Monograph FN/2026/FMT/043: Standardised Cannabis Preparation (THC, CBD) in Oral Solution

1. Legal nature and regulatory framework

Monograph FN/2026/FMT/043 constitutes the mandatory technical standard of the National Formulary of the AEMPS that standardises and typifies, for the first time, the compounding of standardised Cannabis extracts for therapeutic purposes in Spain. Promulgated in direct execution of the statutory mandate established by Royal Decree 903/2025, its purpose is not to approve a commercial pharmaceutical specialty (such as industrially manufactured Sativex or Epidyolex), but rather to set a reproducible benchmark of verifiable analytical quality governed by hospital-level clinical best practices.

Unlike industrially registered medicines, a standardised compounded formulation allows Hospital Pharmacy Services to modulate cannabinoid profiles by tailoring the exact ratio of THC and CBD prescribed on an individualised basis by a medical specialist, strictly within an evidence-based safety envelope.

2. Galenic composition and raw materials

The standardised formulation is designed as a homogeneous liquid oral solution formulated in an inert lipidic vehicle. The foundation of the preparation relies on standardised extracts derived from the flowering tops of Cannabis sativa L. manufactured under Good Manufacturing Practice (GMP) standards and conforming to the monographs of the Spanish Pharmacopoeia or European Pharmacopoeia.

Standardised Active Raw Materials

To enable absolute dosage flexibility and adapt to specialist instructions, the monograph specifies two standard reference extracts characterised by certified assay titres:

• THC-dominant extract: Standardised Cannabis extract with a certified and assayed concentration of 150 mg/ml of delta-9-tetrahydrocannabinol (Δ9-THC), with minimal or quantified residual concentrations of other phytocannabinoids.
• CBD-dominant extract: Standardised Cannabis extract with a certified and assayed concentration of 150 mg/ml of cannabidiol (CBD), containing trace THC levels below statutory analytical thresholds.

Vehicle and Excipients: Medium-Chain Triglycerides (MCT)

The monograph explicitly rules out hydroalcoholic vehicles (found in oromucosal sprays) and oxidisable vegetable oils (such as virgin olive oil or sesame seed oil), adopting medium-chain triglycerides (MCT) as the official vehicle:

• Lipophilic solubilisation: Cannabinoids demonstrate high lipophilicity (logP > 6). Pharmaceutical-grade MCT oil guarantees complete liquid-phase solubilisation, preventing crystalline precipitation.
• Oxidative stability: Composed predominantly of saturated fatty acids of 8 and 10 carbon atoms (caprylic and capric acids), MCT oil lacks double bonds susceptible to lipid peroxidation, ensuring galenic inertness.
• Predictable bioavailability: Enhances gastric dispersion and steady enteral lymphatic and portal absorption, attenuating inter-individual pharmacokinetic fluctuations during titration.

Analytical Quality Control of Raw Materials

Starting active substances must be accompanied by batch-by-batch certificates of analysis issued by AEMPS-authorised manufacturers, verifying compliance with pharmacopoeial limits:

• Heavy metals (lead, cadmium, mercury, arsenic) within European Pharmacopoeia specifications.
• Pesticide and agrochemical residues below official limits of quantification.
• Mycotoxins (aflatoxins B1, B2, G1, G2 and ochratoxin A).
• Microbial contamination (total viable aerobic count and proven absence of Escherichia coli and Salmonella).
• Residual extraction solvents (supercritical CO2 or pharmaceutical-grade ethanol).

3. Hospital compounding methodology (PN/L/FF/007/00)

Compounding must take place within the Pharmacotechnology Unit of the Hospital Pharmacy Service, in strict adherence to Standard Operating Procedure PN/L/FF/007/00, governed by Good Compounding and Quality Control Practices for Magisterial Formulations:

Operational Procedure Stages

1. Individualised stoichiometric calculation: According to the ratio prescribed by the medical specialist (e.g. 1:1, 1:20, 20:1, or single-cannabinoid formulations of CBD or THC), the exact volumetric or gravimetric aliquots of the 150 mg/ml dominant extracts are calculated for the total prescribed batch volume (typically 30 ml or 60 ml bottles).
2. Weighing and volumetric dispensing: Measurement using a calibrated analytical balance with milligram accuracy or positive-displacement pipettes suitable for viscous oily fluids inside a laminar flow cabinet or clean compounding area.
3. Dilution and incorporation into lipidic vehicle: Sequential addition of reference extracts into a fraction of pharmaceutical-grade MCT excipient, subsequently bringing to target volume in a graduated cylinder or volumetric flask.
4. Standardised mechanical homogenisation: Continuous magnetic or mechanical stirring for 20 minutes at constant speed to produce a microscopically uniform solution free of particulate matter and with consistent density distribution.
5. Primary packaging: Immediate filling into type III amber glass bottles equipped with tamper-evident child-resistant closures and dedicated adaptors for fine-dose oral syringes graduated in 0.1 ml increments.

Storage Conditions, Stability, and Shelf Life

Galenic stability and degradation studies establish the following operational shelf-life specifications:

• Unopened original container: Store at controlled room temperature below 25 °C, protected from direct sunlight, inside the original outer cardboard carton.
• In-use shelf life after opening: The product maintains its certified chemical and microbiological stability for a strict maximum of 30 days following first opening. Any remaining solution must be safely discarded thereafter.
• Do not refrigerate: Refrigeration below 8 °C is discouraged to avoid viscosity spikes that could compromise dosing precision with oral graduated syringes.

4. Pharmacokinetic profile and bioequivalence

Mastery of the pharmacokinetic behaviour of the oral MCT solution is crucial for clinical monitoring, as it differs substantially from inhalation (vaporisation) and oromucosal formulations (sublingual sprays).

5. Last-line clinical indications

The clinical scope established by the monograph and Royal Decree 903/2025 restricts the therapeutic use of this compounded formulation to severe, refractory conditions. It constitutes an indispensable last-line therapeutic recourse, admissible solely after objective therapeutic failure or documented intolerance to standard first- and second-line approved pharmaceutical therapies.

1. Spasticity in Multiple Sclerosis

Add-on treatment for moderate-to-severe spasticity secondary to multiple sclerosis in adult patients who have failed to respond adequately to optimised regimens of standard oral antispasmodics (baclofen, tizanidine, dantrolene), and where Sativex oromucosal spray is not tolerated due to local adverse reactions (mucosal irritation, stomatitis) or supply unavailability.

2. Refractory Paediatric and Adult Epilepsies

Adjunctive therapy for drug-resistant epileptic seizures, specifically including developmental and epileptic encephalopathies such as Dravet syndrome and Lennox-Gastaut syndrome, as well as tuberous sclerosis complex, under the direct supervision of neurology / paediatric neurology teams alongside standard baseline antiepileptic drug regimens. In this category, CBD-dominant extracts with zero or trace THC predominate.

3. Chemotherapy-Induced Nausea and Vomiting (CINV)

Prevention and symptomatic relief of severe, intractable nausea and vomiting induced by moderate- to high-emetogenic cancer chemotherapy, following the exhaustion of guideline-directed antiemetic regimens combining 5-HT3 receptor antagonists (ondansetron, palonosetron), NK1 receptor antagonists (aprepitant), and dexamethasone.

4. Refractory Chronic Pain (Neuropathic and Cancer-Related)

Management of refractory peripheral or central neuropathic pain (e.g. post-herpetic neuralgia, painful diabetic neuropathy, chronic radiculopathy) and intractable cancer-related pain failing to achieve clinically meaningful relief (≥ 30% reduction on the visual analogue scale) following stepped analgesia according to WHO analgesic ladders, including gabapentinoids, SNRIs, and strong opioids, or in patients suffering dose-limiting opioid toxicities.

6. Dosage, individual titration, and deprescribing

There is no single fixed universal dose. Every prescription must define the individualised ratio (THC:CBD) and adhere strictly to the overarching pharmacological rule: "Start low, go slow" (initiate at baseline minimal doses and titrate gradually).

Ceiling Safety Thresholds

Clinical Upward Titration Schedule

• Initiation phase (Days 1 to 3): Single nocturnal administration of a minimal baseline dose (e.g. 1.25 mg to 2.5 mg of THC in adults, or 2.5 to 5 mg/kg/day of CBD in paediatrics) to assess somnolence and vestibular tolerance.
• Weekly adjustment phase (Days 4 to 21): Gradual upward increments every 3 to 5 days guided by analgesic or antispastic response, closely monitoring sedation or dizziness. Fractionate into daytime doses if tolerated.
• Maintenance phase: Stable titration at the lowest effective dose that delivers clear symptomatic improvement with optimal tolerability. Regular outpatient hospital appointments must review clinical benefit.

Discontinuation and Deprescribing Protocol

If treatment failure or unacceptable toxicity occurs, therapy must never be abruptly discontinued in patients receiving prolonged THC-containing regimens. A gradual step-down reduction of 25% per week must be implemented to prevent potential cannabinoid withdrawal symptoms (restlessness, rebound insomnia, diaphoresis, emotional lability).

7. Clinical safety, contraindications, and precautions

Absolute Contraindications

• Diagnosed hypersensitivity to Cannabis sativa L. extracts or to the medium-chain triglycerides (MCT) excipient.
• Personal history or first-degree family history of psychosis, schizophrenia, or severe psychiatric disorders with delusional symptoms (particularly relevant for THC-containing formulations).
• Active severe substance use disorder or history of illicit substance dependence.
• Pregnancy, suspected pregnancy, and breastfeeding (cannabinoids cross the placenta and pass into breast milk, presenting proven neurodevelopmental risks).
• Severe hepatic impairment (Child-Pugh C) or end-stage renal disease not managed by haemodialysis.

Adverse Reactions by System Organ Class

• Nervous system disorders: Daytime sedation, dizziness, ataxia, headache, transient anterograde amnesia, impaired concentration.
• Psychiatric disorders: Euphoria, dysphoria, transient disorientation, anxiety episodes, acute panic attacks (dose-dependent with THC).
• Gastrointestinal disorders: Dry mouth (xerostomia), transient nausea, constipation or mild diarrhoea (attributable to the lipid vehicle at higher volumes).
• Hepatobiliary disorders: Asymptomatic elevation of serum transaminases (ALT, AST), observed primarily with high-dose CBD regimens co-administered with sodium valproate.
• Vascular disorders: Orthostatic hypotension, reflex tachycardia, conjunctival injection.

8. Enzymatic interactions (CYP450 / UGT)

Cannabinoid metabolism involves critical isoenzymes of the cytochrome P450 superfamily and UDP-glucuronosyltransferases. Both THC and CBD serve not only as enzymatic substrates but also as competitive inhibitors or potential inducers, necessitating an exhaustive clinical audit of baseline medication regimens.

9. Official pharmacovigilance and SEFV-H Registry

The regulatory model enacted by Royal Decree 903/2025 institutes a comprehensive end-to-end traceability system for standardised medicinal Cannabis, subjecting it to priority post-marketing surveillance:

Duties of Prescribing Specialists and Hospital Pharmacists

• Computerised clinical registry: Every treatment initiation must be recorded in an institutional hospital digital register detailing confirmed diagnosis, objective prior refractoriness, prescribed ratio, allocated hospital compounding batch number, and written informed consent.
• Mandatory adverse reaction reporting: Any unexpected symptoms, suspected adverse reactions (ADRs), or therapeutic failures must be promptly reported to the Spanish Pharmacovigilance System for Human Medicines (SEFV-H) via the AEMPS online portal NotificaRAM.
• Annual activity audits: Hospital Pharmacy Services must submit an annual audit report to regional health authorities and the AEMPS, detailing total extract volumes utilized, patient headcount, ratios dispensed, and retention rates at 6 and 12 months.

10. Annotated bibliography: the nine official references

Monograph FN/2026/FMT/043 bases its regulatory and clinical provisions on nine foundational reference sources selected by the AEMPS. Each source provides distinct evidence: from authorised product characteristics and comparative health policy frameworks to historical pivotal oncology trials and modern registered research protocols.