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  • Systematic Review
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28 October 2024

Cannabidiol (CBD): A Systematic Review of Clinical and Preclinical Evidence in the Treatment of Pain

,
and
1
Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, 50830 Zaragoza, Spain
2
Instituto Agroalimentario de Aragón-IA2, CITA-Universidad de Zaragoza, 50009 Zaragoza, Spain
*
Author to whom correspondence should be addressed.
Pharmaceuticals2024, 17(11), 1438;https://doi.org/10.3390/ph17111438
This article belongs to the Section Natural Products
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Abstract

Background/Objectives: Cannabis sativa L. is a plant that has been used for thousands of years for its industrial and medicinal properties. In recent years, there has been a rise in the study of this plant due to its bioactive compounds for pharmaceutical applications. Particularly, cannabidiol has demonstrated analgesic and non-psychoactive properties. The objective of this systematic review is to update and to gather the clinical and preclinical evidence on CBD in pain treatment. Methods: This study was performed following the PRISMA guidelines and using the following search terms “((cannabidiol) NOT (THC)) NOT (tetrahydrocannabinol)) AND (pain treatment)” in PubMed and Web of Science, with the following inclusion criteria: CBD pain treatment without THC in monotherapy, including both clinical and preclinical trials. From the initial sample of more than 500 articles, a total of 40 studies were selected, eliminating duplicate studies from the databases and considering the inclusion and exclusion criteria. On one hand, clinical trials were analyzed using CBD products without THC used in monotherapy, assigning a Jadad score to evaluate the quality/bias of the trials; on the other hand, the main preclinical trials were analyzed, grouping the results into in vivo and in vitro trials. Results: Based on the review conducted, there is sufficient clinical and preclinical evidence of CBD in pain treatment, so CBD could be an effective and safe treatment in reducing pain due to its analgesic and anti-inflammatory properties. These effects appear to be primarily mediated by the activation of TRPV-1, 5HT-1A, and CB1, with emerging therapeutic relevance in the management of osteoarthritis and chronic pain. Conclusions: Although clinical and preclinical research show promising results, clinical evidence is limited, and more studies should be performed in the future with isolated CBD.

1. Introduction

The hemp plant, also known as cannabis or botanically as Cannabis sativa L. (Cannabaceae), is a plant species with a historical use for thousands of years both for textile applications but also as a medicinal or food ingredient. It appears that its medicinal use dates to 2800 BC, when it was included in the Chinese Emperor Shen Nung Pharmacopoeia. In addition, the therapeutic properties of this species have been described in Hindu, Assyrian, Greek, and Roman texts, with clear indications for treating pain, inflammation, or lack of appetite.
Although cannabis is considered a monospecies (Cannabis sativa L.), there are different subspecies and varieties. The main varieties of cannabis are Cannabis sativa f. chinensis originating in China, Cannabis sativa var. indica originating in India, and Cannabis sativa var. ruderalis originating in Russia [1,2].
Cannabis sativa L. is an annual dioecious plant in which female and male flowers are found in separate organisms. It has a strong pivoting root (30/60 cm–2.5 m deep) and erect stems, which are usually angular, furrowed, and branched (opposite or alternative) with woody interior, varying from 1 to 6 m in height. The leaves are green and palmate (seven lobes) but the inflorescences consist of numerous flower heads that can be found on the long, leafy stems of each leaf armpit. The stamina (male flower) consists of five pale green hairy sepals about 2.5 to 4 mm long and five hanging stamens, with thin filaments and stamens. The pistillate (female flowers) are almost sessile and exist in pairs [3].
From a phytochemical point of view, the main compounds of pharmaceutical interest are cannabinoids, secondary metabolites with a unique structure that come from different biosynthetic pathways and therefore are usually referred to as terpenphenols due to the phenolic skeleton with isoprene units. In addition, we can find non-cannabinoid monoterpenes, sesquiterpenes, phenolic compounds of flavonoid type, and traces of alkaloids, fatty acids, and sterols. Terpenes are bioactive compounds whose main function is to favor the survival of the plant, the protection of predators, or the attraction to pollination, with 10 to 15 carbon atoms being the most abundant in Cannabis. The most abundant monoterpene is β-myrcene, which is an anti-inflammatory that acts by the E-2 prostaglandin pathway. The β-caryophyllene is the most common sesquiterpene in cannabis and it acts synergistically with some cannabinoids, producing antipruritic and anti-inflammatory effects. Among flavonoids, cannavaflavin A has also been positioned as an anti-inflammatory [4].
Within cannabinoids, tetrahydrocannabinol (THC) is the most common and characteristic chemical compound of the plant, together with CBD. It acts by receptor-dependent mechanisms CB1 (greater affinity than CB2) and CB2, which modulate pain, spasticity, sedation, appetite, and mood, in addition to being a bronchodilator, neuroprotector, antioxidant, and anti-inflammatory. It is considered the most important psychoactive component of the plant [4].
Cannabidiol (CBD) (Figure 1) is the other cannabinoid that is found in the highest proportion with THC. CBD has a lower affinity for CB1 receptors compared to other cannabinoids like THC, and the literature indicates that CBD can still engage with CB1 receptors through allosteric modulation (Figure 2). CBD acts significantly through independent mechanisms with CB1 and CB2 receptors and has the unique ability to antagonize the CB1 receptor at low concentrations when THC is present [5,6,7,8,9]. CBD has a wide pharmacological activity from anticonvulsant, anti-inflammatory, and antioxidant to antipsychotic effects. In addition, it has the quality of decreasing some of the adverse effects of THC such as anxiety, hunger, tachycardias, and sedation. As for its mechanism of action, it seems to work through binding to different receptors coupled to protein G (modulation of CB1, CB2, 5HT1a, µ and δ opioid receptors), ionotropic receptors (TRPA1, TRPV1, TRPV2, TRPV4, 5HT3a, GABAA), enzymes (FAAH, LOX), nuclear factors (PPARγ), and transporters (FABP1, FABP3, FABP5, FABP7). CBD interacts with various GPCRs, specifically the µ-opioid receptor (MOR) and δ-opioid receptor (DOR). It exhibits binding affinities with inhibition constants (Ki) of 7000 nM for MOR and 10,000 nM for DOR. In contrast, CBD has a significantly higher affinity for dopamine D2 receptors, with a Ki of 11 nM, indicating functional high-affinity interactions with dopamine [4,10,11].
Figure 1. Chemical structure of CBD.
Figure 2. Mechanisms of action through which CBD exerts its effects at the pharmacological level.
Naturally occurring cannabinoids allowed the discovery of the endocannabinoid system, consisting of endogenous cannabinoids, enzymes, and receptors; endocannabinoids are lipid mediators that bind to CB receptors. One of them is anandamide (AEA), which acts on the CB1, CB2, and TRPV1 receptors. It is mostly distributed in the brain and is part of sleep regulation, relaxation, feeding, neuroprotection, and immunomodulation. On the other hand, 2-arachidonoyl glycerol (2-AG) acts on presynaptic CB1 receptors to inhibit the release of neurotransmitters. AEA is degraded by fatty acid amide hydrolase (FAAH), and 2-AG by monoacylglycerol lipase (MAGL). The CB receptors are the CB1 receptor, found in the brain and the central nervous system, and the CB2 receptor, which is located in the cells of the immune system and in peripheral organs regulating other types of processes [4,10].
Besides the pharmacodynamic parameters, bioavailability is an important parameter of a drug’s understanding. As a part of pharmacokinetics, is essential to know the relation between the blood concentration and time. In this way, it is necessary to identify what route of administration is the most appropriate for CBD depending on the drug formulation. Oral administration has been the main route used in the majority of clinical trials, while the intraperitoneal route is the most indicated in preclinical trials for CBD administration [12,13,14,15]. Epidiolex® is one of the CBD-containing drugs commercialized as an oral formulation. Several studies suggest that Cmax and Tmax depend on the dose [16,17]. However, other sources of oral CBD manifest a greater range in blood levels [18]. But bioavailability is not only essential to understanding the pharmacokinetics, but drug interactions are also important to comprehend, as medical CBD users are polypharmacy patients. Moreover, CBD is metabolized via the cytochrome P450 enzyme pathway, and it could modulate the immune system and increase the risk of viral infections and pneumonia and reduce blood pressure in patients treated with antihypertensives [19,20].
The main objective here in this work is to analyze preclinical and clinical evidence on CBD in monotherapy for pain treatment through a review following the PRISMA guidelines [21]. The secondary objectives are as follows:
  • Analyze the safety of treatments in the clinical trials studied.
  • Elucidate the mechanism by which CBD interacts to produce therapeutic effects through preclinical trials.
  • Determine possible disease treatments based on their analgesic properties.

2. Results

Figure 3 shows the initial result after the search was 570 articles that a priori could be used for this systematic review, considering the two consulted databases. After a first screening and eliminating duplications, 402 articles were located. After deleting all the articles obtained with the search due to the noise of using the terms “(((cannabidiol) NOT (THC)) NOT (tetrahydrocannabinol)) AND (pain treatment)”, or those that did not use only CBD, such as studies with medicinal cannabis or drugs such as Sativex or nabiximol (extract with which Sativex is obtained) that are composed of CBD and THC, finally, a sample of 97 was selected from both databases; of these, 40 were used for the review due to the impossibility of finding the full article, and by deleting articles that seemed to fall within the criteria, but in which CBD was used in the treatment in combination therapy with other drugs.
Figure 3. Flowchart depicting the study selection process following PRISMA guidelines.
The main reason for utilizing these criteria was to assess the presence of studies examining the efficacy of CBD in alleviating pain symptoms. Therefore, the importance of studies focusing on isolated CBD was vital, as they support the determination of whether CBD alone produces analgesic effects or if the therapeutic benefits stem from a combination of active ingredients. The final sample obtained was 40 articles, which were distributed as follows: 11 human clinical trials, 2 dog clinical trials [22,23,24,25,26,27,28,29,30,31,32,33,34], and 27 preclinical articles.
The final sample yielded three tables. Table 1 and Table 2 include details of the human and dog clinical trials, specifying the CBD treatment used, the number of participants, randomization status, and masking presence. These parameters were utilized to assign a Jadad score, aiding in evaluating the trial’s robustness and providing a comparative tool. Table 3 shows the treatments employed and the main conclusions of these preclinical trials.
Table 1. List of human clinical trials of CBD in pain management with Jadad score assignment.
Table 2. List of animal clinical trials of CBD in pain management with Jadad score assignment.
Table 3. Preclinical trials of CBD in pain models with experimental animals.

3. Discussion

As previously mentioned, CBD can be administered intraperitoneally, intravenously, orally (oil, tablets), and topically (cream, oil, emulsion, gel). Depending on the type of administration (route and method), pharmacokinetic processes may be altered, meaning they can be faster or slower and may be magnified or not. There are five main components of pharmacokinetics: liberation, absorption, distribution, metabolism, and excretion (LADME). In veterinary and human practice, CBD is generally administered orally. A unique clinical trial performed in dogs estimated the oral bioavailability of CBD raw material capsules, finding it to be 19% lower compared to other forms without release. This low bioavailability is a crucial factor in determining and establishing an appropriate pharmaceutical dosage not only in animals but also in humans [61,62,63].
Inhalation is one of the fastest routes of administration for reaching plasma concentrations, thanks to the rapid gas exchange that occurs in the alveoli. Indeed, several studies concentrations confirm that CBD are reached promptly (3–10 min) and the inhaled bioavailability and the volumes of distribution (Vd) are higher than oral administration 31% and 10–15%, respectively [14,15,64,65,66]. In vitro studies with human skin have shown that the permeability of CBD is ten times higher than that of delta-9-THC and delta-8-THC, which explains the wide use of CBD-based products topically for pain treatment [67].
The metabolism of CBD is mainly carried out by different hepatic oxidase isoenzymes such as CYP2C19, CYP3A4, CYP1A1, and CYP2D6. Then, phase II conjugating pathways facilitate the elimination of the new metabolites by urinary excretion [13,66]. CBD exhibits a prolonged terminal elimination half-life, with the shortest observed following intravenous administration, followed by inhalation, while the longest elimination half-life occurs with oral administration [12,64]. American researchers concluded that selecting the appropriate CBD formulation is crucial, as pharmacokinetic profiles can vary significantly depending on whether it is administered sublingually, orally, or through smoking. This factor is considered even more critical than using pharmaceutical-grade CBD, provided the drug meets FDA standards for treating pain [68].
Out of the 11 clinical trials, 7 of them obtained results indicating that CBD treatment has pain-reducing properties [22,24,28,29,30,32,34] in osteoarthritis-related pain, chronic or neuropathic pain, bruxism, arthritis, and atopic dermatitis. In the latter four trials, the result was not achieved as expected, and the study conducted by Australian researchers did not exert significant differences respect to placebo [25]. Meanwhile, the administration of 150 mg of CBD oil every 24h in two doses did not deliver pain relief due to the performance of physical exercise in people unaware to training in Chicago (United States) [26]. A lower dose (50 mg of cannabidiol) was selected in another pharmaceutical form, such as chewing gum in a placebo-controlled intervention, but pain was not potentially reduced in patients with irritable bowel syndrome [31]. The article by Bebee et al. [25], despite having a high robustness and displaying no differences from placebo, cannot be used as evidence to rule out the analgesic/pain-reducing properties of CBD, as the study focuses on acute treatment for lower back pain in the emergency room, in which high-potency analgesics or opioids are used, so it is usual to observe no significant differences compared to a placebo. Thus, the absence of such variations does not necessarily imply a lack of analgesic properties. In addition, 83 patients with arthroscopic rotator cuff repair (ARCR) were treated with two different doses of CBD (25 and 50 mg) three times/day for 14 days. In this case, patients did not show significant deficits in pain, satisfaction or in patient-reported outcomes one year after surgery compared to a placebo group [33].
Otherwise, the two clinical trials conducted in dogs demonstrated great results in the treatment of osteoarthritis [23,27]. Both CBD oil doses (2 mg/kg) in capsules (20 mg/day) and unencapsulated (50 mg/day) showed positive results in dogs, even demonstrating anti-inflammatory effects [27] and improving the comfort of the animals. The latter was measured using the Canine Brief Pain Inventory (CBPI) and the Hudson Visual Analog Scale (HVAS) to assess the response to treatment compared to a placebo [23].
Nonetheless, there are five other clinical trials with great robustness that obtained results that support these analgesic properties [24,28,29,30,34]. According to the quality of the studies assessed by the Jadad scale, there are eight clinical trials with the maximum score of 5 points. Most of these works are relatively new and recent, since they have been carried out from 2020 to the present. Of all of them, up to five studies observe positive effects and one of them does not have superiority to placebo, and in many cases the topical route is an effective way for the application of CBD.
The work of Gamble [23] and that of Verrico [27] obtained scores of 4 and 5 points on the scale, respectively. With the first obtaining positive effects in pet animals treated with CBD orally and the second beneficial effects in treated humans with topical CBD. This scale allows us to observe that the majority of studies with a high Jadad score (≥4 points) conclude beneficial effects for CBD as an analgesic substance in certain pathological conditions related to pain. These properties are supported by all the results obtained in preclinical trials, and the pathways by which CBD acts in the body can be elucidated. It appears that the analgesic and anti-inflammatory properties are mediated through the activity on microglia [40,69], the decrease in pro-inflammatory cytokines associated with T cells, modulating their migration rate [53], the activation of TRPV-1 receptors [10,44,45,47,48,59], and the interaction with CB receptors. The decrease in neuropathic pain and part of its anxiolytic properties could be due to the activation of 5HT-1A receptors [10,36,44,45,49,60,70]. Due to their properties and mechanism of action, they could be a potential treatment for osteoarthritis, acute inflammatory eruptions, chronic pain and neuropathic pain, and other autoimmune diseases not only due to the properties mentioned above, but also due to its great safety, since no clinical or preclinical trials reported significant side effects nor treatment rejections. As for the pharmacokinetics, more studies would be needed to know which pharmaceutical form is more suitable for administration according to the pathology, either orally transported, or with no pharmaceutical form, or via the topical route. As such, they would make it clear that CBD is absorbed, distributed, and eliminated [23,27,46].

4. Materials and Methods

4.1. Search Strategy and Data Resources

To carry out this work, a systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [21]. The data sources used in the review process were PubMed and Web of Science; the aim of the search was to find and analyze all the articles that were preclinical and clinical studies on CBD isolated or as a major component of cannabis without the presence of THC for the treatment of pain. The following terms were used for the search in both databases: “((cannabidiol) NOT (THC)) NOT (tetrahydrocannabinol)) AND (pain treatment)”. Terms such as CBD were not used, as it only caused noise in the search by adding articles dealing with common bile duct by sharing the same acronyms. In addition, in Web of Science we had to put an additional filter “(NOT (Sativex) NOT (nabiximol))”, eliminating articles dealing with Sativex and nabiximol, which despite being a CBD-based drug also contains THC. In PubMed, it was not necessary to apply the filter, since these terms were not included in the initial search, and adding those filters generated noise, resulting in a less specific search. This study was not registered in PROSPERO

4.2. Eligibility Criteria

The search was not limited by the year of publication, due to the limited number of preclinical and clinical studies performed only with CBD as the major component. So, all articles that assembled the inclusion and exclusion criteria were included until June of 2024. For this purpose, the following inclusion and exclusion criteria were used; the inclusion criteria were: clinical and preclinical trial articles (in vitro and in vivo) which were treated with CBD alone or as a major component of cannabis, in any pharmaceutical form and free of THC. The exclusion criteria included the presence of other cannabis components such as THC, systematic reviews, narrative reviews, meta-analyses, clinical cases, and articles not in English and/or Spanish. In addition to articles with impossibility of acquiring them in full text, the quality of the clinical trials was analyzed using the Jadad scale, which consists of an instrument to measure the risk of bias, particularly in pain research; each item of the scale is given a score of 1 or 0 points for each yes or no answer [71].

4.3. Selection Procedure

Two independent researchers (M.Y. and G.C.) performed the literature research and V.L. conducted supervision by including studies published until June 2024. Records were organized using Mendeley Reference Manager. Full texts were assessed using predetermined selection criteria

5. Conclusions

Based on the review carried out, there is clinical and preclinical evidence of CBD in the treatment of pain, so CBD is an effective and safe treatment in reducing pain due to its analgesic and anti-inflammatory properties. These effects seem to be mediated mainly by the activation of TRPV-1, 5HT-1A, and the allosteric modulation of CB1, showing great therapeutic promise in the management of osteoarthritis and chronic pain.
It would be interesting to increase the number of CBD studies, especially with a larger patient cohort. Many studies have been conducted using hemp extracts containing CBD, THC, and other cannabinoids, but it is particularly important and decisive to use products that are perfectly characterized in terms of the CBD proportion defining the absence or their psychoactive compounds. Based on the regulatory European market, CBD is orally approved as antiepileptic agent (Epidiolex®); nevertheless, there is room for improvement if new clinical trials are performed with CBD alone as an analgesic agent in different pain conditions.re

Author Contributions

Conceptualization, V.L.; methodology, G.C., M.d.Y.-S. and V.L.; formal analysis, G.C. and M.d.Y.-S.; writing—original draft preparation, G.C. and M.d.Y.-S.; writing—review and editing, V.L.; supervision, V.L.; project administration, V.L.; funding acquisition, V.L. All authors have read and agreed to the published version of the manuscript.

Funding

We acknowledge Universidad San Jorge (Proyecto Interno 2324026) and Gobierno de Aragón for financial support of the Phyto-Pharm research group (B44_23R).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Data is contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Bioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines
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