Introduction

Cannabinoids are obtained from plants belonging to the genus Cannabis, Cannabaceae family. Cannabis, particularly Cannabis sativa, has been known for its therapeutic and psychotomimetic applications for over 6000 years. Every Cannabis sativa plant produces active compounds, but the levels and proportions of these compounds vary among different varieties. These variations cannot be attributed solely to genetic makeup, as environmental factors such as climate and growing conditions may also influence them. Therefore, it is more accurate to refer to these variables as chemical varieties or chemovars, instead of strains.1 The main active components present in Cannabis sativa comprise ∆9-tetrahydrocannabinol ((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol) (THC) and cannabidiol (2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol) (CBD).2

The mechanism of action of cannabinoids is dependent on their interaction with two cannabinoid receptors known as CB1 and CB2, which are found throughout the central and peripheral nervous systems. They are present in axons, dendrites, and cell bodies, and they influence neuronal, glial, and microglial activity.3 When these receptors are activated, they inhibit adenylyl cyclase production causing hyperpolarization of neurons, which stops the transmission of electric impulses. CB1 and CB2 receptors are highly concentrated in the hippocampal formation and olfactory bulb, where they impact memory, cognition, smell, and pain perception.4 Additionally, CB1 receptors can be found in the dorsal horn of the spinal cord and on afferent A-β and A-ẟ fibers, suggesting their potential as analgesics for nerve damage.5 CB2 receptors, on the other hand, are unique as their presence is not solely limited to the nervous system and can be found on immune cells, macrophages, and solid tumor tissues, indicating their potential anti-cancer activity.6–8 Furthermore, the activation of CB1 receptors in the brain via THC is responsible for the mind-altering effects of Cannabis sativa, whereas CBD has no psychoactive effects.9

Medicinal Cannabis refers to the use of Cannabis or cannabinoids with an intention to treat a disease or alleviate some of its symptoms. There are several ways, in which cannabinoids can be administered to a patient.10 Smoking is the most widespread form of Cannabis consumption, yet it is not accepted for therapeutic purposes, due to health hazards evoked by pyrolytic by-products.2 Cannabinoids can be administered orally, sublingually, and topically, they can be vaporized and inhaled or even mixed into food.10–12 For instance, CBD inhalation and intranasal administration provides a rapid rise of the drug’s concentration in the plasma, thus reaching the brain faster. On the other hand, transdermal route of CBD administration delivers the drug systemically in a slower manner, gradually over time.13 Prescribed cannabinoids include the oromucosal spray nabiximols (Cannabis-based extract with CBD:THC in a 1:1 ratio) and capsules with the synthetic analogue of THC - dronabinol or nabilone.10–12

Cannabinoids’ beneficial features have given them a new therapeutic meaning in the treatment of a wide range of conditions. These include multiple sclerosis (MS), epilepsy, post-traumatic stress disorder (PTSD), anxiety, cancer, and, most critically, chronic pain.14 Furthermore, Cannabis sativa-based products have gained significant popularity and attention in the areas of cosmetology and dermatology. CBD, in particular, has caught the attention of scientists due to its multiple therapeutic characteristics, including anti-inflammatory and antioxidant properties. Furthermore, CBD has a noteworthy therapeutic potential in the treatment of skin disorders such as atopic dermatitis, pruritus, psoriasis, and acne.15

Despite the various healing benefits that cannabinoids offer, their effectiveness in therapy is significantly limited due to their physical and chemical properties, such as their low solubility in water and instability. Studies performed by Fairbairn et al in 1976 and Pacifici et al in 2018 demonstrated that cannabinoids can undergo degradation when exposed to heat, light, or long-term storage, which can affect their potency.16,17 According to the study conducted by Drooge et al, THC undergoes rapid degradation within a few hours of exposure to air, and this process is accelerated at higher temperatures.18 The Biopharmaceutics Classification System (BCS) classifies cannabinoids such as THC and CBD as drugs with high lipophilicity (logP of around 6.3 and 6.97 respectively) and low water solubility (12.6 and 28.0 mg/L respectively). Additionally, the pKa values of THC and CBD are 9.29 and 10.6, respectively.19–21

The inconsistent and unreliable absorption patterns observed with cannabinoids can be attributed to their physicochemical properties. When taken orally, THC-based medications have a lower bioavailability rate (between 6% and 10%) due to their instability in the acidic environment of the stomach. Additionally, they are heavily metabolized by the CYP450 enzymes in the liver (specifically, CYP3A4 and CYP2C9) into an equally potent metabolite called 11-OH THC, which is then further metabolized into the inactive THC-COOH form.22 According to the reports, the absorption of THC is limited by the excretion of P-glycoprotein (P-gp) from the enterocytes.23 Like THC, CBD also exhibits low oral bioavailability in humans, typically falling in the range of 9% to 13%. This is owing to its low solubility in water and extensive initial metabolism by CYP enzymes (specifically, CYP3A4 and CYP2C19) into a 7-OH metabolite, which results in the loss of roughly 75% of the drug that enters systemic circulation.24,25 The inhalation of cannabinoids through smoking has been found to have the highest bioavailability, ranging from 2% to 56%. The reason for this is that smoking enables swift and effective delivery of drugs to the brain via the lungs and bloodstream. Likewise, the use of smoking for medicinal purposes cannot be endorsed because it poses health risks from the combustion by-products produced.2 Given the limitations of cannabinoids, innovative drug delivery strategies that protect these compounds from oxidation, while increasing their potency and bioavailability, are required.26

What Do We Know About Clinically Important Cannabinoids?

In recent years, the scientific community has exhibited a growing interest in investigating Cannabis’ possible therapeutic applications. Many researchers have presented encouraging results from preclinical and clinical studies, indicating that cannabinoids have the potential to treat a wide range of conditions, including pain, cancer, neurological, and psychiatric illnesses. Considering cannabinoids’ pharmacological targets are not only limited to CB1 and CB2 receptors, their physiological activities and potential therapeutic applications are still being investigated and expanded.27

In the subsequent sections of this review, the therapeutic potential of cannabinoids in the treatment of various disorders will be addressed.

Cannabinoids in Pain Management

Pain can be defined as an unpleasant sensory and emotional experience, which is concurrent with actual or potential tissue damage. Such discomfort can also occur without any physical derangement, as stated in the definition proposed by the International Association for the Study of Pain (IASP).28 Despite significant advances in pain management, it remains a challenging burden both for the patients and their doctors. The most pain-affected group of patients comprises cancer patients, who suffer from pain chronically.29 Every patient who suffers from pain is more susceptible to immune and metabolic upset, thus slowing down the regeneration process. Inadequate pain relief caused by insufficient analgesic dosage or worse, complete lack of pain management therapy leads to augmented morbidity and mortality.30

Pain-managing strategies are most commonly based on the three-step World Health Organization (WHO) analgesic ladder scheme. As the first-line treatment of mild pain, physicians use non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen with or without adjuvants. If the analgesia is insufficient or the pain aggravates to moderate intensity, the doctors continue the treatment with the drugs from the first step with the addition of weak opioids such as hydrocodone, codeine or tramadol.31 The management of severe and persistent pain is the most troublesome due to the high-risk profiles of potent opioid drugs administered as the third step of the pain ladder. These drugs include eg morphine, fentanyl, oxycodone, hydromorphone or buprenorphine.32

NSAIDs are the first-line treatment of pain in the world due to their wide availability. Often, patients self-administer these drugs without consulting their doctors, which can lead to improper or excessive use. The overuse of NSAIDs can lead to minor gastrointestinal (GI) side effects such as dyspepsia, but utter abuse can induce serious complications like bleeding from ulcers or perforation of the GI tract. Furthermore, NSAIDs can cause cardiovascular or nephrological adverse effects.33

Adjuvants can be used additionally to primary analgesic medications on every step of the WHO pain ladder. The term “adjuvant analgesics” refers to any drug with a primary indication other than pain, that can have an analgesic effect in certain painful conditions.34 Some adjuvants are known for their multipurpose analgesic properties in diverse pain syndromes, eg tricyclic antidepressants, corticosteroids, α2-adrenergic agonists or neuroleptics. On the other hand, adjuvants may have specific conditions, in which they can be successfully used. Anticonvulsants and local anaesthetics aid in neuropathic pain; bisphosphonates, calcitonin and radiopharmaceuticals are widely administered in conditions associated with bone pain; muscle relaxants are useful during musculoskeletal pain and anticholinergics relieve patients with symptoms of bowel obstructions. Furthermore, ketamine, capsaicin and cannabinoids are also known for their adjuvant properties.35

As the global market and interest in herbal medicine surges, more attention is being directed towards the use of plant-derived drugs.36 In the United States, it is estimated that almost twenty million Americans use herbal medicine.37 An annual turnover of more than 1.5 billion dollars and yearly growth of almost 25% is noted.38

Herbal products are very important in Chinese traditional medicine. A wide variety of medicinal plants have been associated with anticancer effects. It is speculated that these plants could become a rich source of natural antioxidants and helpful chemopreventive substances.39 Furthermore, many plants comprise natural analgesics that target various pathological mechanisms involved in the perception of pain, contrary to traditional analgesics, which usually act on a single pathway.40

However, the most common reason why American adults seek herbal medicine is pain management. In some cases of chronic pain, such as musculoskeletal pain, arthritis or migraine, biological changes to the central nervous system (CNS) or peripheral tissues are permanently established. Patients are condemned to chronic use of NSAIDs or opioids, which can lead to serious side effects, especially considering the elderly. To limit the dosage of administered traditional drugs and improve the analgesic effect, patients often turn to herbal medicines.36

The pain-relieving effects of THC are due to a variety of mechanisms of action that involve cannabinoid receptors CB1 and CB2. Additionally, THC interacts with other pathways, such as delta and kappa opioid receptors, the GABA-ergic/glutamatergic system, and the noradrenergic system.40 These interactions influence the way the pain is perceived.3,41,42 Furthermore, THC acts as an agonist on the transient-receptor potential vanilloid 1 receptor, which helps to block hyperalgesia and allodynia and regulates stimuli that cause thermal and mechanical pain. Other receptors sensitive to cannabinoids include calcitonin gene-related peptide, nuclear factor kappa-light-chain-enhancer of activated B-cells, G protein-coupled receptor 18, and peroxisome proliferator-activated receptors. These interactions contribute to vasodilatation, regulation of the host’s immune response during infection as well as the induction of apoptosis of proinflammatory macrophages.43 Cannabinoids also affect adenosine, serotonin, and dopamine receptors, which is followed by pain alleviation and sensation of relief.44 Moreover, cannabinoids can inhibit cyclooxygenase (preferably COX-2 than COX-1) and block the production of pain and inflammatory mediators at the location of the tumor, explaining its anti-inflammatory action. Activation of CB1 receptors in the central nervous system produces an analgesic effect, while activation of peripheral CB2 receptors amplifies this effect.45

The analgesic role of cannabinoids is studied in various pain conditions.46 A double-blind randomised clinical trial was conducted to assess the impact of nabiximols on pain in advanced cancer patients, who suffer from opioid-resistant pain. Patients, who were administered with nabiximols presented a statistically significant improvement in baseline scores on the numerical pain rating scale, compared with placebo.45 There is low-quality data regarding the influence of cannabinoids on neuropathic pain. In a Cochrane systematic review, 16 clinical trials have been evaluated. A moderate improvement of neuropathic pain sensation among studied participants was observed when treated with cannabinoids, compared with placebo (21% vs 17%).47 There are no high-quality clinical trials focused on the application of cannabinoids in patients suffering from musculoskeletal pain. The use of cannabinoids is recommended as an adjunctive after first and second-line recommended treatments.48Cannabis has been found to aid in chronic pain management in patients with fibromyalgia. Although clinical data is limited, there are placebo-controlled clinical trials suggesting a potential positive effect of THC-rich Cannabis oil in patients presenting with severe symptoms.49,50 In a systematic review, Stockings et al concluded that cannabinoids significantly reduce MS related neuropathic pain when compared to placebo, yet they do not treat MS-related musculoskeletal pain.51

Regardless of positive aspects of analgesic treatment of chronic pain disorders, the physicians must not neglect the side effects when prescribing medical Cannabis for such application. After reviewing the Danish nationwide registers, Holt et al conducted an analysis to determine the relationship between Cannabis use and the incidence of specific cardiovascular side effects. First-time arrhythmia and acute coronary syndrome incidence was compared between medical Cannabis users and non-users. The study results revealed that patients suffering from chronic pain, who had used prescribed medical Cannabis, are at greater risk of developing a new-onset arrhythmia in the 180 days following the beginning of the treatment. No such association was found regarding the acute coronary syndrome.52

Cannabinoids in the Treatment of Neurological Disorders

Alzheimer’s disease (AD) is the most prevalent neurodegenerative condition worldwide and accounts for around 60–80% of all instances of dementia.53 The main features of AD include the presence of β-amyloid plaques, phosphorylated tau proteins, neurofibrillary tangles, glial activation, and the loss of neurons.54 Preclinical research has shown that CBD can be effective in animal models of AD due to its serotonergic activity. A study conducted on mice demonstrated that administering CBD intraperitoneally could regulate the activation of microglia by beta-amyloid and improve cognitive function. To mimic cognitive decline related to AD, β-amyloid was injected intracerebroventricularly in mice. The study showed that mice administered with CBD had reduced latencies in the Morris water maze compared to those given a control substance.55 Moreover, when given to a transgenic mouse model of AD that expresses β-amyloid, THC demonstrates neuroprotective properties. It leads to a decrease in neuronal loss and a reduction in the buildup of β-amyloid compared to the control group receiving vehicle controls.56 Recent clinical research has demonstrated that nabilone shows potential as a therapy for neurodegenerative and neuroinflammatory diseases. In a double-blind, randomised crossover study involving AD patients, the administration of nabilone at a daily dose of 0.5–2 mg resulted in a decrease in markers associated with oxidative stress and neuroinflammation, such as tumor necrosis factor-alpha (TNF-α). Additionally, this reduction suggested a positive correlation between the use of nabilone and a decrease in agitation.57,58

Parkinson’s disease (PD) ranks as the second most prevalent neurodegenerative disorder, following AD. PD is distinguished by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. This neural loss disrupts the flow of dopamine in the striatum, resulting in the characteristic symptoms of PD. These symptoms encompass diminished motor function, including resting tremor, bradykinesia, postural instability, and rigidity. In addition to motor symptoms, PD can also lead to cognitive impairment, mood disorders, and sensory disturbances related to pain perception.53,59 Proinflammatory signalling is believed to contribute to disease progression. As a result, cannabinoids are considered to have therapeutic potential due to their anti-inflammatory properties.60 Clinical studies have shown that when CBD is given to patients with PD, there is a decrease in the frequency of psychotic symptoms such as sleep problems, hallucinations, and delusions. Additionally, patients experience a reduction in the intensity of tremors and an overall improvement in their well-being and motor function.61–63 In a recent clinical trial using CBD (Epidiolex®), researchers observed similar positive outcomes in symptoms related to PD. Patients in the trial reported good tolerability with no significant side effects when following a daily dosage of 5–25 mg/kg.64 In a recent randomised, double-blind, placebo-controlled Phase II study, researchers investigated the potential of nabilone in alleviating non-motor adverse effects associated with PD. The study has found that PD patients who were administered doses of nabilone up to 1 mg reported positive responses. Clinical assessments and self-scoring methods used in the study indicated that patients receiving nabilone experienced improvements in non-motor adverse effects compared to the placebo group, which reported increased disturbances caused by non-motor adverse effects.65

Further, seizures occur when there is an abnormal synchronized activity among neurons in the brain. The causes of seizures can vary and may include factors such as genetic susceptibility, brain injuries, the presence of brain tumors, and neurodegenerative disorders.66 Cannabinoid compounds have shown the ability to reduce spasms in various neurodegenerative diseases. This provides additional evidence for the use of cannabinoids in treating epileptic seizures. The anticonvulsant effects of THC are believed to be due to the stimulation of CB1 receptors. The conducted studies proved that mice lacking functional CB1 receptors or having genetic changes affecting the activity of the endogenous cannabinoid system are more susceptible to seizures.67,68 Furthermore, clinical studies have shown positive results when using cannabinoids to manage epilepsy. However, much of the research has focused on CBD due to its well-tolerated nature and lack of psychoactive effects.69 The utilization of CBD in clinical trials for treatment-resistant epilepsy and Dravet syndrome, specifically with the use of the clinically approved Epidiolex®, resulted in a notable decrease in the frequency and duration of epileptic seizures. Additionally, long-term safety and quality-of-life studies with this drug demonstrated that CBD offers effective and well-tolerated long-term treatment while enhancing the overall quality of life for patients.70–73 The neuroprotective potential of CBD consequently suggests its applicability in becoming an alternative remedy for patients suffering from epilepsy.74

MS is a chronic and disabling neurological disease that primarily impacts individuals in their early adulthood. Pathologically, it exhibits distinct features such as inflammation, loss of neuronal and axonal cells, demyelination, and the presence of astrocytic gliosis in the brain stem and spinal cord. Physiologically, MS is characterized by intermittent episodes of sensory and motor dysfunction, primarily caused by neurodegeneration.75,76 In the initial clinical trials, nabiximols demonstrated potential in effectively reducing spasticity associated with MS when compared to placebo controls, by decreasing the frequency and intensity of muscle spasms experienced by individuals undergoing treatment.77,78 In a more recent clinical research, nabiximols demonstrated greater effectiveness in improving spasticity caused by MS compared to solely adjusting the dosage of standard anti-spasticity medication.79 Dronabinol, however, despite being well tolerated by the patients, was found to have no positive impact on cognitive function. In fact, there were indications that cognitive function may even decline over time with the use of this drug.80 Additionally, it was discovered that a whole Cannabis extract provided relief from muscle stiffness in individuals with MS.81 Lastly, it was determined that medicinal Cannabis contributed to a slight decrease in fatigue among individuals with MS, in comparison to age and sex-matched controls who had no history of Cannabis usage.82

A recently published three-arm, randomized, double-blind clinical trial by Walczynska-Dragon et al provides new data on the efficacy of CBD formulations in temporomandibular disorders. The emphasis was put on the myorelaxing, pain-relieving and bruxism-reducing properties of CBD in patients suffering from muscle-related temporomandibular disorders. The study discovered that oral administration of CBD formulations successfully reduced the pain reported by patients while also reducing the muscle spasticity and thereby minimising the bruxing activity. A concentration of 10% CBD was found to induce superior effects, when compared to the formulation containing 5% CBD.83

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition where muscle control progressively diminishes due to muscle weakness and deterioration. This ultimately causes a decline in the ability to perform tasks such as chewing, swallowing, talking, and breathing, eventually resulting in death.84,85 Although the exact cause and mechanisms that lead to the onset of ALS are yet to be fully understood, it is believed that factors such as excitotoxicity, oxidative stress, and neuroinflammation contribute to the development of the condition. In particular, sporadic cases which make up 90–95% of all ALS cases, have no known specific cause.86,87 A multicenter, randomised placebo-controlled clinical trial on the ALS patients indicated that nabiximols reduced spasticity symptoms. Furthermore, no notable adverse effects were reported during the study.88 In addition, a clinical trial was conducted to assess the effectiveness of THC in relieving cramps in ALS patients. However, the trial did not find any significant reduction in cramp intensity based on patient feedback. Despite this, the use of THC at a daily oral dose of 10 mg was found to be well tolerated, and no significant adverse effects were reported.89

Cannabinoids in the Treatment of Anxiety

Fear and anxiety are natural biological processes that help individuals prepare for potential harm. They trigger various responses in behaviour, physiology, the autonomic nervous system, and hormones. In the short term, this is advantageous since it promotes quick detection of potential threats through heightened vigilance and enables a swift response. However, prolonged, unnecessary, or exaggerated fear and anxiety can have significant adverse effects on health. Anxiety tends to persist even when the threat has diminished.90 Clinical experiments with rimonabant, a CB1 receptor antagonist initially studied as an obesity treatment, revealed the importance of endocannabinoid system (ECS) signalling in controlling human anxiety. During a meta-analysis of four randomised, double-blind, placebo-controlled studies, it was found that the continuous administration of rimonabant, at a dosage of 20 mg per day, resulted in a significant elevation of anxiety levels measured by the Hospital Anxiety and Depression Scale. As a result, many individuals in the rimonabant group decided to discontinue their participation in the studies.91

In general, small amounts of exogenous cannabinoids typically produce calming effects similar to anti-anxiety medications, while larger doses often trigger the opposite effect. However, inhibiting the breakdown of endocannabinoids appears to overcome these dual effects by boosting CB1 receptor activity in a limited and specific way, resulting in reduced anxiety-related behaviours.92 THC exhibits a two-phase response regarding anxiety in animals, which is dependent on the dosage and the form of administration. Specifically, when given in high doses, THC has an anxiety-inducing effect during acute administration,93,94 whereas low doses are anxiolytic.95,96

Habitual Cannabis use has been thought to be related to a higher possibility of developing anxiety disorders. Beletsky et al conducted a critical systematic review of literature on the relation between Cannabis use and anxiety disorders. The researchers concluded that the hypothesized correlation may be explained by the anxiety predisposing individuals who seek for Cannabis as a remedy, rather than the Cannabis use itself, that leads to anxiety development. Despite numerous studies suggesting the causal relation between Cannabis use and progression of anxiety, such association appears to be less likely.97

More recently, scientists have been utilizing more targeted pharmacological treatments to address anxiety disorders. In a double-blind placebo-controlled study, the daily use of the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279 for 12 weeks showed improvement in the severity of symptoms related to social anxiety disorder (SAD). The effects of the treatment were even more pronounced in individuals with higher levels of FAAH inhibition.98,99 This observation in especially intriguing given preliminary data indicating that persons with SAD may have increased levels of central FAAH expression.100 Importantly, this data suggests that using pharmacological approaches to target the ECS could be a realistic and successful therapy option for anxiety disorders.90

Cannabinoids in the Treatment of Sleep Disorders

Sleep is a crucial biological process that serves a critical function in replenishing and restoring necessary bodily functions for optimal performance during wakeful hours.101 Achieving optimal sleep health involves ensuring sufficient duration, appropriate timing, efficient sleep patterns, and restful sleep that leaves individuals feeling alert and capable during the day.102 About 30 to 35% of the population experiences insufficient sleep.103

The activation of CB1 receptors located in the pons and basal forebrain is thought to contribute to the initiation of sleep. This is believed to happen by stimulating cholinergic neurons in the basal forebrain and pons through CB1 receptors, which helps facilitate the process of sleep induction.104 The sleep-wake cycle is also influenced by the serotonergic transmitter system in the brainstem’s dorsal raphe nucleus.105 Some studies suggest that the ECS may regulate the serotonin system through the activation of CB1 receptors, potentially affecting sleep-wake cycles.106

Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the endogenous ligands for both CB1 and CB2 receptors.107 Both clinical and preclinical studies have reported the presence of a daily rhythm in the levels of endocannabinoids circulating in the body.108 The level of 2-AG in the human blood plasma gradually rises from the middle of sleep to the early afternoon. This increase is more significant when sleep is restricted. Medications that inhibit the activity of monoacylglycerol lipase (MAGL), the enzyme responsible for breaking down 2-AG, have been found to increase the levels of 2-AG in the brain. This leads to wakefulness in rats, resulting in a decrease in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep.109 As compared to 2-AG, AEA has been found to have a positive impact on sleep. Researchers have discovered that by administering drugs that inhibit the FAAH enzyme and increase the levels of natural AEA, they could improve the sleep quality of males who were experiencing withdrawal symptoms due to Cannabis dependency. This treatment specifically helped to normalize the “slow wave” sleep patterns.110

There is limited data available on the impact of CBD on sleep. However, studies conducted on rats showed some interesting findings. When given lower doses of CBD via injection, the rats had an increase in the overall percentage of sleep and a decrease in the time taken to enter the REM phase. On the other hand, higher doses of CBD resulted in an increase in the amount of time it took the rats to enter REM sleep.111,112 In a recent double-blinded, randomised controlled trial, 1793 participants took part in a 5 week observation period, in which their sleep disturbances were assessed. Each participant received a 4-week supply of randomly assigned capsules containing either 15 mg of CBD or 5 mg of melatonin, alone or in combination with other cannabinoids. The sleep disturbance data was collected via weekly online surveys. The scientists discovered that continuous usage of low-dose CBD is safe and may improve sleep quality. The improvement, however, did not exceed the effects of administration of 5 mg of melatonin.113 Some individuals who report the use of Cannabis products for mild-to-moderate anxiety claim to experience a better quality of sleep on the following night. Interestingly, the highest perceived quality of sleep was noted by the respondents who ingested Cannabis products containing high CBD concentration.114

When THC is used for a short period, it shows certain effects on sleep. Studies conducted on rabbits and cats suggest that these effects include improved sleep continuity, reduced sleep onset latency (SOL), increased overall sleep duration (OSD), and decreased wake after sleep onset (WASO). Moreover, taking THC for a short duration has been associated with a decrease in REM sleep and an increase in slow-wave sleep (SWS).115,116 Unlike previously mentioned, continuous use of THC has demonstrated a decrease in SWS, indicating the potential development of tolerance over time.117 Additionally, there is an indication of heightened sleep disturbances characterized by an increase in SOL, an increase in WASO, and a decrease in OSD.118 During a four-armed crossover study, which was conducted in a double-blinded and placebo-controlled environment, the researchers used electroencephalography monitoring to observe the effects of combining CBD and THC. The study concluded that the combination of CBD and THC resulted in more stimulating properties. Furthermore, CBD had a tendency to reduce the sedative effects of THC, especially when larger doses were administered.119

Many people in the community use medicinal cannabinoid products to aid sleep without seeking guidance from healthcare professionals. However, the evidence supporting the use of cannabinoids for insomnia and other sleep disorders is not comprehensive enough to definitively support their clinical use. Nonetheless, the increasing knowledge of how the ECS regulates sleep-wake cycles gives a strong reason to explore and refine Cannabis products for potential therapeutic benefits.106,109,120

Cannabinoids in the Treatment of Cancer

Cancer is a condition that impacts around 40% of individuals during their lifetime.121 According to the American Cancer Society, it is predicted that in 2024 there will be over 2 million new cancer cases and the death toll will exceed 610,000 among cancer patients in the United States. Almost half (48%) of newly diagnosed cancer cases in men are attributed to prostate, lung and colorectal cancers, with prostate cancer alone accounting for 29% of diagnoses. In women, breast cancer, lung cancer and colorectal cancers constitute 51% of all new diagnoses, and breast cancer alone is responsible for 32% of overall female cancer cases.122,123 For a long time, oncological patients had limited choice when it came to the treatment options. These options primarily involved surgery, radiation therapy and chemotherapy, either used individually or in combination.124 Due to high toxicity of commonly used chemotherapeutic drugs and their low targeting specificity, their activity does not limit to cancer cells, but also causes harm to healthy tissues. These toxic agents destroy not only the abruptly proliferating cancer cells, but also the healthy cells, what leads to serious side effects such as reduced appetite, nausea, difficulty sleeping, and heightened anxiety and may even result in patients’ death.121,125 Untargeted radiotherapy faces the same issue of lacking specificity. This form of treatment induces DNA damage, leading to fragmentation of DNA strands, which ultimately results in the death of cells. Acute radiation damage primarily affects rapidly dividing cells, such as cancer cells, but also the stem cells of the skin and the lining of the digestive tract. This causes a disruption in the protective barrier, commonly observed in the skin, oral mucosa and in the GI tract. These effects are most commonly occurring within 5 years after radiotherapy completion. Eventually, the stem cells undergo compensatory hyperplasia, leading to recovery and resolution of symptoms within a few weeks. However, if the acute damage is not completely healed and persists for an extended period, the resulting lesions are considered late effects with long-term consequences.126 Innovation is sought after for novel forms of drug delivery that can release drugs selectively and efficiently target cells at specific sites. This is crucial for enhancing patients’ well-being and reducing the risk of toxicity.127

Cancer is a condition characterized by abnormal and unregulated cell division and growth. The development of cancer relies on the presence of mutations in multiple genes.128 Numerous studies have been conducted to demonstrate the expression or overexpression of CB1 and/or CB2 receptors in various types of human cancers such as glioma, lymphoma, leukaemia, breast, lung, ovarian, pancreatic, prostate, skin, thyroid cancers, endometrial, esophageal, head and neck, hepatocellular, renal, and mobile tongue carcinomas. These studies have utilized various techniques such as immunohistochemical staining, Western blotting, qRT-PCR, or a combination of methods to determine the expression levels of these receptors.121 Components found in Cannabis extracts, such as cannabinoids and terpenes, could offer an alternative approach to managing side effects. These compounds also have the potential for use alongside synthetic cytostatic drugs to assist in tumor disappearance.121

There have been numerous in vitro and in vivo studies demonstrating that cannabinoids have the ability to impact nearly all critical aspects of cancer. They can hinder cell growth, decrease inflammation, promote programmed cell death, impede the spread and growth of tumors, as well as their angiogenesis and metastasis.129,130 Autophagy and apoptosis play a crucial role in regulating excessive cell growth. It has been observed that cannabinoids have the ability to induce autophagy in various types of cancer.131,132 Inflammation plays a significant role in the development of cancer. The ECS regulates immune system function and controls inflammation. Some cannabinoids effectively reduce inflammation locally or systemically.133,134 There have been several reports indicating that cannabinoids have the ability to inhibit the migration, invasion, and spread of cancer cells.135 A recently published review on glioblastoma treatment with cannabinoids, suggests that glioblastoma cells express CB1 and CB2 receptors, through which cannabinoids may mediate signals leading to inhibition of proliferation and migration of tumor cells. Thus, utilizing cannabinoids might become a beneficial treatment option for patients suffering from glioblastoma.136,137 Lately, it has also been described that in vitro oral cancer cells’ exposure to cannabinoids triggers apoptosis and inhibits cell proliferation. Furthermore, the downregulation of multiple signalling pathways has been associated with anti-cancer features of cannabinoids.138

CBD has displayed promising potential in managing cancer in preclinical studies and some human clinical trials. However, there is still a limited understanding of the mechanisms behind its anticancer effects. To explore CBD’s potential as a cancer treatment and unravel its underlying mechanisms of action, further research is needed, especially in large-scale clinical trials. Additionally, the variations among CBD products available in the market pose a significant challenge, along with the limited knowledge of CBD’s efficacy in treating cancer and its potential side effects.121,139

Although there is not enough data to directly confirm the anti-cancer effect of cannabinoids, their potential in managing cancer symptoms has received significant attention. According to a report published by the National Academies of Sciences, Engineering, and Medicine: The Health Effects of Cannabis and Cannabinoids, one of the most significant clinical findings indicates that oral cannabinoids have helpful antiemetic properties. They can effectively alleviate chemotherapy-induced nausea and vomiting in adults.140,141 A randomised study was conducted involving 469 adults suffering from advanced cancer and weight loss. This study is one of the largest controlled trials of dronabinol. The trial compared the effects of three different treatments namely dronabinol 2.5 mg, megestrol acetate (a progestational agent) 800 mg, or a combination of both. The results showed that 49% of those who received dronabinol experienced an increase in their appetite, while 75% of those who received megestrol and 66% of those who received both also experienced an increase in appetite. Only 3% of the Cannabis recipients and 11% of those on megestrol gained more than 10% of their body weight. Interestingly, although dronabinol was found to be effective in increasing appetite, it was found to be ineffective in promoting weight gain.142 Synthetic cannabinoids have shown potential as a future treatment for cancer-associated cachexia syndrome (CACS). However, limited high-quality trials have been conducted in recent years, hindering the evaluation of their uses. Theoretical evidence suggests that cannabinoids could be an ideal treatment option for CACS patients. However, further high-quality research is necessary to determine the appropriate dosage and the applicability of these treatments.143 Enhanced levels of the CB1 receptor can be found in specific regions of the brain that regulate pain signal processing. Opioid medications are widely used among oncology patients. Initially, it was believed that opioids and cannabinoids affect similar pathways. However, they operate on distinct receptors, and unlike opioids, cannabinoid pain-relieving effects are not inhibited by opioid antagonists. Additionally, both CB1 and CB2 receptor agonists demonstrate analgesic properties both centrally and peripherally. Cannabinoids, along with terpenoids, may also exhibit anti-inflammatory effects, which contribute to their analgesic properties. The report by the US National Academies of Sciences, Engineering, and Medicine concludes that there is compelling evidence for the therapeutic benefits of Cannabis in pain relief.141,144

A recent research study explored the potential use of CBD as a self-assembly inducer for the production of nanoparticle (NP) structures that contain anticancer drugs. These drug-loaded NP complexes were formed by linking the CBD to various anticancer medications (namely N-desacetylthiocolchicine, podophyllotoxin, and paclitaxel) through a linker that enhances drug release. The NPs were created using a technique called solvent displacement, which resulted in consistently sized and stable structures with hydrodynamic diameters ranging from 160 to 400 nm. In the study, the researchers evaluated the potential of NPs complexes to prevent the growth of three different human tumor cell lines - biphasic mesothelioma cell line (MSTO-211H), colorectal adenocarcinoma cell line (HT-29), and hepatocellular carcinoma cell line (HepG2). The results showed that the concentration required to inhibit cell growth, known as GI50 values, was in the low micromolar range. These findings provide additional evidence that NPs can deliver the drug into the cells, enabling their cytotoxic effects. Furthermore, the research suggests that it may be possible to adjust the activity of anticancer drugs by changing the type of linker.145

Cannabinoids Use in Dermatology and Cosmetology

Recent research indicates that CB1 and CB2 receptors have natural ligands present in the skin, suggesting the existence of an ECS specific to the skin (Figure 1).146

Figure 1 Scheme of endocannabinoid system (ESC) specific to the skin.

Cannabinoids have the ability to either activate or inhibit ECS, which impacts various processes including sebum production, keratinocyte proliferation, inflammation, and hair growth. The activation of CB1 in specific epidermal layers and CB2 in the basal layer may result in increased DNA methylation in keratinocytes, which ultimately inhibits their proliferation. The discovery of a potential ECS in the skin suggests that it is possible to use selective agonists and antagonists for CB1 and CB2 receptors to manipulate the cannabinoid receptors in the treatment of various dermatological conditions.147 The presence of cannabinoid receptors on nerve fibers and mast cells in the skin suggests that cannabinoid receptor agonists may have anti-inflammatory and pain-relieving effects. This implies that these agonists have a wide spectrum of therapeutic potential.148 The transient receptor potential (TRP) channels are another set of skin receptors that can be targeted by cannabinoids. The TRPs are channels that allow cations to pass through. They have six transmembrane segments labelled as S1-S6, and a hydrophilic loop. The pore for ions is located between the S5 and S6 transmembrane segments. These channels can be divided into six subgroups by their amino acid sequences. The subgroups include TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystin), and TRPML (mucolipin).149 The topical application of substances that activate TRPA1 and TRPM8 receptors demonstrated positive effects on both epidermal proliferation and regaining epidermal permeability after injuries.150,151 The inhibition of TRPV1 by AEA, has been demonstrated by several research studies to have antipruritic effects. TRPV1 ion channel is mainly expressed in nociceptive neurons in the peripheral nervous system and plays a significant role in causing skin irritation, such as burning pruritus.152,153

In a study conducted by Stander et al, a cream containing palmitoylethanolamide (PEA) has been administered to 22 patients suffering from pruritus, prurigo, and lichen simplex. PEA acts on the cannabinoid receptor by inhibiting the FAAH enzyme, thereby activating AEA. The application of PEA resulted in a reduction of itch by 86.4% in these patients.154 Cannabinoids have the potential to hinder the excessive growth of keratinocytes in psoriasis. According to Wilkinson et al, it is suggested that the main mechanism through which THC inhibits keratinocyte proliferation is by targeting the peroxisome proliferative-activated receptor gamma (PPARγ).155 Another way in which cannabinoids can inhibit keratinocyte proliferation is through the downregulation of keratin K6 and K16 expression, which is achieved through the activation of CB1 receptors.156,157 In March 2016, AXIM Biotechnologies initiated human clinical trials on a topical ointment that includes cannabigerol and other cannabinoids in different concentrations. The ointment, known as RenecannTM, aims to treat psoriasis. If these tests are a success, RenecannTM will be the first cannabinoid treatment for psoriasis to gain approval of the US Food and Drug Administration (FDA).147

Endocannabinoids are crucial in the modulation of pain perception. When the peripheral CB1 receptor is activated, it effectively reduces hyperalgesia caused by mild heat injury in a dose-dependent manner. Moreover, the selective activation of the peripheral CB2 receptor demonstrated antiallodynic effects in a rodent model of post-incisional pain. When both the peripheral CB1 and CB2 receptors are activated simultaneously, they have a synergistic effect on preventing pain transmission in the peripheral nervous system.158

CBD demonstrates antioxidant properties, most likely due to the presence of a phenolic ring within its chemical structure. It interrupts and disrupts the chain reactions that lead to the creation of harmful free radicals. In addition, CBD either captures or transforms these radicals into less reactive forms. It also binds to transition metal ions that play a role in the Fenton reaction, preventing the generation of hydroxyl radicals. Additionally, CBD has the potential to influence the levels and activity of other antioxidants.15 Apart from antioxidant properties of cannabinoids, literature describes their lipostatic, anti-inflammatory and anti-proliferative effects. CBD expresses remarkable anti-acne features, which is why it is pursued as a reassuring treatment of acne vulgaris.159

The possibility of topical administration of CBD and its favourable cutaneous biodistribution throughout epidermis and dermis highlights it as a patient-friendly therapeutic formulation to treat multiple dermatological conditions.160 For instance, a variety of in vitro and in vivo studies exposed that cannabinoids may potentially aid in the healing process of postsurgical and chronic wounds.161 The effectiveness of using oil with a high concentration of CBD topically for hair loss and thinning has been assessed through clinical trials. These issues tend to be connected to androgenetic alopecia. ECS receptors that are located in hair follicles play a role in the growth of cells and control the various phases of the hair growth cycle, which include anagen, catagen, and telogen phases. Through interaction with appropriate receptors, CBD has shown potential to elongate the hair shaft. A study conducted by Szabó et al on cultured hair follicle cells found that lower doses of CBD contributed to hair growth, while higher doses resulted in an earlier entry into the catagen phase, which halts hair growth.162

Studies that focus solely on isolated THC and CBD without considering the complete range of cannabinoids and other important substances found in Cannabis may overlook the potential biological advantages offered by whole Cannabis extracts that contain a diverse range of compounds like terpenes, carotenoids, or flavonoids.163 The high concentration of essential fatty acids (EFA) in hemp seed oil is thought to have beneficial effects on conditions such as atopic dermatitis, psoriasis, and especially acne. However, there have been numerous studies that have yielded contradictory findings, suggesting that the effects of EFA depend on the dose and duration of use.164 Both α-linolenic acid and linoleic acid have been shown to decrease the harmful effects of UV radiation and minimize hyperpigmentation.165 Furthermore, hemp seed oil, which is a non-comedogenic dry oil, does not produce a greasy or sticky residue on the skin. As a result, it has been utilized in manufacturing long-lasting moisturizing patches and stable emulsions in sunscreen cosmetics.166,167 The full-spectrum Cannabis extracts contain carotenoids, particularly β-carotene, lutein, and zeaxanthin. These carotenoids have antioxidant and UV-filtering properties because they are highly solubilised in the lipid bilayer membrane. Carotenoids can enhance skin hydration, support skin rejuvenation, and stimulate fibroblasts to produce collagen and elastin.168 Terpenes are unsaturated hydrocarbons that have a volatile nature and constitute the most significant category of organic compounds found in plants. Although more than 200 terpenes have been discovered in Cannabis, there are three monoterpenes (β-myrcene, D-limonene, and α-pinene) and one sesquiterpenoid (β-caryophyllene) that have been identified to exhibit important biological significance. β-myrcene, α-pinene and β-caryophyllene enhance CBD’s anti-inflammatory effects by inhibiting the production of prostaglandin E2 through the COX-2 pathway.163 Apart from their individual effects, these Cannabis-derived terpenoids are believed to influence the effects of cannabinoids through the entourage effect. The term refers to the ability of two or more cannabinoids or non-cannabinoids to have a more potent synergistic effect when used together compared to when used separately.168,169

What are Drug Delivery Systems?

The term “drug delivery systems” (DDSs) refers to a wide range of carriers designed to improve the selectivity of action and the pharmacodynamic and pharmacokinetic properties of the drug. The vast majority of drugs currently in use are low molecular weight compounds. They are distinguished by rapid metabolism and excretion from the human body, as well as low selectivity of pharmacodynamic properties, necessitating the search for formulations capable of overcoming the aforementioned challenges.170 Furthermore, DDSs allow the modification of drug properties by increasing solubility, preventing the drug from being transformed into an inactive form, resulting in a beneficial modification of pharmacokinetics and biodistribution parameters.171 The matrix material used as a carrier for the active substance must meet a number of criteria, including nontoxicity, biocompatibility, non-immunogenicity, and lack of accumulation in the body.170 Furthermore, the size, surface character, drug bonding type, and presence of functional groups on the surface all play important roles in DDSs action.172

Due to the type of connection between the polymer carrier and the active substance, two types of DDSs may be distinguished; namely those obtained by the physical incorporation/absorption of the drug and the systems obtained by conjugation of the drug to the carrier. The concept of the drug-polymer carrier conjugates was proposed by Helmut Ringsdorf in 1975. The Ringsdorf’s model included a framework made of a biocompatible polymer combined with a solubility-modifying group, a labelling element (antibody or another tropic group) ensuring transport to the target site of action, and a drug (Figure 2).173

Figure 2 Scheme of a polymer-drug conjugate structure (the Ringsdorf’s model).172

The type of bonding between the polymer carrier and the drug is a critical parameter for the controlled drug release characteristic, as it determines conjugates’ susceptibility to hydrolytic and enzymatic degradation.174

It is worthwhile to mention the DDSs obtained through physical incorporation/adsorption carriers such as micelles, NPs and liposomes. Polymeric micelles (PMs) (Figure 3) are spherical, colloidal nanosystems that spontaneously form in aqueous solutions when the critical micelle concentration (CMC) of amphiphilic block copolymers is exceeded.175 In PMs, the hydrophilic part of the copolymer faces outwards, while the lipophilic (hydrophobic) part forms the core. Conversely, in reverse micelles, the lipophilic part is directed outwards, while the hydrophilic component faces the core.176

Figure 3 Schematic structure of polymeric micelles (PMs).177

PMs are a promising group of carriers, particularly in the field of oncology. In preclinical studies, PMs demonstrated significant potential as a vehicle for lipophilic drugs and small molecules in cancer treatment, as well as in tumor imaging.178 The physicochemical properties of PMs primarily depend on the type of used polymer together with the sizes of their hydrophilic and lipophilic blocks. In PMs, the drug can be bonded to the core via electrostatic interact