Phytocannabinoids

Phytocannabinoids

1. Identity: Botanical and Chemical Overview

1.1 Botanical Source and Classification

Cannabis sativa L. is an annual herbaceous flowering species from the Cannabaceae family, originating from Central Asia, with a rich history of diverse applications throughout human history. The plant is classified into three subspecies: Cannabis sativa subsp. sativa, Cannabis sativa subsp. indica, and Cannabis sativa subsp. ruderalis.

Phytocannabinoids are a diverse group of naturally occurring compounds extracted from the Cannabis plant that have attracted interest due to their potential pharmacological effects and medicinal uses. Chemically, phytocannabinoids are meroterpenoids biosynthesized in Cannabis sativa L. through the alkylation of alkylresorcinols with terpenoid moieties. Over 200 structurally diverse phytocannabinoids have been identified, showing wide variability in their isoprenyl substituents (monoterpenyl, sesquiterpenyl, cyclic or acyclic), alkyl chain length, and functionalization of the aromatic core (e.g., O-methylation, oxidation, or dimerization).

The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. These compounds play a crucial role in the plant's interactions with the environment, including defense mechanisms against pests and environmental stressors. Phytocannabinoids are concentrated primarily in the plant's secretory structures: cannabis has many trichomes, which are collected from protuberances close to the plant's leaves, flowers, seeds, and other important sections, and are divided into various types of glandular and non-glandular structures.

1.2 Key Compounds

From the more than one hundred cannabinoids identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids. In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN).

• Δ9-Tetrahydrocannabinol (Δ9-THC): The primary psychoactive constituent; the Δ9-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content.
• Cannabidiol (CBD): A non-psychoactive compound which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions.
• Cannabigerol (CBG): A non-psychoactive cannabinoid found in the cannabis plant; CBG converts from its acid form cannabigerolic acid (CBGA), which is the principal precursor to most of the other cannabinoids found in cannabis, such as Δ-9-THC, CBD, cannabinol (CBN), and cannabichromene (CBC).
• Cannabichromene (CBC): CBC was identified in 1966 and is one of the most abundant phytocannabinoids alongside Δ9-THC, CBD, and CBN.
• Cannabinol (CBN): THCA can be oxidized to cannabinolic acid (CBNA), the precursor to cannabinol (CBN). CBN is therefore considered a degradation product of THC found in aged or oxidized plant material.
• Acidic precursors (THCA, CBDA, CBGA, CBCA): Tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and cannabichromenic acid (CBCA) are the acidic biosynthetic precursors of the neutral cannabinoids Δ9-THC and CBD.
• Propyl-variant cannabinoids (THCV, CBDV): These are structural analogs with a shortened side chain; C. sativa is a source of several minor phytocannabinoids such as CBG, CBN, CBC, Δ9-tetrahydrocannabivarin (THCV), cannabivarin (CBV), and cannabidivarin (CBDV).

1.3 Biosynthesis

The synthesis of the cannabinoids involves two pathways located in two separate sites within the glandular trichomes. In the first pathway, olivetolic acid (OA) is produced in the cytosol of the gland cells from hexanoic acid. In the second, geranyl diphosphate (GPP) is generated in the plastidial organelles via the mevalonate-dependent isoprenoid (MEP) pathway. The convergence of these two pathways occurs through a prenylation reaction catalyzed by geranyl olivetolate transferase (GOT), also called CBGA synthase, where GPP is transferred to OA to form CBGA.

CBGA is widely referred to as the "mother cannabinoid" because it serves as the central biochemical precursor for THCA, CBDA, and cannabichromenic acid (CBCA). These conversions are mediated by FAD-dependent oxidocyclase enzymes — THCA synthase, CBDA synthase, and CBCA synthase — whose expression patterns vary by plant genotype, environmental factors, and developmental stage. The decarboxylation of acidic cannabinoids is a non-enzymatic thermal process in which the carboxyl group (–COOH) is cleaved as carbon dioxide (CO₂), yielding neutral cannabinoids with enhanced pharmacological activity.

1.4 Common Forms and Preparations

Cannabidiol can be taken internally in multiple ways, including by inhaling cannabis smoke or vapor, swallowing it by mouth, and through use of an aerosol spray inside the cheek. It may be supplied as CBD oil containing only CBD as the active ingredient, CBD-dominant hemp extract oil, capsules, dried cannabis, or prescription liquid solutions. Cannabinoids are typically consumed by smoking, vaporization, buccal spray, or ingested orally in the form of soft gels, oil drops, or cookies. In addition to cannabinoids, cannabis also contains terpenoids and flavonoids, which are frequently present in full-spectrum and broad-spectrum preparations.

2. Traditional and Historical Use

Cannabis sativa has been used for recreational, therapeutic, and other uses for thousands of years. Records of the medicinal use of cannabis appear before the Common Era in China, Egypt, and Greece (Herodotus), and later in the Roman empire (Pliny the Elder, Dioscorides, Galen). Cannabis was used for its therapeutic properties by multiple ancient cultures since it was first documented in China in 2800 BC.

Over centuries, cannabis has been a valuable resource for producing hemp fiber (utilized in clothing, rope, and paper) and seeds (consumed as food), and has served as a medicinal plant. In the 19th century, orientalists like Silvestre de Sacy, and Western physicians coming into contact with Muslim and Indian cultures, like O'Shaughnessy and Moreau de Tours, introduced the medicinal use of cannabis into Europe.

Preparations used historically included crude plant material consumed orally (as teas, decoctions, or food preparations such as the Indian preparation bhang), dried resinous extracts (hashish), and smoked or inhaled preparations. Botanical preparations were made from botanical raw materials by one or more of the following processes: pulverisation, decoction, expression, aqueous extraction, or ethanolic extraction. Traditional medicinal purposes included relief of pain, spasms, nausea, insomnia, and inflammation across multiple cultures and medical traditions. Cannabis has ethnomedicinal usage as a natural medicine in Bangladesh and was cultivated during the British Empire period.

The structure of the main psychoactive phytocannabinoid, tetrahydrocannabinol (THC), was determined in Israel by Mechoulam and Gaoni in 1964, and this discovery opened the gate for many of the subsequent developments in the field of endocannabinoid system (ECS) research.

3. Key Constituents and Mechanisms of Action

3.1 The Endocannabinoid System

The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. There are at least two types of cannabinoid receptors (CB1R and CB2R) identified. CB1 receptors are highly expressed in the central nervous system, mostly in the presynaptic region, and there is substantial CB1 expression in the nociceptive sensory neurons. CB2 is mostly expressed in immune cells and mediates the anti-inflammatory effects of cannabinoids, which indirectly contributes to the anti-nociception of acute inflammatory pain.

3.2 THC: Mechanism of Action

THC ranges from acting as a partial agonist for the CB1 and CB2 receptors to being a full agonist for the GPR55/GPR18, TRPV2-4/TRPA1, PPARα/γ receptors, to being an antagonist for the TRPM8/5HT3A receptor. THC administered occasionally causes increased neuronal activity by increasing the amount of dopamine; however, long-term exposure to THC causes reduced dopamine concentration and, consequently, reduced neuronal activity.

3.3 CBD: Mechanism of Action

CBD acts as a negative allosteric modulator of the CB1 receptor and has an agonist effect on the CB2 receptor. CBD also has an agonistic effect on 5-HT1A and α1-adrenergic receptors. CBD is an inhibitor of GPR55 receptors as well as TRPM8 channels; however, it is an activator of PPARγ receptors and TRP channels.

Certain activities of CBD have been related to endocannabinoid-mediated mechanisms: e.g., inhibition of endocannabinoid inactivation, allosteric modulation of classic cannabinoid receptors, activity at atypical cannabinoid receptors as GPR55, and members of the transient receptor potential (TRP) family, e.g., TRPV1. Conversely, others seem to be the result of endocannabinoid-independent processes: e.g., binding to serotonin receptor types, adenosine uptake inhibition, targeting nuclear receptors of the PPAR family, and modulation of ion channels.

3.4 PPAR and TRP Channel Modulation

Some cannabinoids activate the different isoforms of PPARs (α, β, and γ). Activation of all isoforms, but primarily PPARα and γ, mediates some of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal, and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel.

Specific channels within the TRP family, such as TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8, have been identified as responsive to endogenous, phyto-, and synthetic cannabinoids.

3.5 Non-CB1/CB2 Targets

Besides their CB1/CB2 activity, numerous cannabinoids of endogenous, phytogenic, and synthetic nature have shown to exert their effects through the modulation of non-CB1, non-CB2 targets. This includes orphan GPCRs, such as GPR55, GPR18, GPR3, GPR6, or GPR12; GPCRs from well-established families such as adenosine, opioid, or serotonin receptors; TRP channels; nuclear receptors; or ligand-gated ion channels.

3.6 CBG: Mechanism of Action

CBG acts as a partial agonist of the CB1 and CB2 cannabinoid receptors. Cannabigerol (CBG) is a cannabinoid from the plant Cannabis sativa that lacks psychotomimetic effects. Its precursor is the acidic form, cannabigerolic acid (CBGA), which is, in turn, a biosynthetic precursor of the compounds CBD and Δ9-THC.

4. Scientific Evidence by Area of Use

4.1 Epilepsy

Cannabidiol has the most robust clinical evidence base of any single phytocannabinoid, particularly for pediatric treatment-resistant epilepsy syndromes. The aim of one systematic review was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques. Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Four trials involving 550 patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period was 19.5 [95% CI 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg/kg/day and placebo groups, and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg/kg/day and placebo arms, in favor of CBD.

The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg/kg/day group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. A separate systematic review focused on pediatric and juvenile populations: the included studies reported positive outcomes, with CBD leading to a reduction in seizure frequency ranging from 50% to complete seizure freedom. Adverse effects were mostly mild and reversible, including drowsiness, diarrhea, and loss of appetite. CBD emerges as a promising tool for refractory epilepsy in pediatric patients, showing efficacy in reducing seizure frequency and improving overall quality of life.

A meta-analysis of placebo-controlled trials found that CBD treatment was more efficacious compared to placebo (OR = 2.45, 95% CI = 1.81–3.32, p < 0.01). Despite this evidence, there are many challenges with CBD that hamper its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines.

Cannabigerol (in an animal-model dose range of 5 to 20 mg·kg⁻¹) and cannabidivarin (range 0.2 to 400 mg·kg⁻¹) displayed efficacy in animal models of Huntington's disease and epilepsy. Evidence for minor cannabinoids in epilepsy in human trials remains absent or very preliminary.

4.2 Pain

The National Academies of Sciences, Engineering, and Medicine report concluded that there was conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of pain in adults. However, the nature and degree of benefit varies by pain type. There is reasonable evidence that cannabinoids improve nausea and vomiting after chemotherapy. They might improve spasticity (primarily in multiple sclerosis). There is some uncertainty about whether cannabinoids improve pain, but if they do, it is neuropathic pain and the benefit is likely small.

A 2024 systematic review of CBD monotherapy for pain found that based on the review conducted, there is sufficient clinical and preclinical evidence of CBD in pain treatment, so CBD could be an effective and safe treatment in reducing pain due to its analgesic and anti-inflammatory properties. However, this review included both clinical and preclinical data, and trials evaluating CBD-only formulations generally demonstrated minimal or no statistically significant improvement in pain outcomes when considered in isolation from THC-containing formulations.

4.3 Nausea and Vomiting (Chemotherapy-Induced)

Among FDA-recognized indications for cannabinoid-based medicines are severe nausea and vomiting associated with chemotherapy (nabilone), spasticity associated with multiple sclerosis (nabiximols), and two types of treatment-resistant childhood seizure disorders — Dravet syndrome and Lennox-Gastaut syndrome — (cannabidiol). Synthetic THC products such as dronabinol (Syndros, Marinol) are available as capsules and oral solutions for the treatment of chemotherapy-induced nausea and vomiting as well as AIDS-related anorexia. No published trials have investigated the utility of cannabidiol or CBD-enriched products for combating nausea and vomiting, a question often asked by cancer patients seeking to avoid the psychoactive effects associated with THC.

4.4 Multiple Sclerosis and Spasticity

Nabiximols (Sativex), a combination THC/CBD oromucosal spray, is approved in several countries outside the United States for multiple sclerosis spasticity. The systematic review of systematic reviews by Allan et al. concluded that cannabinoids might improve spasticity, primarily in multiple sclerosis. Evidence strength here is rated as moderate by major systematic reviews.

4.5 Anxiety

CBD, a non-psychoactive compound derived from cannabis, has shown potential as an anxiolytic through its partial agonism of the 5HT-1A receptor and its negative allosteric modulation of CB1 receptors, which may help mitigate the anxiogenic effects of THC. A 2024 systematic review of randomized controlled trials on CBD and anxiety disorders evaluated the impact of CBD on individuals diagnosed with various anxiety disorders, comparing its effects to placebo and conventional pharmaceutical treatments. Clinical research on CBD has included studies related to the treatment of anxiety, addiction, psychosis, movement disorders, and pain, but there is insufficient high-quality evidence that CBD is effective for these conditions per the Wikipedia summary of the regulatory evidence base. Overall, the evidence for CBD in clinical anxiety disorders remains preliminary, with most studies small and short in duration.

4.6 Sleep

Cannabinoids, including the two main phytocannabinoids THC and CBD, are being increasingly utilized as pharmacological interventions for sleep disorders. THC and CBD are known to interact with the endocannabinoid and other neurochemical systems to influence anxiety, mood, autonomic function, and circadian sleep/wake cycle. However, their therapeutic efficacy and safety as treatments for sleep disorders are unclear. There is insufficient evidence to support routine clinical use of cannabinoid therapies for the treatment of any sleep disorder given the lack of published research and the moderate-to-high risk of bias identified within the majority of preclinical and clinical studies completed to date. The National Academies report found moderate evidence for secondary sleep disturbances.

4.7 Neuroprotection and Neurodegenerative Conditions

Cannabichromene (10–75 mg·kg⁻¹), Δ9-tetrahydrocannabinolic acid (20 mg·kg⁻¹), and tetrahydrocannabivarin (range 0.025–2.5 mg·kg⁻¹) showed promise in animal models of seizure and hypomobility, Huntington's and Parkinson's disease. Among the neuroprotective models studied were epilepsy, Huntington's disease, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, Rett syndrome, neuroinflammation, Alzheimer's, and oxidative stress. This evidence is entirely preclinical (animal and cell-based); no robust human clinical trial data currently supports the use of specific minor phytocannabinoids for these conditions.

4.8 Minor Cannabinoids: Emerging Preclinical Areas

Minor cannabinoids, including cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC), are gaining scientific attention for their distinct therapeutic potential beyond THC and CBD. Despite this growing interest, research on these compounds remains fragmented and underrepresented in the literature.

The use of minor cannabinoids has been advanced, in part, by the idea of providing relief from pain and inflammation without the burden of unwanted psychogenic effects associated with Δ9-THC. Investigators have focused on the effects of minor cannabinoid activation/desensitization of peripheral sensory neurons on nociceptive signaling and/or peripheral inflammation. Data reveal partial agonist activity for many phytocannabinoids at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids.

5. Body Systems and Health Areas

Phytocannabinoids interact with multiple physiological systems:

• Central Nervous System: CBD exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions. THC produces psychoactive effects via CB1 receptor agonism in the brain.
• Immune System: CB2 is mostly expressed in immune cells and mediates the anti-inflammatory effects of cannabinoids.
• Pain / Nociceptive System: Activation of PPARα and γ mediates some of the analgesic effects of some cannabinoids, in conjunction with activation of the CB1 and CB2 receptors and the TRPV1 ion channel.
• Gastrointestinal System: THC possesses analgesic and antiemetic properties, contributing to its therapeutic potential. CB1 and CB2 receptors are expressed throughout the gastrointestinal tract.
• Metabolic System: Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids.
• Cardiovascular System: PPARα and PPARγ activation by cannabinoids has been linked to cardiovascular effects in preclinical models, though human evidence is limited.
• Dermatological System: Topical phytocannabinoid preparations are used for skin conditions; CB1 and CB2 receptors are expressed in skin cells, but robust clinical trial evidence is currently lacking.

Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways.

6. Dosage Forms and Reported Dosages

6.1 Bioavailability by Route

The oral bioavailability of cannabidiol is approximately 6% in fasting state and 36.5–57.3% in fed-state in humans, while its bioavailability via inhalation is 11 to 45% (mean 31%). The sublingual bioavailability of cannabidiol is approximately 12 to 35%. The elimination half-life of cannabidiol in blood is 56 to 61 hours after oral doses twice per day over 7 days.

Following the oral intake of cannabis, multiple pharmacokinetic parameters contribute to a delayed onset, lower peak concentrations, and an extended duration of pharmacodynamic effects. Delayed oral absorption often results in repeat dosing and difficulty in dose titration by patients, which in turn can cause unintentional intoxication or overdose.

For THC, pharmacokinetics of the sublingual formulations of THC differ from oral formulations, with a faster onset of action (15–60 minutes), shorter time to reach peak effects (45 minutes), and a shorter duration of action (4–6 hours). Bioavailability of oral and smoked CBD in humans was found to be around 6% and 31%, respectively; and bioavailability of oral and smoked Δ9-THC is shown to be 4–12% and 10–27% respectively.

Several factors account for the low oral bioavailability of cannabinoids compared to intravenous administration, including low solubility and dissolution, variable absorption, degradation in the stomach, and significant first-pass metabolism to active and inactive metabolites in the liver.

6.2 Dosages Reported in Clinical Studies

• CBD for epilepsy (Dravet/LGS): Four trials involving 550 patients used CBD at doses of 10 mg/kg/day and 20 mg/kg/day as oral adjunctive treatment.
• CBD for pain (systematic review): Doses varied widely across included studies; no single standard dose was established across trials reviewed in the PRISMA-based 2024 systematic review.
• CBD sublingual wafer pharmacokinetics study: In an open-label, 4-way crossover study in 12 healthy volunteers, single doses of CBD as a sublingual wafer (25 or 50 mg CBD), oil solution (50 mg CBD), or nabiximols oromucosal spray (20 mg CBD + 21.6 mg THC) were used. For the multiple-dose study, sublingual wafer at 50 mg CBD was administered twice a day for 5 days.
• Nabiximols (Sativex) oromucosal spray: Sativex delivers 2.7 mg THC and 2.5 mg CBD per actuation.
• CYP interaction study: Participants received a brownie containing a CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC) or a Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD).
• Minor cannabinoids (animal models only): Cannabigerol was studied at a range of 5 to 20 mg·kg⁻¹ in animal models; cannabidivarin at 0.2 to 400 mg·kg⁻¹; and cannabichromene at 10–75 mg·kg⁻¹. No established human dosages exist for these compounds.

7. Safety Considerations and Drug Interactions

7.1 Cytochrome P450 Enzyme Interactions

Phytocannabinoids, the main bioactive compounds of Cannabis sativa, are metabolized by hepatic cytochrome P450 (CYP450) enzymes and can also modulate their function. Since CYP450 isoforms are responsible for the metabolism of approximately 80% of therapeutic drugs, interactions between phytocannabinoids and these enzymes may have clinically relevant consequences.

Studies report that phytocannabinoids, particularly CBD, exert inhibitory effects on several CYP450 isoforms, including CYP3A4, CYP2C9, and CYP2C19. One study indicated that CYP2C19 activity could also be induced under certain conditions. In contrast, CYP2D6 showed minimal or no modulation. Overall, CBD was consistently identified as a potent inhibitor of CYP enzymes responsible for drug metabolism.

Cannabidiol is metabolized primarily in the liver by CYP3A4 and to a lesser extent by CYP2C19. Strong interactions were determined to likely occur with high-dose oral CBD (700 mg) and CYP3A substrates, followed by moderate interactions with CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 substrates.

7.2 Specific Drug Interactions with Clinical Evidence

In clinical studies, an increased anticoagulant effect of warfarin was previously observed in smokers of cannabis, potentially due to inhibition of CYP2C9-mediated warfarin metabolism by cannabinoids and THC metabolites. THC, 11-OH-THC, THC-COO-Gluc, and CBD also strongly inhibited CYP2D6. Although CYP2D6 comprises a relatively small percentage (2–6%) of the total CYP450 protein in the liver, it is involved in the metabolism of 25% of the most commonly prescribed drugs (e.g., antidepressants, antipsychotics, opioids, and β-blockers).

In general, the interaction between antiepileptics and CBD increases antiepileptic drug levels, particularly for eslicarbazepine and brivaracetam. Although severe adverse effects were not reported in these interactions, it is recommended to monitor their plasma levels when they are co-administered with CBD. Other notable antiepileptics that interact with CBD are stiripentol and valproate. These interactions are especially crucial as they typically result in severe adverse effects, including rashes and raised liver enzymes.

Co-administering CBD with stiripentol and valproate led to elevated liver enzymes (AST/ALT). Rifampicin (a CYP3A4 inducer) decreased the concentrations of THC and CBD in 82–100% of participants in one study. Conversely, ketoconazole (a CYP3A4 inhibitor) increased THC and CBD concentrations by 63–100% among participants; due to the increased risk of adverse effects such as somnolence and dizziness, the ketoconazole dose should be reduced when co-administered with CBD.

7.3 Adverse Effects

Adjunctive CBD in patients with LGS or DS is associated with a greater reduction in seizure frequency and a higher rate of adverse events than placebo. In the clinical pharmacokinetics study, the extract was generally well tolerated by participants when administered in either wafer or oil form, with some adverse events, including mild or moderate somnolence, sedation, and altered perception. Adverse effects are very common, meaning that benefits would need to be considerable to warrant trials of therapy.

The ratio of 11-OH-THC to THC is greater than 1:1 following oral ingestion compared to less than 1:20 following inhalation. Production of the hydroxy metabolite 11-OH-THC, which is approximately 10 times more potent than THC itself, can cause psychogenic effects, including acute psychosis, especially in patients who take repeat doses because they do not feel the initial effects.

7.4 Variability and Standardization Concerns

There may be variation in potency of cannabinoid constituents from crop to crop and even in the same cannabis depending upon its age, moisture content, and methods of curing. Furthermore, oral ingested products often lack accurate information of the cannabinoid content per dosage and an accurate and reliable method to regulate the dosage of cannabinoids administered.

The absorption of CBD administered by various application routes is limited, erratic, and results in highly variable pharmacokinetic profiles. The poor aqueous solubility and extensive first-pass metabolism are thought to be the main reasons for the limited oral bioavailability.

8. Evidence Summary and Limitations

The evidence base for phytocannabinoids is highly heterogeneous across different compounds and indications. Although cannabinoids have been promoted for an array of medical conditions, the evidence base is challenged by bias and a lack of high-level research. The strongest clinical evidence exists for CBD in specific pediatric epilepsy syndromes (Dravet syndrome and Lennox-Gastaut syndrome), where multiple randomized controlled trials and meta-analyses support efficacy. For pain, nausea/vomiting from chemotherapy, and MS-related spasticity, there is conclusive or substantial evidence from systematic reviews, though largely for THC-containing preparations rather than CBD alone. Evidence for minor cannabinoids (CBG, CBC, CBN, THCV, CBDV) in humans remains absent or extremely limited, with most data derived from in vitro cell studies and animal models. The exploration of novel phytocannabinoids is rapidly evolving, offering exciting prospects for future therapeutic applications; beyond well-established compounds like THC and CBD, the quest for novel cannabinoids widens the scope of potential treatments.

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