1.2. Basic Cannabis Chemotaxonomy
1.3. Brief Introduction to the Endocannabinoid System
1.4. Cannabinergic Compounds
2. Chronology of Cannabis-Based Drug Development
2.1. Drugs of One Molecule
2.1.1. Cannabis-“Inspired” Drugs
2.1.2. Cannabis-Derived Drugs
2.2. Drugs of Combinatoric Formulations
3. Taking Advantage of the “Entourage Effect”
4. Other “Entourage” Considerations
4.1. The “Parasitage Effect”
4.2. Interaction between Endocannabinoids and Cannabinoids (Synthetic or Plant-Derived)
4.3. Degradation and Loss of Activation
5. Drug–Drug Interactions
6. Registration Drugs: One Molecule or Combinatoric Formulations
7. Conclusions and Future Prospects
Conflicts of Interest
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|Drug Name||Indication||Basic Formulation||Clinical Studies||Proved Efficacy||Key Limiting Toxicity||Recommended Dosage||Drug–Drug Interactions Reported||Approval||Reference|
|Drugs of one molecule|
|MARINOL® (GW Pharmaceuticals, Cambridge, UK)||Appetite stimulation; antiemetic associated with cancer chemotherapy||Dronabinol (synthetic THC)||Yes||Yes||100 mg/day|
or 30 mg/kg
|Appetite stimulation: 2.5 mg twice daily; antiemetic: 5 mg 3–4 times daily||FDA|||
|EPIDIOLEX® (GW Pharmaceuticals)||Lennox–Gastaut syndrome and Dravet syndrome in patients||Plant derived CBD||Yes||Yes||20 mg/kg/day||5–20 mg/kg/day||CYP1A2, CYP2B6|
substrates, uridine 5’ diphospho-glucuronosyltransferase 1A9 (UGT1A9) and UGT2B7.
CYP2C8 and CYP2C9 substrates
|SYNDROS® (Benuvia Therapeutics Inc, Chandler, AZ, USA)||Anorexia; nausea and vomiting associated with cancer chemotherapy||Dronabinol (synthetic THC)||Yes||Yes||25 mg/day||4.2 mg/day||Neuropsychiatric adverse reactions; hemodynamic instability||FDA|||
|CESAMET® (Valeant Pharma Int, Laval, QC, Canada)||Nausea and vomiting induced|
by cancer chemotherapy
|Yes||2 mg/day||Diazepam 5 mg; sodium secobarbital 100 mg;|
alcohol (absolute) 45 mL; codeine 65 mg
|INM-755 cream (Inmed pharma, Vancouver, BC, Canada)||Skin diseases and wounds; epidermolysis bullosa||Bacteria Escherichia coli fermentation derived from one rare CBN (Cannabinol)||Yes Phase 1–2 ongoing||No||Two doses of INM-755 cream are currently being tested|||
|Drugs of combinatoric formulations|
|SATIVEX® Oromucosal spray (GW Pharmaceuticals)||Pain relief||Plant-derived CBD:THC and terpenes||Yes||Yes||90 mg/day||5–60 mg/day||Reversible inhibitor of CYP3A4, 1A2, 2B6, 2C9, and 2C19||EU, Canada|||
|1. Initial drug research||Discovering and identifying various chemical and biological substances or other products on the way toward developing a drug; testing for activity, efficacy, toxicity, and ultimately gathering preliminary information on its effectiveness and safety. If the results are promising, researchers proceed to the next stage of development.|
|2. Preclinical studies||Administration of the drug to selected species of animals (in vivo) or cells (in vitro). The drug must be shown to cause no serious harm (toxicity) at the doses required to have an effect either in a single compound or in DDIs. If results from these initial studies are promising and further tests show acceptable safety levels and clear or potential efficacy, then the next step would be to submit a clinical trial application.|
|3. Clinical trials||The results of clinical trials conducted with humans are key components of the review process by the regulatory agency. The purpose of a trial is to gather clinical information about a drug’s effectiveness and safety, determine best dosing/usage in humans, evaluate any adverse drug reactions and DDIs, and compare results to already existing treatments for the same disease or condition or to placebo when no treatment already exists for the aimed pathology (when ethically possible). The information gathered from these trials is then included in the dossiers to be reviewed by the relevant agencies.|
|4. Drug approval process||If results of all the preclinical studies and the clinical trials show that a drug’s potential therapeutic benefit outweighs its risks (side effects, toxicity, etc.), and the chemistry and manufacturing dossier is complete, then the sponsor may decide to file a new drug submission (NDS) with the appropriate regulatory agency in order to be granted authorization to sell the drug in the country.|
|5. After approval||The regulatory agency requires a sponsor to ensure that the use of its drug is done under the terms of its market authorization. In addition, life cycle management activities (post-approval submissions, for new indications, new dosage forms, new strengths, manufacturing changes, etc.) are required to ensure the maintenance of the product license with its related improvements. In summary, sponsors need to ensure its continued compliance with the food and drug regulations while their products are on the market.|
On the other hand, the regulatory agency monitors drug information and adverse drug reaction reporting, conducts market surveillance, investigates complaints, and manages recalls if necessary, amongst other things.
|6. Additional regulations||There are also more processes and regulations to follow and consider before, during, or after the review process, and before the drug is officially marketed, distributed, and sold in a country. Topics included licensing, warehousing, wholesale distribution rules, and the Drug Establishment License (DEL), as well as regulations around distribution to consumers, regulations around the marketing and advertising activities, provincial requirements, and health insurance funding rules, among others.|
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