects. According to preclinical studies, CBD increases serotonin signaling in a manner similar to selective serotonin reuptake inhibitors (SSRIs), which are often administered to treat depression and anxiety (26) . Data from the study showed that CBD significantly reduced the symptoms of social anxiety disorder (SAD) in people undergoing a public speaking test. However, a similar study reported that CBD can help regulate emotional processing by modulating limbic and paralimbic brain activity, contributing to its antidepressant effects (27) . Recent studies have also shown a role for CBD in treatment-resistant depression. An advanced clinical trial showed that CBD administration improved symptoms in patients unresponsive to conventional antidepressants. These findings confirm the potential of CBD as an adjunctive therapy, especially in cases where SSRIs alone are not as effective. Studies indicate that chronic THC consumption can lead to cognitive decline, increased risk of psychiatric disorders and cardiovascular complications (28) . THC, on the other hand, has a biphasic effect on anxiety. Lower doses can reduce anxiety, while high doses can induce paranoia and exacerbate anxiety symptoms, due to its strong affinity for binding to CB1 receptors in the amygdala, an area of the brain involved in fear processing. This underscores the need for controlled dosing and careful therapeutic use. Findings have shown that microdoses of THC can improve relaxation and mood without significant cognitive impairment, supporting the controlled use of THC in the treatment of anxiety (29).

Post-traumatic stress disorder (PTSD).

Cannabinoids have been studied as potential treatments for PTSD due to their ability to modulate fear extinction and memory consolidation. Recent studies have shown that CBD increases fear extinction in both animal models and humans, suggesting its potential use in the treatment of PTSD. THC has been shown to reduce nightmares and symptoms of excessive anxiety in patients with PTSD, additionally by interacting with CB1 receptors in the prefrontal cortex. Concerns remain, however, about THC's potential to worsen psychiatric symptoms in vulnerable individuals (28) . A randomized, controlled trial showed that CBD significantly reduced PTSD-related sleep disorders and anxiety in veterans, further confirming its clinical utility (30) . These findings have sparked growing interest in cannabinoid-based interventions to treat PTSD, although additional large-scale studies are needed.

Schizophrenia and psychosis

CBD has shown promise as an antipsychotic agent, potentially offering a safer alternative to traditional antipsychotic drugs. The study found that CBD reduced psychotic symptoms in patients with schizophrenia and improved cognitive function without causing significant side effects. Unlike THC, which has been linked to an increased risk of psychosis in susceptible individuals, CBD appears to counteract the psychotomimetic effects of THC, likely through negative allosteric modulation of CB1 receptors (31) . A recent meta-analysis confirmed these findings, indicating that CBD treatment was associated with a significant reduction in symptom severity in patients with schizophrenia. The study highlighted the neuroprotective properties of CBD, suggesting its advanced role in modulating glutamatergic signaling and oxidative stress pathways (32).

Bipolar affective disorder and mood stabilization

The contribution of cannabinoids to bipolar disorder is still under debate. Some studies point to the possible dangers of THC escalating manic episodes, while others suggest that CBD may have mood-stabilizing properties due to its neuroprotective benefits. The therapeutic effect, during which marijuana can help treat mental disorders without causing harmful side effects, is still under investigation. A recent study examined how CBD affects the ability of patients with bipolar disorder to stabilize mood, and discovered early signs of symptom relief. However, more detailed studies are needed to create consistent dosing recommendations and long-term safety profiles (33).

CBD and THC in sleep disorders

The possible effects of THC and CBD, two chemicals produced from cannabis, on sleep regulation have been investigated. Their associations with serotonin receptors, GABAergic pathways and the endocannabinoid system (ECS) suggest a potential function in sleep regulation, particularly in disorders including sleep apnea, REM sleep behavior disorder (RBD) and insomnia (34) . It has been observed that THC shortens the time needed to fall asleep (sleep onset latency) by rapidly activating CB1 receptors in the central nervous system (CNS), which influence sleep-wake cycles. Some clinical studies suggest that THC increases total sleep time, although long-term use can lead to tolerance and withdrawal-related sleep disturbances. In turn, CBD exhibits a biphasic effect—at low doses it may promote wakefulness, while at higher doses it has a sedative effect. It is believed that CBD improves sleep by reducing anxiety and modulating cortisol levels. (35).

THC inhibits the REM sleep cycle, which is the phase associated with dreams. This effect has been studied in conditions such as post-traumatic stress disorder (PTSD), where nightmares are a common symptom. Some studies indicate that cannabis-based therapies can reduce the intensity of nightmares in PTSD patients. CBD has been studied for its role in REM sleep behavior disorder (RBD), a condition in which individuals physically act out their dreams (36).

Research on Parkinson's disease (PD) patients suggests that CBD may reduce RBD symptoms, possibly by interacting with serotonin 5-HT1A receptors. Various studies indicate that THC may help regulate breathing patterns in sleep apnea by modulating neurotransmission in the brainstem. CBD's effects on sleep apnea remain inconclusive, as some suggest it may increase alertness rather than improve respiratory function during sleep, according to this study (37) . The circadian rhythm, which regulates sleep cycles, is metabolized by melatonin, cortisol and the endocannabinoid system. CBD can then help regulate sleep-wake cycles by reducing cortisol levels at night, leading to better sleep maintenance. Chronic THC use, however, has been associated with disrupted sleep architecture, such as reduced deep sleep (slow-wave sleep) and withdrawal-related sleep disorders, indicating potential long-term risks of (38).

Metabolic and endocrine effects of CBD and THC

Cannabinoids, especially tetrahydrocannabinol (THC) and cannabidiol (CBD), are important for hormonal regulation, energy balance and metabolism. Their association with the endocannabinoid system (ECS), which controls appetite, glucose metabolism and fat storage, raises the possibility of therapeutic applications in diseases such as metabolic syndrome, diabetes and obesity (39).

Role in appetite regulation and energy balance

THC is well known for its ability to increase appetite, which is often referred to as the „munchies.” Activation of the CB1 receptor in the hypothalamus mediates this effect by raising levels of ghrelin, the hunger hormone, and encouraging food consumption. THC-containing medications, such as dronabinol, are used to increase appetite in cancer and HIV/AIDS patients experiencing cachexia due to this mechanism. On the other hand, CBD can suppress appetite. Because it acts as a negative allosteric modulator of CB1 receptors, it can reduce the appetite-stimulating effects of THC. This impacts how obesity is treated. (40).

Effects on glucose metabolism and insulin sensitivity

The effects of CBD on glucose metabolism and insulin control have been studied. Based on preclinical studies, CBD may reduce the risk of type 2 diabetes (T2D), increase insulin sensitivity and reduce inflammation in pancreatic beta cells. CBD improves glucose tolerance and lowers fasting insulin levels in animal models. The beneficial effects of THC on glucose metabolism are more complicated (41) . While some studies indicate that chronic cannabis use is associated with lower fasting insulin levels and a reduced risk of diabetes, other studies suggest that long-term exposure to THC may increase the risk of deregulated metabolism and fat accumulation (42).

Effects on lipid metabolism and fat storage

CBD can promote the conversion of white adipose tissue (WAT) into brown adipose tissue (BAT), a process known as fat browning. Brown fat is more metabolically active and helps burn calories instead of storing them, which may explain CBD's potential role in weight management. On the other hand, THC has been linked to increased fat storage in chronic users, although its effects depend on the dose and frequency of use (43).

Effects on hormonal regulation

CBD and THC interact with the endocrine glands, affecting cortisol, thyroid hormones and reproductive hormones. CBD has been shown to reduce cortisol secretion, which can be beneficial for stress management and metabolic balance. Chronic THC use has been associated with lower testosterone levels in men and disrupted menstrual cycles in women, likely due to activation of the CB1 receptor on the hypothalamic-pituitary-gonadal (HPG) axis (42).

Anti-inflammatory effects of CBD and THC

Inflammation is a key component of many chronic diseases, including autoimmune disorders, neurodegenerative diseases and cancer. Both CBD and THC exhibit anti-inflammatory properties, although through different mechanisms (44).

Anti-inflammatory mechanisms of CBD

CBD is a potent modulator of the immune response and exerts its anti-inflammatory effects through multiple pathways: Inhibition of pro-inflammatory cytokines: CBD reduces the production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). This effect has been demonstrated in models of arthritis, multiple sclerosis and inflammatory bowel disease (IBD) (44) . CBD activates peroxisome proliferator-activated receptor gamma (PPARγ), which plays a role in regulating immune response and inflammation. PPARγ activation has been linked to reduced oxidative stress and inflammation in neurodegenerative disorders such as Alzheimer's disease. The NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway is a key regulator of inflammation. CBD inhibits NF-κB activation, thereby reducing the expression of inflammatory genes. TRPV1 is involved in pain perception and inflammation. CBD's interaction with TRPV1 receptors contributes to its analgesic and anti-inflammatory effects (45).

Anti-inflammatory mechanisms of THC

THC also exhibits anti-inflammatory effects, mainly by interacting with CB2 receptors found on immune cells: THC binds to CB2 receptors, reducing immune cell activation and cytokine production. This mechanism is beneficial in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Macrophages play a key role in inflammatory reactions. THC has been found to inhibit macrophage activity and reduce inflammation in diseases such as Crohn's disease. Oxidative stress contributes to inflammation and tissue damage. THC reduces the production of ROS, thereby protecting cells from inflammatory damage (45).

Clinical applications of CBD and THC in inflammatory diseases

Autoimmune diseases

Autoimmune diseases are characterized by an abnormal immune response against body tissues, leading to chronic inflammation and tissue damage. CBD and THC have demonstrated immunomodulatory effects that may benefit conditions such as rheumatoid arthritis (RA) and multiple sclerosis (MS).

Clinical studies suggest that CBD and THC formulations (e.g., Sativex) can reduce muscle spasticity and pain in multiple sclerosis patients by modulating neuroinflammation. CBD has been shown to reduce joint inflammation and pain in preclinical models of rheumatoid arthritis, potentially offering an alternative to traditional NSAIDs and steroids (46).

Inflammatory bowel disease (IBD).

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are associated with chronic inflammation of the gastrointestinal tract. The role of cannabinoids in treating IBD symptoms has been investigated, although evidence regarding their anti-inflammatory effects remains inconclusive. A study found that cannabis-based therapies led to symptom relief in IBD patients with Crohn's disease and ulcerative colitis, likely due to cannabinoid-mediated modulation of intestinal inflammation (47).

Neuroinflammation and neurodegenerative disorders

Chronic inflammation in the nervous system is a contributing factor to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Cannabinoids have been investigated for their potential neuroprotective and anti-inflammatory properties in these contexts. CBD has shown promise in reducing neuroinflammation, a key factor in Alzheimer's disease pathology. The study showed that CBD reduces beta-amyloid-induced inflammation in neuronal cultures. Emerging evidence suggests that cannabinoids may protect against neuroinflammatory damage in Parkinson's disease by modulating microglia activation (48).

The role of cannabinoids in dermatology

The therapeutic potential of cannabinoids extends beyond pain management to include dermatology. Both CBD and THC have been studied for their role in the treatment of various skin conditions, due to their anti-inflammatory, anti-itch and sebostatic properties (49).

CBD has been shown to modulate sebum production, making it a potential treatment for acne vulgaris. The study showed that CBD inhibited lipid synthesis in human sebocytes and exerted anti-inflammatory effects, suggesting its effectiveness in treating acne. Moreover, the anti-inflammatory properties of cannabinoids have been studied in the context of atopic dermatitis. A randomized, controlled trial involving the use of a topical cannabinoid emulsion containing N-palmitoyl ethanolamine (PEA) and anandamide (AEA) in patients with atopic dermatitis showed a significant reduction in flaky, dry and itchy skin (49) . Similarly, in a cohort study evaluating the effects of topical adelmidrol (a PEA derivative) in patients with atopic dermatitis, complete resolution of symptoms was observed in 80% participants (50).

In the treatment of pruritus, cannabinoids have also shown promise. An open-label study evaluating the efficacy of a topical cannabinoid cream containing AEA and PEA in patients with uremic pruritus reported a significant reduction in the intensity of pruritus (51) . In addition, a cohort study examining the effect of topical PEA in patients with chronic pruritus observed a significant reduction in visual analog scale pruritus scores after a two-week treatment period. The potential of cannabinoids in the treatment of psoriasis has also been investigated (51) . The case report details the resolution of psoriatic lesions following the use of THC-containing soap and hair oil, with maintenance therapy to prevent recurrence. What's more, a retrospective cohort study evaluating the use of topical CBD ointment in psoriasis patients observed a reduction in plaques and improved Psoriasis Area and Severity Index (PASI) scores at three months (52) . Together, these studies underscore the potential of cannabinoids, applied topically, in the treatment of various dermatological conditions. Moreover, further large-scale randomized controlled trials are warranted to establish standardized treatment protocols and fully elucidate the therapeutic efficacy and safety profiles of cannabinoids in dermatology.

The role of THC and CBD in the treatment of pain

Cannabidiol (CBD) and tetrahydrocannabinol (THC), the main cannabinoids derived from the Cannabis sativa plant, have been extensively studied for their analgesic properties. Their effectiveness in treating pain is attributed to their interaction with the endocannabinoid system, which plays a key role in modulating pain perception. THC exerts its analgesic effects primarily through activation of CB1 receptors in the central nervous system, inhibiting the release of neurotransmitters and subsequently suppressing pain. This mechanism is particularly beneficial in treating neuropathic pain, which often responds inadequately to conventional pain medications (53) . Clinical studies have shown that THC-containing drugs such as nabiximole (Sativex) are effective in relieving neuropathic pain associated with multiple sclerosis and chemotherapy-induced neuropathy. For example, a systematic review highlighted the efficacy of cannabinoids in reducing chronic neuropathic pain in adults, suggesting that such treatment can provide significant relief for patients unresponsive to standard therapies (54) . On the other hand, CBD's anti-inflammatory and immunomodulatory effects give it analgesic properties. Transient receptor potential vanilloid receptor 1 (TRPV1), which has been linked to pain and inflammation, is one of the non-cannabinoid receptors with which it interacts (55) . In addition, CBD's ability to inhibit endocannabinoid reuptake enhances its analgesic potential. Clinical evidence supports the use of CBD in the treatment of chronic pain. For example, a study evaluating the effects of CBD-based oil in patients with lower extremity peripheral neuropathy showed significant reductions in intense pain, acute pain, cold and itching in the CBD group compared to the placebo group (55) . The combined use of THC and CBD has been studied to take advantage of the synergistic effects of both cannabinoids. This combination has shown promise in treating pain associated with conditions such as rheumatoid arthritis and fibromyalgia. A randomized, double-blind, placebo-controlled study evaluating the efficacy of THC-CBD extract in patients with untreatable cancer-related pain showed significant pain relief compared to placebo, highlighting the potential benefits of cannabinoid combination therapy (56).

Side effects and safety issues

CBD and THC have numerous therapeutic benefits, but their use is associated with several side effects and safety concerns. These concerns vary depending on the dose, frequency of use and individual susceptibility.

Adverse effects of THC

THC's psychoactive properties contribute to a variety of short- and long-term side effects, including cognitive impairment, psychiatric effects, cardiovascular risk and addiction potential. Excessive THC use is associated with deficits in memory, attention and executive function, particularly in adolescents. High doses of THC can cause anxiety and paranoia, and in some cases exacerbate psychotic disorders such as schizophrenia. THC can cause a temporary increase in heart rate and blood pressure, posing a risk to people with cardiovascular disease. Regular use of THC can lead to cannabis use disorder (CUD), characterized by addiction, withdrawal symptoms and difficulty controlling consumption (57).

Adverse effects of CBD

CBD is generally well tolerated, but some side effects have been reported, especially at high doses in gastrointestinal disorders, liver problems, etc. CBD can cause nausea, diarrhea and appetite changes. High doses of CBD have been linked to an increase in liver enzymes, which requires caution in people with pre-existing liver disease. CBD can inhibit cytochrome P450 enzymes, affecting the metabolism of various drugs, including anticoagulants and anticonvulsants. Some users report drowsiness and dizziness, especially when combined with other central nervous system depressants (57).

Long-term security concerns

Regular cannabis use during adolescence may affect brain development, particularly in areas related to cognition and emotion. Smoking cannabis, especially THC-rich varieties, has been linked to chronic bronchitis and respiratory disease, although the risk of lung cancer remains unclear. Recent studies show that cannabis use during pregnancy is associated with adverse fetal outcomes, including low birth weight and neurodevelopmental deficits. While cannabinoids have anti-inflammatory properties, long-term immune suppression can increase susceptibility to infection (58).

Regulatory and safety issues

The lack of regulatory oversight of cannabis-derived products raises concerns about contamination, potency variability and mislabeling. Due to individual variability in cannabinoid metabolism, establishing standard therapeutic doses remains a challenge. Although medical marijuana is legal in many regions, regulatory inconsistencies hinder research and clinical use (National Academies of Sciences, Engineering, and Medicine, 2017) (59).

Future prospects and applications

The growing body of research on cannabinoids suggests promising future applications in various medical fields. However, several challenges must be faced before their widespread clinical use is possible.

Progress in drug development

The pharmaceutical industry is exploring new cannabinoid-based formulations to increase bioavailability and therapeutic efficacy. Nanotechnology-based drug delivery systems and synthetic cannabinoids can provide more controlled effects and reduced side effects.

Personalized medicine

With advances in pharmacogenomics, personalized cannabinoid therapies tailored to an individual's genetic makeup and metabolic profile may improve efficacy and minimize side effects.

Streamlining clinical trials

Although preclinical studies show significant therapeutic potential, randomized, controlled large-scale trials (RCTs) are necessary to establish standard treatment protocols for conditions such as chronic pain, epilepsy and neurodegenerative diseases.

Contributions to mental health care

CBD's anti-anxiety and antipsychotic properties are being studied for the treatment of anxiety disorders, PTSD and schizophrenia, offering a potential substitute for conventional drugs.

Cancer therapy and palliative care

Ongoing studies are evaluating cannabinoids as adjuvants in anticancer therapy, particularly for chemotherapy-induced nausea, appetite stimulation and tumor suppression through mechanisms of apoptosis and anti-angiogenesis.

Autoimmune and inflammatory diseases

CBD and THC continued to be studied for their immunomodulatory effects in conditions such as multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease.

Changes in policy

As public attitudes toward cannabis evolve, policy changes will be crucial to facilitate research, ensure product safety and address ethical issues related to cannabis use.

Security health public

As cannabinoid-based therapies gain greater acceptance, ensuring safe and responsible use remains a priority. Key challenges include:

• Educate healthcare professionals and patients about appropriate dosage, potential side effects and contraindications.
• Balancing the medical use of cannabis with the risks associated with recreational cannabis consumption, especially in populations prone to addiction.
• Develop standard guidelines for workplace drug policy and driving regulations to address cannabinoid pharmacokinetics .(60)

Applications

Cannabis sativa's two main bioactive components, cannabidiol (CBD) and tetrahydrocannabinol (THC), have become important therapeutic substances with a wide range of pharmacological applications. They have multiple physiological effects due to their different modes of action, with THC acting mainly through activation of CB1 and CB2 receptors, and CBD acting as a modulator of several receptor systems. These cannabinoids have shown potential in oncology, neuropsychiatry, pain management, autoimmune diseases, metabolic disorders and dermatology, highlighting their ability to modulate inflammatory pathways, neurotransmitter release and immune responses. THC and CBD show different effects on sleep; THC is better at reducing sleep latency and inhibiting REM sleep, while CBD is involved in REM sleep disorders and sleep regulation. However, long-term use of THC can alter sleep patterns and cause addiction, so further clinical studies are needed to determine safe and effective dosage recommendations. They have different metabolic and hormonal effects; THC increases appetite and can cause weight gain and hormonal changes over time, while CBD can improve insulin sensitivity, reduce inflammation and promote fat browning. Gaining insight into these processes may help direct potential therapeutic applications in metabolic disease, diabetes and obesity. There is strong evidence from clinical trials that THC and CBD are effective in treating epilepsy, multiple sclerosis, chemotherapy-induced nausea and chronic pain. Due to its neuroprotective and anxiolytic properties, CBD in particular has shown promise in treating neurological and psychiatric conditions such as anxiety, schizophrenia and post-traumatic stress disorder (PTSD). Despite the therapeutic potential, possible side effects and regulatory hurdles continue to limit the clinical use of cannabis. While CBD's interaction with liver enzymes may require caution in polypharmacy situations , THC's euphoric properties, psychiatric disorders and cardiovascular risks require regulated dosing. In addition, long-term safety data remain insufficient, especially with regard to adolescent exposure, neurodevelopmental effects and immune modulation. To maximize efficacy while minimizing side effects, the future of cannabinoid-based therapies depends on rigorous clinical trials, standardized dosing regimens and the development of drug delivery technologies. Continued scientific and translational research will be required to integrate cannabinoid therapy into evidence-based medical practice and ensure both clinical safety and therapeutic efficacy as the regulatory framework changes.

Disclaimer

This article was written for educational purposes and is intended to raise awareness of the substance under discussion. It is important to note that the article is about the substance in general - it is not a description of a specific product (chemical reagent). We do not suggest the use of chemical reagents on humans - this is prohibited by law, for a product to be used for treatment it must be registered as a drug. The information contained in the text is based on available scientific research and is not intended to serve as medical advice or promote self-medication. The reader should consult any health and treatment decisions with a qualified health professional.

References

1. Stella N. THC and CBD: Similarities and differences between siblings. Neuron [Internet]. 2023 [cited 2025 Mar 17];111(3):302-27. Available from: https://www.cell.com/neuron/fulltext/S0896-6273(22)01119-9
2. Crocq MA. The history of cannabis and the endocannabinoid system. Dialogues Clin Neurosci [Internet]. 2020 Sep 30 [cited 2025 Mar 17];22(3):223-8. Available from: https://www.tandfonline.com/doi/full/10.31887/DCNS.2020.22.3/mcrocq
3. Friedman D, Sirven JI. A historical perspective on the medical use of cannabis in the treatment of epilepsy: from ancient times to the 1980s. Epilepsy Behav [Internet]. 2017 [cited 2025 Mar 17];70:298 -301. Available from: https://www.sciencedirect.com/science/article/pii/S1525505016306667
4. Karki P, Rangaswamy M. A review of the historical context and current research on cannabis use in India. Indian J Psychol Med [Internet]. 2023 Mar [cited 2025 Mar 17]; 45 (2): 105-16. Available from: https://journals.sagepub.com/doi/10.1177/02537176221109272
5. Russo E. Cannabis in India: ancient knowledge and modern medicine. In: Mechoulam R, editor. Cannabinoids as Therapeutics [Internet]. Basel: Birkhäuser-Verlag; 2005 [cited 2025 Mar 17]. p. 1-22. (Milestones in MDT drug therapy). Available from: http://link.springer.com/10.1007/3-7643-7358-X_1
6. Anywar G, Kakudidi E, Tugume P, Asiimwe S. The Cannabis/Marijuana (Cannabis sativa L.) Landscape in Africa: an overview of its cultivation and legal aspects. In: Agrawal DC, Kumar R, Dhanasekaran M, editors. Cannabis/Hemp for Sustainable Agriculture and Materials [Internet]. Singapore: Springer Singapore; 2022 [cited 2025 Mar 17]. p. 297-310. Available from: https://link.springer.com/10.1007/978-981-16-8778-5_10
7. Liu J, Chen H, Newmaster S, Wang S, Liu C. Global trends in cannabis and cannabidiol research from 1940 to 2019. Curr Pharm Biotechnol [Internet]. 2021 [cited 2025 Mar 17];22(5):579-91. Available from: https://www.ingentaconnect.com/content/ben/cpb/2021/00000022/00000005/art00004
8. Sinclair J, Adams C, Thurgood GR, Davidson M, Armour M, Sarris J. Cannabidiol (CBD) oil: A review of research, roles and regulation in Australia. Aust J Herb Naturop Med [Internet]. 2020 [cited 2025 Mar 17]; 32(2): 54-60. Available from: https://search.informit.org/doi/abs/10.3316/INFORMIT.218546138513880
9. Chayasirisobhon S. Mechanisms of action and pharmacokinetics of cannabis. Perm J [Internet]. 2021 Mar [cited 2025 Mar 17];25(1):1-3. Available from: http://www.thepermanentejournal.org/doi/10.7812/TPP/19.200
10. Peng J, Fan M, An C, Ni F, Huang W, Luo J. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD). Basic Clin Pharmacol Toxicol [Internet]. 2022 Apr [cited 2025 Mar 17];130(4):439-56. Available from: https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13710
11. Lee MA. CBD: how it works. O’Shaughnessy’s Internet [Internet]. 2011 [cited 2025 Mar 17]; Available from: https://www.alchimiaweb.com/blogfr/wp-content/uploads/2015/11/CBDiary21-CBD-How-It-Works.pdf.
12. Lucas CJ, Galettis P, Schneider J. Pharmacokinetics and pharmacodynamics of cannabinoids. Br J Clin Pharmacol [Internet]. 2018 Nov [cited 2025 Mar 17];84(11):2477-82. Available from: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.13710
13. Millar SA, Stone NL, Yates AS, O’Sullivan SE. A systematic review of cannabidiol pharmacokinetics in humans. Front Pharmacol [Internet]. 2018 [cited 2025 Mar 17];9:425858 . Available from: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01365/full?source=post_page—————————
14. Yau GTY, Tai W, Arnold JC, Chan HK, Kwok PCL. Cannabidiol in the treatment of brain disorders: Therapeutic potential and modes of administration. Pharm Res [Internet]. 2023 May [cited 2025 Mar 17]; 40(5): 1087-114. Available from: https://link.springer.com/10.1007/s11095-023-03469-1
15. Martin-Santos R, A. Crippa J, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, et al. Acute Effects of a Single, Oral Dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers. Curr Pharm Des [Internet]. 2012 Sep 12 [cited 2025 Mar 17];18(32):4966-79. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1381-6128&volume=18&issue=32&spage=4966
16. Freeman TP, Lorenzetti V. „Standard THC units”: a proposal to standardize dosing across all cannabis products and delivery methods. Addiction [Internet]. 2020 Jul [cited 2025 Mar 17];115(7):1207-16. Available from: https://onlinelibrary.wiley.com/doi/10.1111/add.14842
17. Zuardi AW, Hallak JEC, Crippa JAS. Interaction between cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC): effect of dosing interval and dose ratio between cannabinoids. Psychopharmacology (Berl) [Internet]. 2012 Jan [cited 2025 Mar 17];219(1):247-9. Available from: http://link.springer.com/10.1007/s00213-011-2495-x
18. Smith SC, Wagner MS. Clinical endocannabinoid deficiency (CECD) re-examined. Neuroendocrinol Lett [Internet]. 2014 [cited 2025 Mar 17];35(3). Available from: https://budandblossomcoaching.com/s/Clinical-endocannabinoid-deficiency-CECD-revisited.pdf
19. Russo EB. Clinical endocannabinoid deficiency reconsidered: Current research supports theory of migraine, fibromyalgia, irritable bowel and other treatment-resistant syndromes. Cannabis Cannabinoid Res [Internet]. 2016 Dec [cited 2025 Mar 17];1(1):154-65. Available from: http://www.liebertpub.com/doi/10.1089/can.2016.0009
20. Engeli S. Dysregulation of the endocannabinoid system in obesity. J Neuroendocrinol [Internet]. 2008 May [cited 2025 Mar 17];20(s1):110-5. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2826.2008.01683.x
21. Seltzer ES, Watters AK, MacKenzie D, Pomegranate LM, Zhang D. Cannabidiol (CBD) as a promising anticancer drug. Cancers [Internet]. 2020 [cited 2025 Mar 17];12(11):3203. Available from: https://www.mdpi.com/2072-6694/12/11/3203?ref=healthdecider.com
22. Heider CG, Itenberg SA, Rao J, Ma H, Wu X. Mechanisms of action of cannabidiol (CBD) in cancer treatment: A review. Biology [Internet]. 2022 [cited 2025 Mar 17];11(6):817. Available from: https://www.mdpi.com/2079-7737/11/6/817
23. O’Brien K. Cannabidiol (CBD) in Cancer Treatment. Cancers [Internet]. 2022 [cited 2025 Mar 17];14(4):885. Available from: https://www.mdpi.com/2072-6694/14/4/885
24. Cherkasova V, Wang B, Gerasymchuk M, Fiselier A, Kovalchuk O, Kovalchuk I. Use of cannabis and cannabinoids in cancer treatment. Cancers [Internet]. 2022 [cited 2025 Mar 17];14(20):5142. Available from: https://www.mdpi.com/2072-6694/14/20/5142
25. Cherkasova V, Wang B, Gerasymchuk M, Fiselier A, Kovalchuk O, Kovalchuk I. Use of cannabis and cannabinoids in cancer treatment. Cancers [Internet]. 2022 [cited 2025 Mar 17];14(20):5142. Available from: https://www.mdpi.com/2072-6694/14/20/5142
26. Khan R, Naveed S, Mian N, Fida A, Raafey MA, Aedma KK. Therapeutic role of cannabidiol in mental health: a systematic review. J Cannabis Res [Internet]. 2020 Dec [cited 2025 Mar 17]; 2 (1): 2. Available from: https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-019-0012-y
27. Henson JD, Vitetta L, Hall S. Drugs containing tetrahydrocannabinol and cannabidiol for the treatment of chronic pain and psychiatric illness. Inflammopharmacology [Internet]. 2022 Aug [cited 2025 Mar 17];30(4):1167-78. Available from: https://link.springer.com/10.1007/s10787-022-01020-z
28. Rup J, Freeman TP, Perlman C, Hammond D. Cannabis and mental health: Prevalence of cannabis use and routes of administration by mental health status. Addict Behav [Internet]. 2021 [cited 2025 Mar 17];121:106991 . Available from: https://www.sciencedirect.com/science/article/pii/S0306460321001763
29. Ahmed S, Roth RM, Stanciu CN, Brunette MF. Effects of THC and CBD in schizophrenia: a systematic review. Front Psychiatry [Internet]. 2021 [cited 2025 Mar 17];12:694394 . Available from: https://www.frontiersin.org/articles/10.3389/fpsyt.2021.694394/full
30. Telch MJ, Fischer CM, Zaizar ED, Rubin M, Papini S. Use of cannabidiol (CBD) oil in the treatment of PTSD: Study design and rationale for a randomized placebo-controlled clinical trial. Contemp Clin Trials [Internet]. 2022 [cited 2025 Mar 17];122:106933 . Available from: https://www.sciencedirect.com/science/article/pii/S1551714422002592
31. Ahmed S, Roth RM, Stanciu CN, Brunette MF. Effects of THC and CBD in schizophrenia: a systematic review. Front Psychiatry [Internet]. 2021 [cited 2025 Mar 17];12:694394 . Available from: https://www.frontiersin.org/articles/10.3389/fpsyt.2021.694394/full
32. Hindley G, Beck K, Borgan F, Ginestet CE, McCutcheon R, Kleinloog D, et al. Psychiatric symptoms induced by cannabis constituents: a systematic review and meta-analysis. Lancet Psychiatry [Internet]. 2020 [cited 2025 Mar 17];7(4):344-53. Available from: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30074-2/abstract
33. Arjmand S, Behzadi M, Kohlmeier KA, Mazhari S, Sabahi A, Shabani M. Bipolar disorder and the endocannabinoid system. Acta Neuropsychiatr [Internet]. 2019 [cited 2025 Mar 17];31(4):193-201. Available from: https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/bipolar-disorder-and-the-endocannabinoid-system/0C3191AF7BECA6D5A6EBED3C94CAA57B
34. Kaul M, Zee PC, Sahni AS. Effects of cannabinoids on sleep and their therapeutic potential in sleep disorders. Neurotherapeutics [Internet]. 2021 [cited 2025 Mar 17];18(1):217-27. Available from: https://www.sciencedirect.com/science/article/pii/S1878747923011911
35. Monti JM, Pandi-Perumal SR. Clinical treatment of sleep and sleep disorders with cannabis and cannabinoids: implications for practicing psychiatrists. Clin Neuropharmacol [Internet]. 2022 [cited 2025 Mar 17];45(2):27-31. Available from: https://journals.lww.com/clinicalneuropharm/fulltext/2022/03000/Clinical_Management_of_Sleep_and_Sleep_Disorders.3.aspx
36. Kolla BP, Hayes L, Cox C, Eatwell L, Deyo-Svendsen M, Mansukhani MP. Effects of cannabinoids on sleep. J Prim Care Community Health [Internet]. 2022 Jan [cited 2025 Mar 17];13:21501319221081277 . Available from: https://journals.sagepub.com/doi/10.1177/21501319221081277
37. Suraev AS, Marshall NS, Vandrey R, McCartney D, Benson MJ, McGregor IS, et al. Cannabinoid therapies for the treatment of sleep disorders: A systematic review of preclinical and clinical studies. Sleep Med Rev [Internet]. 2020 [cited 2025 Mar 17];53:101339 . Available from: https://www.sciencedirect.com/science/article/pii/S1087079220300824
38. Kolla BP, Hayes L, Cox C, Eatwell L, Deyo-Svendsen M, Mansukhani MP. Effects of cannabinoids on sleep. J Prim Care Community Health [Internet]. 2022 Jan [cited 2025 Mar 17];13:21501319221081277 . Available from: https://journals.sagepub.com/doi/10.1177/21501319221081277
39. Inglot J, Inglot J, Sowa D, Szczepanski M, Zapasek D, Mamczur M, et al. The Effects of Cannabinoid Compounds on the Endocrine System. Qual Sport [Internet]. 2024 [cited 2025 Mar 17];36:56516 -56516. Available from: https://apcz.umk.pl/QS/article/view/56516
40. Nielsen RL, Bornæs O, Christensen LWS, Juul-Larsen HG, Storgaard IK, Kallemose T, et al. Appetite stimulating effects and safety of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in elderly patients with poor appetite: A triple-blind, randomized, placebo-controlled crossover study. Clin Nutr [Internet]. 2025 [cited 2025 Mar 17]; Available from: https://www.sciencedirect.com/science/article/pii/S0261561425000597
41. Miederer I, Uebbing K, Röhrich J, Maus S, Bausbacher N, Krauter K, et al. Effects of tetrahydrocannabinol on glucose uptake in the rat brain. Neuropharmacology [Internet]. 2017 [cited 2025 Mar 17];117:273 -81 Available from: https://www.sciencedirect.com/science/article/pii/S0028390817300564
42. Meah F, Lundholm M, Emanuele N, Amjed H, Poku C, Agrawal L, et al. Effects of marijuana and cannabinoids on the endocrine system. Rev Endocr Metab Disord [Internet]. 2022 Jun [cited 2025 Mar 17];23(3):401-20. Available from: https://link.springer.com/10.1007/s11154-021-09682-w
43. Gorelick J, Assa-Glazer T, Zandani G, Altberg A, Sela N, Nyska A, et al. THC and CBD affect metabolic syndrome parameters including the microbiome in mice fed a high-fat-cholesterol diet. J Cannabis Res [Internet]. 2022 Dec [cited 2025 Mar 17];4(1):27. Available from: https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00137-w
44. Henshaw FR, Dewsbury LS, Lim CK, Steiner GZ. Effects of cannabinoids on pro- and anti-inflammatory cytokines: A systematic review of studies in vivo. Cannabis Cannabinoid Res [Internet]. 2021 Jun 1 [cited 2025 Mar 17];6(3):177-95. Available from: https://www.liebertpub.com/doi/10.1089/can.2020.0105
45. Cabrera CLR, Keir-Rudman S, Horniman N, Clarkson N, Page C. Anti-inflammatory effects of cannabidiol and cannabigerol alone and in combination. Pulm Pharmacol Ther [Internet]. 2021 [cited 2025 Mar 17];69:102047 . Available from: https://www.sciencedirect.com/science/article/pii/S1094553921000596
46. Burstein S. Cannabidiol (CBD) and its analogues: a review of their effects on inflammation. Bioorg Med Chem [Internet]. 2015 [cited 2025 Mar 17];23(7):1377-85. Available from: https://www.sciencedirect.com/science/article/pii/S0968089615000838
47. Naftali T, Mechulam R, Lev LB, Konikoff FM. Cannabis in inflammatory bowel disease. Dig Dis [Internet]. 2014 [cited 2025 Mar 17];32(4):468-74. Available from: https://karger.com/ddi/article-abstract/32/4/468/96037
48. Kim SH, Yang JW, Kim KH, Kim JU, Yook TH. Review of marijuana studies in Alzheimer's disease – focusing on CBD, THC. J Pharmacopuncture [Internet]. 2019 [cited 2025 Mar 17];22(4):225. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6970569/
49. Sheriff T, Lin MJ, Dubin D, Khorasani H. The potential role of cannabinoids in dermatology. J Dermatol Treat [Internet]. 2020 Nov 16 [cited 2025 Mar 17];31(8):839-45. Available from: https://www.tandfonline.com/doi/full/10.1080/09546634.2019.1675854
50. Mounessa JS, Siegel JA, Dunnick CA, Dellavalle RP. The role of cannabinoids in dermatology. J Am Acad Dermatol [Internet]. 2017 [cited 2025 Mar 17];77(1):188-90. Available from: https://www.jaad.org/article/S0190-9622(17)30308-0/abstract
51. Avila C, Massick S, Kaffenberger BH, Kwatra SG, Bechtel M. Cannabinoids in the treatment of chronic pruritus: A review. J Am Acad Dermatol [Internet]. 2020 [cited 2025 Mar 17];82(5):1205-12. Available from: https://www.sciencedirect.com/science/article/pii/S0190962220301201
52. Eagleston LR, Kalani NK, Patel RR, Flaten HK, Dunnick CA, Dellavalle RP. Cannabinoids in dermatology: A scoping review. Dermatol Online J [Internet]. 2018 [cited 2025 Mar 17];24(6). Available from: https://escholarship.org/uc/item/7pn8c0sb
53. Boyaji S, Merkow J, Elman RNM, Kaye AD, Yong RJ, Urman RD. The role of cannabidiol (CBD) in the treatment of chronic pain: An assessment of current evidence. Curr Pain Headache Rep [Internet]. 2020 Feb [cited 2025 Mar 17]; 24 (2): 4. Available from: http://link.springer.com/10.1007/s11916-020-0835-4
54. Zubcevic K, Petersen M, Bach FW, Heinesen A, Enggaard TP, Almdal TP, et al. Oral tetra-hydro-cannabinol ( THC ), cannabidiol ( CBD ) capsules and their combinations in the treatment of peripheral neuropathic pain. Eur J Pain [Internet]. 2023 Apr [cited 2025 Mar 17]; 27(4): 492-506. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ejp.2072
55. Russo EB. The role of marijuana and cannabinoids in pain management. Pain Manag Pract Guide Clin [Internet]. 2002 [cited 2025 Mar 17];357-75. Available from: https://www.taylorfrancis.com/chapters/edit/10.1201/9781420093193-43/role-cannabis-cannabinoids-pain-management
56. Longo R, Oudshoorn A, Befus D. Cannabis in the treatment of chronic pain: a rapid systematic review of randomized controlled trials. Pain Manag Nurs [Internet]. 2021 [cited 2025 Mar 17];22(2):141-9. Available from: https://www.sciencedirect.com/science/article/pii/S1524904220302253
57. Gottschling S, Ayonrinde O, Bhaskar A, Blockman M, D’Agnone O, Schecter D, et al. Safety Considerations in Cannabinoid-Based Medicine. Int J Gen Med [Internet]. 2020 Dec [cited 2025 Mar 17]; Vol. 13: 1317-33. Available from: https://www.dovepress.com/safety-considerations-in-cannabinoid-based-medicine-peer-reviewed-article-IJGM
58. Arnold JC. A primer on the safety of medicinal marijuana and its potential side effects. Aust J Gen Pract [Internet]. 2021 [cited 2025 Mar 17];50(6):345-50. Available from: https://search.informit.org/doi/abs/10.3316/informit.815676967959754
59. Stains EL, Kennalley AL, Tian M, Boehnke KF, Kraus CK, Piper BJ. Medical marijuana in the United States: Comparison of 2017 and 2024 state qualifying conditions with the 2017 National Academies of Sciences report. Mayo Clin Proc Innov Qual Outcomes [Internet]. 2025 [cited 2025 Mar 17]; 9 (2): 100590. Available from: https://www.sciencedirect.com/science/article/pii/S2542454825000013
60. Leinen ZJ, Mohan R, Premadasa LS, Acharya A, Mohan M, Byrareddy SN. Therapeutic potential of cannabis: a comprehensive review of current and future applications. Biomedicines [Internet]. 2023 [cited 2025 Mar 17];11(10):2630. Available from: https://www.mdpi.com/2227-9059/11/10/2630