For decades, medical cannabis was a taboo subject in mainstream medicine. Today, a landmark peer-reviewed review published in the journal Diseases on February 23, 2026 is making researchers rethink everything they thought they knew about cannabinoids — not just for pain and epilepsy, but for some of the rarest and most devastating conditions on the planet.
The study, “Cannabinoid Therapies in Less-Common Disorders: Clinical Evidence and Formulation Strategies” by Afonso et al. from the University of Beira Interior (Portugal), synthesizes five years of clinical evidence — from 2020 to 2025 — covering cannabinoid treatment in conditions ranging from Rett syndrome and Tourette disorder to epidermolysis bullosa, Crohn’s disease, and chronic insomnia. The findings are nuanced, sometimes humbling, and full of genuine promise.
Key Takeaways
- Cannabidiol (CBD) and related compounds have shown meaningful clinical benefits in several rare and treatment-resistant conditions, including certain refractory epilepsies, autism spectrum disorder, anxiety disorders, Crohn’s disease, and rare skin diseases.
- The evidence is real but still patchy: most studies are small, short-term, and conducted in specific populations. Bigger, better-controlled trials are urgently needed.
- Not everything works: well-designed clinical trials in Fragile X syndrome, Parkinson’s disease, and essential tremor showed no significant benefit over placebo — a reminder that biological plausibility does not guarantee clinical results.
- How cannabinoids are delivered (pills, sprays, skin gels, nanocarriers) makes an enormous difference to how well they work in the body — and this is an area of active pharmaceutical innovation.
- Regulatory frameworks remain fragmented worldwide. Only a handful of cannabinoid-based drugs hold full approval from the FDA and EMA.
What Are Cannabinoids, Exactly?
Before diving into the diseases, it helps to understand what we are actually talking about. Cannabis contains more than 100 different active compounds called cannabinoids. The two most studied are THC (tetrahydrocannabinol) — the psychoactive molecule responsible for the “high” — and CBD (cannabidiol), which is non-intoxicating and has attracted most of the medical interest in recent years (see CBD explained for a deeper primer).
These compounds work primarily through the body’s own endocannabinoid system, a biological network of receptors found throughout the brain, nervous system, immune cells, gut, skin, and many other organs. CB1 receptors, concentrated in the brain and nervous system, govern pain perception, mood, and motor control. CB2 receptors, found mainly in immune cells, regulate inflammation. CBD, somewhat unusually, acts on a wide range of additional molecular targets — serotonin receptors, vanilloid pain channels, adenosine pathways — which is part of why researchers believe it may have effects across so many different conditions.
It’s worth noting that the broader cannabinoid family extends beyond THC and CBD — acidic precursors like CBDA and THCA are also attracting growing research attention for their own distinct therapeutic properties.
The key word here is “may.” And that’s precisely what the new review sets out to test.
The Diseases Where Cannabinoids Are Showing Real Promise
Epilepsy’s Hardest Cases
The clearest medical wins for cannabinoids so far have come from epilepsy — specifically, two severe childhood syndromes called Dravet and Lennox-Gastaut. Epidiolex (purified CBD) is now FDA-approved for both. But what about the many other forms of drug-resistant epilepsy? The new review looks at the evidence, and it’s cautiously encouraging. For a broader picture of how cannabinoids are being evaluated across major neurological conditions, see our in-depth neurology review covering epilepsy, Alzheimer’s, and Parkinson’s.
In children with Rett syndrome — a rare genetic neurological disorder affecting mostly girls — a Phase 1 trial using a compound called CBDV (cannabidivarin) achieved a median seizure reduction of 82%, with four out of five patients cutting seizures by at least half. In patients with tuberous sclerosis complex, a post-hoc analysis of a large Phase 3 trial found CBD reduced seizure frequency significantly. And in adults with drug-resistant focal epilepsy, a transdermal CBD formulation (absorbed through the skin) showed that 60.8% of patients achieved at least a 50% seizure reduction over six months.
Critically, benefits in epilepsy often extended beyond seizure control — patients also reported improvements in mood, anxiety, sleep, and quality of life, even in cases where seizure reduction was modest.
Autism Spectrum Disorder
This is one of the more striking areas of emerging evidence, and also one of the most contentious. Three independent clinical investigations found that cannabinoid treatments — primarily CBD-dominant preparations — led to meaningful improvements in behavioral symptoms in children with autism spectrum disorder (ASD), including reductions in irritability, withdrawal, and hyperactivity. One randomized controlled trial using whole-plant CBD:THC in children aged 5 to 21 found that 49% of treated patients were rated as “much or very much improved” compared to just 21% on placebo.
That’s not a slam dunk — it’s a proof-of-concept result in a relatively small study. But in conditions where existing treatments often cause significant side effects, it’s the kind of signal that warrants much larger follow-up trials.
Anxiety and PTSD
In perhaps the strongest psychiatric evidence reviewed, a Phase 3 multicentre randomized controlled trial in adults with mild-to-moderate anxiety found that a nanodispersible oral CBD solution produced significantly greater reductions in anxiety and depression scores compared to placebo, including clinically meaningful changes on standardized scales like the GAD-7 and HAM-A. The question of how CBD and THC compare head-to-head in anxiety contexts is explored in detail in our dedicated piece on CBD vs. THC anxiety study results.
In post-traumatic stress disorder (PTSD), the picture is more complex. A single dose of 300mg CBD showed measurable effects on cognitive impairment following trauma recall and — in a separate brain imaging study — partially normalized the activity of the prefrontal cortex, a region involved in emotional regulation. Related research suggests this memory-protective dimension of cannabinoids may extend beyond PTSD; for more, see our coverage of how CBD and THC may protect memory under stress. However, whether these neurological changes translate into lasting symptom relief remains an open question.
Rare Skin Diseases
Epidermolysis bullosa (EB) is one of the most painful conditions in medicine — a genetic disorder in which the skin blisters and tears from minimal friction. Affected patients, many of them children, often describe it as living in constant burning pain. A clinical trial examining a sublingual cannabinoid spray (Transvamix, containing both THC and CBD) for chronic pain in EB is currently underway, designed with robust quantitative endpoints for the first time in this indication. Meanwhile, a 12-week clinical study in atopic dermatitis patients using a topical CBD-and-ginger emulsion showed sustained reductions in itch severity, improved skin barrier function, and even a steroid-sparing effect — meaning patients needed less corticosteroid medication. This finding echoes results from a dedicated CBD and CBG eczema treatment study we covered earlier. The anti-inflammatory potential of CBD on skin is also being explored across other dermatological conditions — from psoriasis and itch relief to acne and broader skincare applications, and emerging research is even examining cannabinoids in the context of skin cancer.
Crohn’s Disease and Gut Disorders
The endocannabinoid system plays a recognized role in gut motility and immune regulation, which is why cannabinoids have attracted attention for inflammatory bowel disease. A randomized controlled trial in Crohn’s disease patients using CBD-rich cannabis oil found significant improvement in disease activity scores and quality of life — but no improvement in endoscopic markers or inflammatory biomarkers. In plain English: patients felt better, but the underlying intestinal inflammation didn’t visibly change. This disconnect between symptom relief and objective disease activity is a recurring pattern in cannabinoid research and remains poorly understood. For a broader look at the evidence in inflammatory bowel conditions, our article on how cannabis and CBD may relieve IBD symptoms covers the full spectrum of findings.
Insomnia and Sleep Disorders
Multiple randomized controlled trials now support the use of cannabinoid preparations for chronic insomnia. One crossover trial found that a sublingual cannabinoid extract reduced the time it took patients to fall asleep and increased total sleep time by more than an hour, with large effect sizes. A large comparative trial in nearly 1,300 adults found that about two-thirds of participants achieved clinically meaningful sleep improvement — though no single formulation was clearly superior to others. Interestingly, even unconventional CBD delivery formats are being explored in sleep research: one study examined whether CBD-infused pillowcases could improve sleep quality in nurses, reflecting just how broad the investigative appetite has become.
When the Science Said No: The Lessons of Failure
Honest science requires publishing negative results, and this review is admirably forthright about the failures. Several well-designed trials found no benefit.
In Fragile X syndrome — a genetic cause of intellectual disability and autism — two clinical trials (one early-phase, one a full Phase 3 randomized controlled trial) found no significant improvement in behavioral functioning with CBD. The Phase 3 trial enrolled 240 patients and used objective outcome measures. The result was unambiguous: CBD did not work for this condition at the doses tested.
In Parkinson’s disease, three separate trials found no significant benefit from cannabinoid treatment on motor function, cognition, or sleep-related symptoms — a sobering finding given the high hopes some researchers had for this application. Our dedicated coverage of medical cannabis in Alzheimer’s and chronic pain explores some of the nuanced findings in neurodegenerative contexts in greater depth. In essential tremor, a single-dose CBD study showed no reduction in tremor amplitude. And in bipolar depression, CBD used as an add-on therapy showed no significant additive benefit over placebo.
These failures matter. They demonstrate that the fact that cannabinoids can modulate relevant biological systems does not automatically mean they will produce therapeutic benefit in a given disease. The review’s authors note that placebo effects are often large in these populations, that subjective outcome measures inflate apparent results, and that “biological plausibility and widespread use do not guarantee clinical efficacy.”
Why Getting the Formulation Right Is Half the Battle
One factor that rarely makes headlines but profoundly shapes clinical outcomes is pharmaceutical formulation — that is, how exactly the cannabinoid is prepared and delivered into the body. CBD is famously difficult to work with pharmaceutically. It is highly fat-soluble, which makes it poorly absorbed when swallowed in simple oral form (bioavailability of less than 20%). It is extensively broken down by the liver before reaching the bloodstream. And its behavior in the body varies enormously between individuals, depending on genetics, body composition, diet, and concurrent medications.
These challenges have driven a wave of pharmaceutical innovation:
Oromucosal sprays, like Sativex (nabiximols), deliver cannabinoids directly to the lining of the mouth, bypassing much of the liver’s first-pass metabolism and achieving more consistent blood levels than oral capsules. This oral-cavity delivery approach is also being explored in oral health contexts — recent research has examined CBD mouthwash as a tool for managing gum inflammation, and the review itself includes a clinical trial showing CBD dental gel reduced gingival inflammation vs. placebo. Transdermal gels and patches similarly bypass the liver and have shown particular promise in conditions requiring steady, long-term drug exposure — and they reduce gastrointestinal side effects that frequently lead patients to stop treatment.
Nanocarrier technology is perhaps the most exciting frontier. By encapsulating CBD in tiny lipid or polymer particles — nanoemulsions, liposomes, or PLGA nanoparticles — researchers have achieved bioavailability increases of up to 1.65 times compared to standard formulations. One preclinical study in dogs achieved CBD bioavailability 17 times greater than free CBD using liposomal encapsulation. Human clinical data are still limited, but the trajectory is promising.
The Safety Picture: Better Than You Might Think, With Caveats
Across the dozens of clinical trials reviewed, cannabinoid formulations demonstrated an acceptable safety profile. Most adverse effects were mild — somnolence, dry mouth, reduced appetite, diarrhea — were dose-dependent, and resolved with dose reduction or on their own. Serious adverse events were rare.
The more important safety concern is drug interactions. CBD is metabolized by, and also inhibits, a family of liver enzymes called the CYP450 system. This is the same system that processes antidepressants, anticonvulsants, benzodiazepines, anticoagulants like warfarin, and immunosuppressants like tacrolimus. In some reported cases, CBD tripled plasma concentrations of co-administered drugs. This is not a theoretical risk — it requires active monitoring, particularly in patients already on multiple medications, which describes most of the rare disease populations where cannabinoids are being explored.
Children represent a particular area of concern. Most cannabinoid pharmacology research has been done in adults, and a child’s developing liver, smaller body fat percentage, and immature drug-metabolizing enzymes mean the pharmacokinetics behave very differently. Long-term effects of cannabinoid exposure on the developing brain remain largely unknown.
The Regulatory Maze
The global regulatory landscape for medical cannabis remains fragmented and often confusing. In the United States, the FDA has approved only four cannabinoid-based medications: Epidiolex (CBD) for rare epilepsies, and three synthetic THC preparations (Marinol, Syndros, and Cesamet) for chemotherapy-induced nausea and appetite loss in AIDS. In Europe, the European Medicines Agency has authorized nabiximols (Sativex) for multiple sclerosis spasticity, alongside the synthetic agents. Epidiolex has also received EMA approval for rare epilepsies.
Beyond these approvals, the use of medicinal cannabis varies dramatically by country and, in the US, by state. Many cannabinoid products reaching patients — particularly CBD oils, tinctures, and topical preparations sold commercially — operate entirely outside regulatory oversight, with no standardized quality controls and no clinical evidence specific to the conditions for which they are marketed. This is a genuine public health concern.
The situation is slowly improving. Orphan drug designations, which provide extended market exclusivity and financial incentives to develop therapies for rare conditions affecting small patient populations, have begun to be applied to cannabinoid-based medicines. This may accelerate research into the rare disease applications where the clinical need is greatest and existing options are fewest.
FAQ
No. CBD (cannabidiol) does not produce intoxication. It has very low affinity for the brain receptors responsible for THC’s psychoactive effects, and most medical-grade formulations are either CBD-only or contain only trace amounts of THC. Products approved by the FDA and EMA for medical use are standardized and subject to quality controls that commercial CBD products often are not.
Not yet, and not without careful medical supervision. While the evidence reviewed here shows genuine promise across a range of rare conditions, most findings come from small studies. For the majority of rare diseases, there is currently no robust clinical evidence to guide treatment. Any use in rare disease contexts should be under specialist supervision, with close monitoring for drug interactions and adverse effects — particularly in children or patients on multiple medications.
This is one of the most important open questions in the field. The most likely explanation is that different diseases involve different biological mechanisms, and the endocannabinoid system’s role varies accordingly. Fragile X syndrome involves specific genetic and synaptic abnormalities that may not be adequately modulated by CBD at the doses tested. It also illustrates why promising preclinical data and biological rationale are not enough — each indication requires its own rigorous clinical evaluation.
Definitively not. Commercial CBD products vary enormously in actual CBD content, are frequently mislabeled, may contain contaminants, and have no standardized manufacturing processes. The clinical trials described in this article used pharmaceutical-grade, standardized formulations with verified composition and dose. This distinction matters enormously for both safety and efficacy.
Disclaimer: This article is intended for informational and educational purposes only. It does not constitute medical advice and should not be used to guide treatment decisions for any medical condition. The evidence summarized here is preliminary in nature and does not support the use of cannabinoid products outside of medically supervised settings. Patients with rare or chronic conditions should consult a qualified healthcare provider before considering any cannabinoid-based therapy. The Cannex does not endorse any specific product, brand, or treatment.
