Cannabinoid Therapies in Less-Common Disorders: Clinical Evidence and Formulation Strategies

Abstract

Background/Objectives: Cannabinoids are increasingly recognised for their therapeutic potential beyond well-established indications such as chronic pain, multiple sclerosis, and specific epileptic syndromes. Recent advances have highlighted their possible role in less-common or orphan diseases, opening new avenues for pharmaceutical research and clinical application.

Methods: This review provides a critical synthesis of the most recent evidence (2020–2025), available in PubMed and Scopus, regarding the use of cannabinoids in conditions including refractory epilepsies beyond Dravet and Lennox–Gastaut syndromes, movement disorders such as dystonia and Tourette syndrome, rare dermatological diseases like epidermolysis bullosa, and emerging data in Crohn’s disease.

Results: Negative outcomes, such as those reported in Fragile X syndrome trials, are also discussed as instructive examples of methodological and pharmacological challenges. Particular attention is given to the optimisation of pharmaceutical formulations and advanced separation technologies, including oromucosal sprays, transdermal gels, and novel nanocarrier systems, which aim to overcome issues of bioavailability and variability in patient response. Finally, safety concerns, regulatory aspects, and the need for robust clinical trials are addressed.

Conclusions: Overall, cannabinoids represent a promising yet underexplored therapeutic option in rare and complex disorders, warranting further investigation supported by innovative pharmaceutical approaches.

Introduction

Cannabinoids have gained increasing recognition as therapeutic agents over the past two decades, driven by advances in pharmacology, regulatory changes, and a growing body of clinical evidence supporting their medical use [1,2]. While cannabis-derived products have historically been associated with recreational consumption, contemporary research has progressively repositioned cannabinoids as pharmacologically relevant compounds with well-defined mechanisms of action mediated primarily through the endocannabinoid system [3,4]. This system plays a central role in the modulation of pain perception, neuroinflammation, immune responses, motor control, and gastrointestinal function, providing a strong biological rationale for therapeutic intervention across a range of clinical conditions [1,5].

At present, the medical use of cannabinoids is largely confined to a limited number of well-established indications. For example, in Portugal, medicinal cannabis is authorised by the National Authority of Medicines and Health Products (Infarmed) for specific conditions, including chronic pain associated with oncological or neurological disease, spasticity related to multiple sclerosis or spinal cord injury, chemotherapy-induced nausea and vomiting, appetite stimulation in palliative care, treatment-resistant glaucoma, Tourette syndrome, and severe childhood epilepsies such as Dravet and Lennox–Gastaut syndromes [6]. These approved indications reflect areas in which clinical efficacy has been demonstrated with sufficient consistency to justify regulatory acceptance, particularly through standardised cannabis-based preparations and purified cannabidiol formulations [2,7]. Nevertheless, they also highlight the relatively narrow therapeutic scope within which cannabinoids are currently prescribed, despite their broad pharmacodynamic profile and multisystem effects [7,8]. In parallel with these approved uses, there has been a marked expansion of experimental and off-label investigations exploring cannabinoid-based therapies in less-common, rare, or complex disorders [9,10]. Many of these conditions are characterised by chronic symptom burden, limited treatment options, and substantial impact on quality of life, often meeting criteria for orphan disease designation [10]. In such contexts, conventional pharmacological strategies frequently provide inadequate symptom control or are associated with significant adverse effects, creating a pressing need for alternative or adjunctive therapeutic approaches. Cannabinoids, particularly non-psychoactive compounds such as cannabidiol (CBD), have emerged as promising candidates due to their multimodal mechanisms, favourable tolerability profiles, and potential to modulate neuroinflammatory, neuromodulatory, and immune pathways [1,5].

Despite growing clinical interest, the translation of cannabinoid research into routine clinical practice for rare or less-common disorders remains challenging [10]. Evidence is often fragmented, derived from small clinical trials, observational studies, or heterogeneous patient populations, and outcomes are frequently variable [11]. In addition, cannabinoids present well-recognised pharmaceutical challenges related to poor aqueous solubility, variable bioavailability, extensive first-pass metabolism, and marked inter-individual pharmacokinetic variability [12]. These limitations have prompted the development of innovative formulation strategies, including oromucosal sprays, transdermal systems, and nanocarrier-based delivery platforms, aimed at improving absorption, reducing variability, and enhancing therapeutic consistency. The optimisation of formulation and route of administration is therefore a critical determinant of clinical success, particularly in vulnerable populations and rare disease settings [12].

Safety considerations and regulatory frameworks further complicate the clinical adoption of cannabinoid-based therapies. Although cannabinoids are generally well tolerated, their interaction with cytochrome P450 enzymes, potential for drug–drug interactions, and context-dependent adverse effects necessitate careful clinical monitoring [12,13]. Moreover, regulatory acceptance varies substantially between jurisdictions, reflecting differences in risk–benefit assessment, evidentiary standards, and historical perceptions of cannabis-derived products [1,8]. These factors underscore the importance of critically appraising both positive and negative clinical outcomes, as well as identifying methodological limitations and unmet research needs.

Against this background, the present review aims to provide a comprehensive and critical synthesis of the most recent clinical evidence published between 2020 and 2025 regarding the use of cannabinoids in less-common and emerging clinical indications. Particular emphasis is placed on disorders that fall outside currently approved therapeutic uses, including rare neurological, dermatological, gastrointestinal, psychiatric, and sleep-related conditions. In addition, this review examines contemporary formulation strategies designed to overcome pharmacokinetic limitations, discusses safety and regulatory considerations, and highlights key gaps in current knowledge. By integrating clinical evidence with pharmaceutical and regulatory perspectives, this article seeks to clarify the realistic therapeutic potential of cannabinoids in rare and complex disorders and to inform future research and clinical decision-making. In this review, terminology reflects the nomenclature used in the original studies. “Medicinal cannabis” generally refers to whole-plant preparations or extracts, “phytocannabinoids” to plant-derived compounds such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and “cannabinoid therapies” as an umbrella term encompassing plant-derived, synthetic, or purified cannabinoid-based interventions. Where possible, the specific compound or formulation evaluated in each study is explicitly indicated.

4. Formulation Strategies, Safety Considerations and Regulatory Aspects

4.1. Why Formulation Matters in Rare Disorders

Cannabinoids have received increasing attention for their therapeutic potential, although their pharmacokinetics are not fully understood [141]. Regardless of the route, once absorbed, cannabinoids are rapidly distributed systemically [142]. However, only 5% of CBD and THC do not bind to plasma proteins and are therefore responsible for the pharmacological effect [143]. Thus, one of the biggest determinants of the bioavailability of these compounds is related to the form of administration and, above all, to the formulation [142].

Cannabinoids have the ability to inhibit cytochrome P450 enzymes, namely CYP2C9 and CYP34A, which is why potential drug interactions may occur [142]. In fact, inhibiting these enzymes can alter the concentration of drugs in the plasma, leading to an increase in their concentration, which may result in toxicity or more adverse effects [144]. Additionally, given the inhibition of cytochrome P450 enzymes, the combined administration of THC and CBD may result in significant changes in the metabolism of these compounds [12].

The effects of cannabinoids are highly influenced by inter-individual variability, since factors such as genetics, physiology, and environment can affect therapy with these compounds. According to Wright et al. [145], there is a wide spectrum of potential changes in THC and CBD metabolism that contributes to pronounced interindividual variability in response. The results suggest that individuals classified as slow, normal, and ultra-rapid metabolizers for CYP2C9 and CYP34A may exhibit substantial differences in how they process THC and CBD, which could lead to divergent therapeutic outcomes. At the same time, changes in liver function or transporter activity can affect the pharmacokinetics of cannabinoids, influencing both efficacy and tolerability and further increasing interindividual variability [146]. One of the administration routes most influenced by interindividual variability is the oromucosal route. Factors such as differences in saliva production, absorption by the oral mucosa, and swallowing patterns significantly affect the absorption of cannabinoids, thus influencing therapeutic outcomes [147].

A study developed by Reddy et al. [148], demonstrated that pharmacokinetics can be improved by altering the formulations and their excipients. Strategies to improve the pharmacokinetics of cannabinoids focus on overcoming limitations such as low water solubility, first-pass metabolism and variability in absorption [148]. To overcome these limitations, approaches such as the use of lipid-based formulations or emulsions, which increase solubility and facilitate intestinal absorption, are important. Another approach worth mentioning is encapsulation in micro or nanoemulsions and lipid capsules, which protect the molecule and improve systemic delivery. Thus, to avoid first-pass metabolism, the use of transdermal and intranasal routes may constitute a viable alternative [149].

Another important factor for the effectiveness of cannabinoid treatments is patient adherence. Like all medications, both CBD and THC are associated with adverse effects, which can compromise adherence to and compliance with treatment. According to Pomey et al. [150], patients discontinue cannabinoid-based therapies mainly due to limited efficacy and adverse effects. In the case of rare diseases, the very heterogeneity of patients creates a significant obstacle. Furthermore, the small number of people affected makes the process even more challenging [151]. Similarly, the use of orphan drugs is also significant in the treatment of rare diseases. The choice and development of the formulation of these medications are fundamental to ensuring effective and appropriate results in the different profiles of patients with rare diseases [152].

4.2. Relevant Pharmaceutical Approaches

4.2.1. Oromucosal Sprays

Historically, oral administration of medication was the most common and accepted approach, due to its convenience and non-invasive nature. Initially intended for local effects, sublingual and buccal administration began to be used for systemic administration. This last one allows for faster action and better patient adherence, being considered a good alternative to intravenous administration [153]. The oral cavity is the first part of the gastrointestinal tract, extending from the mouth to the beginning of the pharynx, and is made up of the buccal, sublingual, gingival, palatine and labial mucosa [154]. The oral mucosa is characterised by being composed of non-keratinised tissue, which makes it more permeable and elastic [155]. Another important characteristic of this epithelium is that, although rigid, small molecules can pass through it, potentially avoiding first-pass metabolism. However, it is important to note that drug absorption may be limited due to the small contact area and the processes of swallowing and saliva production [155]. Therefore, for medications to be absorbed through the oral mucosa, they must first be dissolved in saliva, the volume of which is significantly lower in the mouth. On the other hand, high saliva concentration can lead to premature swallowing, resulting in inadequate drug release [154].

The drug must then diffuse through the mucosa itself, which is determined by lipophilicity and the degree of ionisation. To diffuse through the mucosa, drugs can permeate via both transcellular and paracellular pathways. Most lipophilic molecules diffuse via the transcellular pathway, while hydrophilic molecules permeate via the paracellular pathway [155]. In order to overcome these limitations, alternative administration methods have been developed, primarily through mucoadhesion and the use of mucoadhesive polymers.

Another strategy that has become very relevant is the use of medications with rapid disintegration of the drug and consequent almost immediate release, as is the case with sprays [154]. Oromucosal sprays are liquid formulations applied directly to the oral mucosa, allowing medications to be absorbed by the oral epithelium for local and systemic effects. Compared to conventional oral administration, they offer greater bioavailability, avoiding first-pass metabolism, and providing a faster onset of action due to direct systemic absorption. The main advantage is greater convenience for patients, especially those with swallowing difficulties, such as children, the elderly and uncooperative patients, as is the case with some patients with rare diseases [154,156].

Nabiximols are botanical preparations containing balanced amounts of THC and CBD and have been used as an oromucosal spray (Sativex®) for patients with multiple sclerosis with moderate to severe spasticity [157]. Studies have shown that nabiximols has significant efficacy in treating the symptoms of multiple sclerosis, showing that this is a consistent therapy, even as monotherapy [157]. Nabiximols have also been used in the treatment of Tourette syndrome [158]. Müller-Vahl et al. [158] carried out a study with nabiximols, where they found a greater number of responders compared to the placebo group. However, the difference was not statistically significant. Secondary analyses indicated that patients with Attention Deficit Hyperactivity Disorder (ADHD) showed a decrease in severe tics. Thus, the study showed that nabiximols may be a good approach to reduce tics in Tourette syndrome [158].

4.2.2. Transdermal/Topical: Gels and Patches

The skin is the largest organ in the body, composed of five layers, including an outer layer, the stratum corneum, which acts as a barrier against hydrophilic substances and large molecules [159]. Transdermal drug delivery systems (TDDS) and topical formulations are a promising non-invasive method for delivering active drugs across the skin barrier [160]. Typically, topical drug administration refers to the treatment of a localised area of skin, while TDDS refers to the administration of drugs through the skin and into the systemic circulation [161]. TDDS tablets are composed of several layers that facilitate the absorption of the medication. The support layer acts as an external protective barrier, shielding the system from the external environment. Next, the adhesive layer attaches the patch to the skin using a hypoallergenic adhesive that is gentle on the skin. At the core, the drug reservoir contains the active pharmaceutical ingredient, which is released at a constant rate through a membrane [159]. On the other hand, gels are systems formed by a polymer and a solvent, arranged in a three-dimensional structure in a cross-linked polymer network and have different drug delivery systems [162].

Drug penetration through the skin requires passage through both the stratum corneum and the skin’s cellular matrix. Drug penetration into the skin occurs through transcellular permeation and intercellular absorption. Transcellular permeation involves the direct absorption of drugs through individual skin cells, while intercellular absorption occurs within the extracellular matrix through the interstitial spaces between neighbouring cells. Another way drugs are absorbed through the skin is through skin appendages, such as hair follicles and sebaceous glands [161].

When developing effective drug delivery systems, several variables must be considered, namely, active pharmaceutical ingredients and skin morphology [161]. Most active pharmaceutical ingredients do not inherently meet the criteria for effective transdermal administration, so it is important to develop new strategies to improve their absorption [160]. Thus, organogels have been used in transdermal delivery systems to improve the transdermal administration of hydrophilic and hydrophobic drugs that present lipophilicity problems [159]. In recent years, several nanocarrier formulations have also been developed to improve transdermal drug delivery, including liposomes and polymeric micelles [163].

Cannabinoids are known for their medicinal properties, especially as anti-inflammatories. Its topical application as anti-inflammatory compounds has been at the forefront of research in the last decade, also receiving increasing attention in the cosmetics field, as it can help alleviate skin problems due to its topical anti-inflammatory effect [163]. However, unlike transdermal delivery systems, such as cannabinoid patches, this route does not involve systemic absorption [164]. Thus, transdermal delivery systems have gained great relevance not only because of the possibility of systemic absorption, but also because they help to bypass first-pass metabolism, increasing user adherence [165]. Studies have shown that emerging transdermal systems, such as transdermal patches, can significantly increase CBD absorption and therefore help in the treatment of skin conditions such as dermatitis and even epidermolysis bullosa, due to their anti-inflammatory action [166]. An experimental topical cream, INM-755, was tested for the treatment of epidermolysis bullosa [167]. In phase II studies, this topical formulation demonstrated good tolerability and safety, without negatively interfering with the healing process. Therefore, the absence of serious adverse effects on such fragile skin and the good acceptance by participants indicate that this type of formulation is suitable for repeated cutaneous application [167]. Another study with the transdermal gel ZYN2-CL-017, which contains CBD, investigated long-term efficacy and safety in populations with fragile X syndrome [128]. The main results of the study show a favourable safety profile and revealed clinically significant improvements [128]. Furthermore, these studies support the idea that transdermal formulations can be effective vehicles for the local and systemic administration of cannabinoids in rare diseases.

Despite some promising results, these systems still have inherent limitations, such as skin permeability, which can be overcome with permeability enhancers like ethanol and oleic acid. Furthermore, a preclinical study with guinea pigs demonstrated that the addition of transcutol HP, a permeation enhancer, increased plasma CBD concentration by 3.7 times when added to a topical CBD gel [168].
Physical permeation enhancers, such as microneedles, can solve the problem of cannabinoid permeation, but studies in this area are still few [164].

4.2.3. Nanocarriers

As previously described, cannabinoids have lower solubility and are easily subjected to oxidation and degradation reactions due to the action of light and temperature. These limitations make them interesting candidates for nanotechnology-based formulations [169]. The technology of encapsulating cannabinoids in nanocarriers has become a good bet to protect the compounds from degradation, increasing their stability [148]. In this regard, both lipid-based carriers and polymeric carriers have been investigated regarding their mode of action.

Polymeric nanocarriers can be produced in capsules and spherical shapes, allowing for better release, while lipid nanocarriers have been shown to favour targeted delivery [170]. Among lipid-based nanocarriers, nanoemulsions showed increased CBD absorption, demonstrating that bioavailability can increase up to 1.65 times, significantly reducing the time to reach peak plasma concentration. However, due to high production costs and instability, Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) emerged, which consist of self-emulsifying systems that spontaneously form nanoemulsions in the gastrointestinal tract [171]. Evidence shows that these not only increase the solubility and stability of cannabinoids, but also their bioavailability. However, most studies consist of small clinical trials, so larger clinical trials are still needed [148]. Additionally, despite being a promising alternative, SNEDDS do not avoid the first-pass mechanism [171].

Liposomes, on the other hand, are spherical vesicles made up of phospholipids and cholesterol, in which one or more layers of phospholipids surround an aqueous core. Although these systems are widely studied, they have low encapsulation efficiency for cannabinoids. Even so, studies in dogs with osteoarthritis showed CBD bioavailability 17 times greater than that of free CBD, demonstrating that encapsulation increases CBD activity, even at reduced doses [169]. On the other hand, there are also polymeric micelles, which consist of amphipathic nanoparticles with a hydrophobic core and a hydrophilic layer, used as reservoirs for lipophilic drugs, such as cannabinoids. Studies have shown that polymeric nanoparticles allow for greater bioavailability. Studies with Polylactic-co-Glycolic Acid (PLGA) nanoparticles loaded with CBD showed rapid initial release and high encapsulation efficiency [171]. Villate et al. [172] developed a study with PLGA nanocapsules loaded with full-spectrum cannabis extract, demonstrating that these formulations protect cannabinoids from gastric degradation and allow their controlled release in the intestine, increasing the local concentration of cannabinoids. Thus, the study demonstrated that, with biocompatible polymers, nanotechnology can be promising in the treatment of gastrointestinal diseases [172]. However, most clinical evidence remains in vitro or in vivo models, so clinical validation is still limited [171].

4.3. Safety Profile Across Rare Conditions

Recreational use of cannabinoids is associated with very worrying side effects, namely psychosis, schizophrenia and cannabis use disorder, especially in adolescents [173]. The adverse effects associated with the use of cannabinoids for medicinal purposes are linked to an increased risk of short-term side effects but are rarely associated with serious effects. In fact, products containing medicinal THC are often associated with changes in perception and thinking, as well as dizziness and sedation, particularly in the elderly. However, CBD does not cause intoxication and presents fewer safety concerns than THC. Still, potential side effects, such as liver toxicity and drug interactions, as well as inadequate regulatory oversight of CBD products, may constitute legitimate concerns [5].

The main adverse effects of prolonged use of cannabinoids include gastrointestinal side effects, namely vomiting, cardiovascular effects such as tachycardia and orthostatic hypotension, and, mainly at the psychiatric level, an increased risk of depression and suicidal ideation [142]. Furthermore, CBD has been reported to cause liver abnormalities, diarrhoea, fatigue and drowsiness in some individuals [141]. Another problem that has been reported is the potential for interaction with other medications. According to a recent study developed by Nachnani et al. [174], cannabinoids can significantly alter the action of many medications, especially those with a narrow therapeutic index. The study reports that cannabinoids interact with warfarin, increasing its clotting time [174]. Other medications, such as tricyclic antidepressants and anticonvulsants like valproate, have also shown significant interactions with CBD [174]. Another study showed that CBD is the main culprit behind interactions with other medications. CBD primarily inhibits CYP2C19, CYP2C9, CYP3A and CYP1A2; therefore, interactions occur mainly during first-pass metabolism [175]. These results indicate that CBD increases exposure to the drug by inhibiting its initial clearance [175]. In fact, the medications with the highest risk of interaction with CBD are those that are metabolised by the enzymes mentioned above. Thus, antidepressants, opioids, benzodiazepines, antihypertensives and anticonvulsants have significant interactions because they are extensively metabolised by cytochrome P450 family enzymes [176]. Epidiolex® is approved for refractory epilepsies, including rare diseases such as Dravet and Lennox–Gastaut [177]. Despite its favourable safety profile, it can cause pharmacokinetic changes and interactions with other anticonvulsants. Concomitant administration with clobazam increases levels of its metabolite, increasing the risk of sedation [177]. Changes in liver enzyme levels can also occur with valproate. Minor interactions were observed with topiramate and levetiracetam; therefore, dose adjustments may be necessary [177].

Another legitimate concern when using medicinal cannabis is its administration to children. In fact, most studies on cannabinoids are conducted in adult animal models; therefore, research on long-term adverse effects in children and adolescents is still limited. As a result, there is some uncertainty about how cannabinoids affect a developing brain [178]. Children are very vulnerable to cannabinoid treatments because their pharmacokinetics vary greatly due to the immaturity of their physiological system. Consequently, oral absorption is less effective, and distribution is affected by the low percentage of fat. Metabolism is also affected by liver enzymes, which are still developing. Therefore, children are equally susceptible to drug interactions. In the specific case of concomitant use with antiepileptic drugs, it should be noted, once again, that CBD significantly increases the concentration of clobazam. It is also important to report the interaction of antidepressants such as sertraline with CBD in children, which can be equally dangerous [179].

Other vulnerable groups, particularly transplant patients whose immune systems are suppressed, have also been a cause for concern. According to a review on the use of CBD in post-organ transplant care, the use of cannabis has been shown to be a good supportive therapy for the relief of chronic pain [180]. However, this group is equally susceptible to the use of cannabinoids, as they can interfere with immunosuppressant medications. Studies report that CBD may interfere with the concentration of tacrolimus and other immunosuppressants, increasing their blood concentration and potentially resulting in increased toxic effects [142,181,182,183,184]. Thus, the use of cannabinoids should also be rigorously monitored in immunosuppressed patients [180].

4.4. Regulatory Considerations

With the expansion of the regulatory framework and the market for cannabis-derived products, the variety of cannabinoid products has increased significantly for both recreational and medicinal use, including in the treatment of diseases for which this use is not indicated. Thus, when these products are used without solid regulatory support regarding safety, patients may be exposed to uncertain risks [185].

The FDA acknowledges that there is growing interest in the therapeutic potential of cannabis in treating diseases, but so far has not approved any marketing authorisation applications for its use. The only approved medicines are cannabis-based, namely Epidiolex® and three synthetic cannabis-based medicines, such as dronabinol (Marinol® and Syndros®) and nabilone (Cesamet®) [83]. With regard to Europe, only dronabinol, nabilone and, in particular, nabiximols have been authorised by the EMA in European member countries. Nevertheless, the regulation of compounded preparations is a national responsibility, leading some Member States to independently authorise the prescription and sale of cannabinoid products [186].

Thus, medicinal cannabis and related products have been available in the Member States of the European Union as individual prescriptions without regular marketing authorisations [187]. Therefore, there is no specific framework for cannabis-based medicines in Europe. Depending on their composition, they may be considered medicinal plant-based products, which can be authorised for the market through registration for traditional use. In the US, despite federal regulations, state laws vary, allowing, in some cases, the medicinal use of cannabis without FDA approval [188]. However, there are very few approved cannabis-based medicines, so their use beyond the indicated options is considered off-label [188].

The FDA acknowledges that there are cannabinoid-based drugs being used for unofficial purposes, highlighting the importance of approved drugs undergoing rigorous evaluations, unlike unapproved products, which can cause unpredictable and serious adverse effects, since there are no clinical trials to prove their safety [83]. Thus, only standardised pharmaceutical cannabinoids are approved by the EMA and FDA, such as Epidiolex®, dronabinol, nabilone and nabiximols (Sativex®), while the use of other medicinal cannabis products remains outside the regulatory scope, without quality assurance and, especially, safety [187,188].

Epidiolex® is approved by the EMA and the FDA for the treatment of seizures associated with Lennox–Gastaut syndrome, Dravet syndrome or tuberous sclerosis complex in patients 1 year of age or older, especially with orphan drug designation: a drug used for the diagnosis and treatment of rare diseases [189,190].

Generally, orphan drugs are supported by incentives such as tax breaks and market exclusivity to encourage their development, despite serving a small patient population [191]. According to Orphanet, a major database of orphan drugs, they are intended to treat diseases so rare that the market is reluctant to develop them under normal market conditions, given their expensive and time-consuming development, which makes rare diseases unattractive to the pharmaceutical industry [152,192]. It is therefore understandable that these medicines are subject to certain limitations, such as high research and development costs, small patient populations involved and the regulatory and market dynamics that govern the industry [191]. To overcome market limitations, in particular, the Orphan Drugs Act (1983) [152] in the United States granted seven years of market exclusivity with tax exemptions to encourage the development of orphan drugs. Meanwhile, in Europe, the Orphan Medicinal Products Regulation (2000/2001) grants ten years of exclusivity with the same fee exemptions. It should be noted that both the FDA and the EMA assist in clinical trials for small populations [152].

Rare diseases also involve very small patient populations, which makes recruitment difficult and often renders traditional clinical trials unfeasible. To overcome this limitation, innovative methods, such as master protocols, have been used, but even so, they require ethical considerations and informed consent, which makes the process more time-consuming, limits the number of volunteers and, consequently, the existence of more robust studies [191]. The approval of orphan drugs, as often happens in smaller studies, can lead to the approval of therapies with uncertain safety and efficacy profiles. Therefore, more robust studies are important to detect risks that may not be evident in smaller studies [193,194]. Furthermore, post-marketing pharmacovigilance is essential to identify safety signals that do not appear in clinical trials or that are specific to subgroups, namely, in patients with rare diseases [195].

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Afonso, S.; Gonçalves, J.; Brinca, A.T.; Rosendo, L.M.; Rosado, T.; Duarte, A.P.; Gallardo, E. Cannabinoid Therapies in Less-Common Disorders: Clinical Evidence and Formulation Strategies. Diseases 2026, 14, 83. https://doi.org/10.3390/diseases14020083

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