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

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

Authors / Affiliation: Guillermo Cásedas, Martín de Yarza‑Sancho, Víctor López; Universidad San Jorge & Instituto Agroalimentario de Aragón, Zaragoza, Spain. MDPI

Goal / Research Questions: To update and assemble the evidence (both clinical trials and preclinical studies) about whether isolated CBD (i.e. without THC) has analgesic properties in pain treatment. MDPI

Secondary goals:

  • Assess safety in the clinical trials.
  • Understand mechanisms of action (from preclinical work).
  • Identify which kinds of pain conditions show promise (e.g. osteoarthritis, chronic pain, neuropathic pain). MDPI


Methods:

  • Systematic review following PRISMA guidelines. MDPI
  • Literature sources: PubMed & Web of Science, with search terms to explicitly exclude THC and products combining CBD + THC (like Sativex or nabiximol). MDPI
  • Timeframe: all years up through ~June 2024. MDPI
  • Inclusion criteria: preclinical (in vitro, in vivo) and clinical trials using CBD alone or with CBD as the major component, free of THC. Articles had to be in English or Spanish. Exclusion: systematic reviews/meta-analyses, case reports, studies with CBD+THC, etc. MDPI
  • Quality of clinical trials assessed using the Jadad scale (scores up to 5) to evaluate bias. MDPI


What They Found (Results):

  • Out of ~500+ initially identified articles, after screening etc., 40 studies met their criteria: 11 human clinical trials, 2 dog clinical trials, 27 preclinical (animal/in vitro) studies. MDPI
  • Clinical findings:

    Positive pain‑reducing effects of CBD were observed in 7 of the 11 human trials: conditions included osteoarthritis-related pain, chronic/neuropathic pain, arthritis, bruxism, atopic dermatitis. MDPI


    In 4 clinical trials, there was no significant effect over placebo or no improvement: for example, acute low back pain in ER setting; post‑surgery rotator cuff repair pain; irritable bowel syndrome (with chewing gum delivery of CBD) etc. MDPI

  • Preclinical findings support analgesic and anti‑inflammatory effects; mechanisms implicated include: activation of TRPV‑1, 5‑HT1A, modulation of CB1 (often allosteric) receptors, reduction of proinflammatory cytokines, microglia modulation, etc. MDPI
  • Safety: No major adverse effects reported in the reviewed trials—CBD seems relatively safe in the contexts studied. MDPI
  • Pharmacokinetics / formulation issues: noted that bioavailability, route (oral vs topical vs inhaled), etc., vary widely; these affect how well CBD can act. For instance, topical CBD showed promising results; oral forms sometimes have low bioavailability. MDPI



Conclusions:

  • CBD (without THC) has both clinical and preclinical evidence suggesting it's potentially effective and safe for reducing pain, especially in some chronic / neuropathic pain conditions and osteoarthritis. MDPI
  • But clinical evidence is still limited (number of studies, sample sizes, consistency, quality). More well‑designed trials are needed. MDPI



Strengths of the Study

  1. Focus on isolated CBD / excluding THC: That helps clarify whether CBD itself has analgesic effects, separate from THC or full cannabis / mixed cannabinoid products. This is important because many prior studies confound the effects.
  2. Use of both clinical and preclinical evidence: Gives a broader base of data, so mechanisms identified can help explain (or suggest) the clinical effects.

  3. Quality assessment with Jadad scale: helps evaluate internal validity of the clinical trials.
  4. Clear identification of gaps: the authors are transparent about where evidence is weak.
  5. Recent time frame: includes studies up through mid‑2024, so it's up‑to‑date as of now.


Limitations / Caveats

  1. Heterogeneity of studies:
    Different pain conditions (osteoarthritis, neuropathic, acute, chronic, etc.).

    Different doses, formulations, delivery routes (oral, topical, etc.).

    Different durations of treatment.

    This makes it hard to draw firm conclusions about how much dose, how long, which routes are effective.
  2. Sample size / trial power:

    Many clinical trials had small n’s.

    Some trials had negative results perhaps due to insufficient dose, or use in acute pain where strong analgesics may dominate.

  3. Placebo / control issues:

    Some trials didn't show statistical superiority versus placebo, which limits claims.

  4. Pharmacokinetics & bioavailability are under‑characterized.

    The issue of how much CBD ends up in the blood / tissues, how quickly, etc., is a big question.


  5. Long‑term safety data is limited. The short‑term safety (in the trials) looks acceptable, but what about long‑term use, interactions, etc.?
  6. Lack of large‑scale, high‑quality RCTs in some pain types.
  7. Regulatory/formulation variability: Different products have different purity, quality, etc., which matters. Some studies used pharmaceutical grade CBD; others less defined formulations.


What We Can Infer

  • For certain chronic pain types (especially osteoarthritis, neuropathic pain), CBD shows promise. It might be especially helpful when used topically (for peripheral pain), or for anti‑inflammatory aspects.
  • The mechanism likely involves multiple pathways (not just CB1/CB2), which could mean CBD has broader effects (e.g. reducing inflammation, modulating nerve sensitivity, etc.).
  • Because of its safety profile, CBD might be an option to consider when other treatments are ineffective or have adverse side effects, though in many cases one can’t yet say it's definitively effective.
  • For clinical practice (or personal use), pay attention to formulation, dosing, route (topical vs oral), and quality/purity of the CBD product.


Future Directions

  1. Larger randomized controlled trials (RCTs) with sufficient power, standardizing doses, routes, and outcome measures.
  2. Dose‑response studies: to figure out minimal effective dose, maximal safe dose.
  3. Longer follow‑ups to assess long‑term efficacy and safety, especially for chronic use.
  4. Standardization of formulations: CBD products should be well‑characterized (purity, pharmacokinetics, etc.).
  5. Comparative studies: comparing CBD vs standard treatments, or as adjuncts.
  6. Better biomarkers / mechanistic studies in humans to verify preclinical findings (e.g. which receptor involvement matters in which pain types).
  7. Attention to individual differences: e.g. metabolic differences, comorbidities, concurrent medications (since CBD can affect cytochrome P450 enzymes