IngredientsCannabidivarin (CBDV) is a non-psychoactive plant constituent with the molecular formula C19H26O2 from the family of cannabinoids (phytocannabinoids), which occurs in various cannabis species. It is also known by the investigational drug designation GWP42006. Other synonyms recorded in the literature include cannabidivarol and CBD-V. Its IUPAC name is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-propylbenzene-1,3-diol.
CBDV is a non-psychoactive phytocannabinoid that belongs to the varinic class of cannabinoids. It is structurally homologous to cannabidiol, through the presence of a shorter propyl side chain. More precisely, it is a homolog of cannabidiol (CBD), with the side-chain shortened by two methylene bridges (CH2 units). The molecular structure of CBDV is similar to CBD (cannabidiol), but it has a propyl chain instead of a pentyl chain. This slight difference classifies CBDV as a propyl cannabinoid, meaning the cannabinoid contains a three-carbon side chain. Similarly to CBD, it has seven double bond isomers and 30 stereoisomers.
CBDV is a chemical in the Cannabis sativa plant. Although cannabidivarin (CBDV) is usually a minor constituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral populations of C. indica (= C. sativa ssp. indica var. kafiristanica) from northwest India, and in hashish from Nepal. It is also present in many Mexican populations of cannabis, although in much smaller quantities. Generally, CBDV is found in plants that are higher in CBD and lower in THC. CBDV is typically present in much smaller amounts, often in less than 1% in most plants.
Cannabidivarinic acid (CBDVA) is the acidic precursor to CBDV. CBDV (and THCV for that matter) are biosynthesized using a different pathway. Geranyl pyrophosphate and divarinolic acid undergo a chemical reaction to biosynthesize cannabigerovarin acid (CBGVA). After this step, the pathway is the same as that required to synthesize CBD and THC, whereby cannabinoid synthases break down CBGVA into THCV or CBDV. The CBDV chemotype results from the breeding of plants which carry both postulated BD and APR genes. The BD gene instructs the plants to synthesize the cyclic part of the CBD molecule and the APR gene instructs the plant to synthesize this molecule with a propyl side chain, as opposed to the usual pentyl chain found in CBD.
A CBDV botanical drug substance (BDS) can be obtained from extraction of CBDV-rich plants. Such chemovars are bred specifically to produce a significant proportion of their cannabinoids as CBDV. CBDV BDS can also be prepared by adding isolated CBDV to a cannabinoid-free BDS. In clinical trial settings, the CBDV sourced from GW Pharmaceuticals was a plant-based oil extract of Cannabis sativa, containing 50 mg/ml of CBDV and <0.2% wt/wt THC. Pharmaceutical development of CBDV is limited due to low oral bioavailability, high oxidative and photolytic sensitivity.
CBDV has no documented history of use as an isolated or recognized compound in traditional medicine. Its identity as a discrete molecule was not established until the modern era. The substance was first identified in 1969 by Vollner et al. In 1971, Frans and Merkus wrote about CBDV and tetrahydrocannabivarin (THCV), stating that they were "two more components of hashish." Only recently did CBDV become the subject of detailed research, well over 40 years after its first identification.
The cannabis plant in which CBDV naturally occurs — including the C. indica varieties from northwest India and Nepalese hashish in which higher concentrations are found — has been used historically in a range of traditional medicinal and ritual systems in South Asia. However, the scientific literature does not document any traditional use of CBDV as a specific, recognized constituent; traditional preparations utilized the whole plant or crude extracts, in which CBDV would have been one of many minor cannabinoids present in trace amounts. There are few studies into CBDV's efficacy for treating any condition before 2012. Because no authoritative source documents traditional use of CBDV specifically (as distinct from cannabis broadly), any association with traditional medicine would be speculative.
CBDV modulates CB2 receptors, transient receptor potential (TRP) channels, G-protein-coupled receptors (GPRs), dopaminergic pathways, and the endocannabinoid system. Crucially, its anticonvulsant and other neurological effects appear to be largely independent of the classical cannabinoid receptor pathway: CBDV botanical drug substances exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor.
TRP Channels: A key documented mechanism involves transient receptor potential (TRP) channels. Research published in ACS Chemical Neuroscience (Iannotti et al., 2014) demonstrated that nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro, with potential for the treatment of neuronal hyperexcitability. CBDV exhibits potent human TRPA1, TRPV1 and TRPV2 agonism and TRPM8 antagonism. At less than 1 μM, TRPA1, TRPM8, and TRPV4 are influenced by CBDV.
Regarding the specific mechanism by which CBDV reduces neuronal hyperexcitability, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg2+-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization.
Endocannabinoid System Modulation: CBDV has also been shown to inhibit the activity of diacylglycerol (DAG) lipase-α, the primary enzyme responsible for the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The clinical implications of this are unclear, however, as this interaction has not been shown to affect CBDV's anticonvulsant activity.
TLR4/MD2 (Neuroinflammation): A 2022 study published in PMC identified a further mechanism: CBDV was identified as an antagonist of TLR4 (Toll-like receptor 4). In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α.
GPR55: In animal models of Rett syndrome, increased levels of GPR55 were found in RTT mouse hippocampus, suggesting this G protein-coupled receptor as a new potential target for the treatment of this disorder.
Glutamate-GABA System: Human neuroimaging research has suggested that CBDV acts upon the brain's excitation-inhibition balance. Findings from magnetic resonance spectroscopy suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the basal ganglia but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry.
Epilepsy-Related Gene Expression: Preclinical molecular work has shown that CBDV exerts effects upon chemically-induced seizures at the molecular level, providing the first molecular confirmation of behaviourally observed anticonvulsant effects of the non-psychoactive cannabinoid.
CB1/CB2 Receptor Affinity: Due to its alkyl chains filling the hydrophobic sites of CB1R and CB2R, CBDV exhibits weaker or even non-psychoactive activity compared to other phytocannabinoids. The binding affinity between CBDV and CB2R reaches a value of 574.2 ± 146.1 nM.
CBDV has gained considerable research interest due to growing preclinical evidence supporting many therapeutic potentials. The foundational preclinical work was published by Hill et al. in the British Journal of Pharmacology (2012), establishing that CBDV is anticonvulsant in multiple rodent models. A subsequent study (Hill et al., 2013) examined CBDV botanical drug substances (BDSs): CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg/kg) and audiogenic seizure models (≥87 mg/kg), and suppressed pilocarpine-induced convulsions (≥100 mg/kg). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. A 2013 study published in PeerJ (Amada et al.) showed that CBDV suppressed pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression, providing molecular-level confirmation of anticonvulsant action.
The most methodologically rigorous human trial to date was a Phase 2 RCT conducted by Brodie et al. (2021), published in Cannabis and Cannabinoid Research. The objective was to assess the efficacy, safety, and tolerability of cannabidivarin (CBDV) as add-on therapy in adults with inadequately controlled focal seizures. One hundred and sixty-two participants (CBDV n=81; placebo n=81) were enrolled. After a 4-week baseline, participants titrated from 400 to 800 mg CBDV twice daily (b.i.d.) or placebo over 2 weeks, followed by 6 weeks stable dosing (at 800 mg b.i.d.) and a 12-day taper period.
Median baseline focal seizure frequencies were 17–18 per 28 days in both groups, and similar reductions in frequency were observed in the CBDV (40.5%) and placebo (37.7%) groups during the treatment period. It is likely the 40.5% seizure reduction with CBDV represents an appropriate pharmacological response in this population with focal seizures. The placebo response was, however, high, which may reflect the participants' expectations of CBDV, and a treatment difference from placebo was not observed. CBDV was generally well tolerated. The trial's authors concluded that add-on CBDV treatment in participants with focal seizures had an acceptable safety profile, but there was no difference in seizure reductions between the CBDV and placebo groups. This is a null result for the primary efficacy endpoint. Evidence strength: a single Phase 2 RCT with a negative primary endpoint; insufficient to establish efficacy for focal seizures.
Rett syndrome (RTT), commonly caused by methyl-CpG-binding protein 2 (MECP2) pathogenic variants, has many comorbidities. Fifty to ninety percent of children with RTT have epilepsy, which is often drug-resistant. Cannabidivarin (CBDV), a non-hallucinogenic phytocannabinoid, has shown benefit in MECP2 animal models. This phase 1 trial assessed the safety and tolerability of CBDV in female children with RTT and drug-resistant epilepsy, as well as the effect on mean monthly seizure frequency (MMSF), the electroencephalogram (EEG), and non-epilepsy comorbid symptoms.
Five female children with drug-resistant epilepsy and a pathogenic MECP2 variant were enrolled. CBDV oral solution (50 mg/ml) was prescribed and titrated to 10 mg/kg/day. Patients began CBDV treatment at 2.5 mg/kg twice per day. If no side effects were reported, the dose was increased by an additional 2.5 mg/kg every week up to a maximum dose of 10 mg/kg per day. The final mean dose was 9.9 mg/kg daily.
Key findings: Cannabidivarin (CBDV) dosing at 10 mg/kg/day is safe and tolerated in a pediatric RTT population, and CBDV reduced mean monthly seizure frequency in females with RTT and drug-resistant epilepsy. No serious adverse events reported were related to CBDV. No significant change was noted in EEG or non-epilepsy-related symptoms of RTT. Evidence strength: preliminary Phase 1 safety data only, n=5; efficacy findings are hypothesis-generating.
A 2019 study published in Translational Psychiatry (Pretzsch et al.) used a repeated-measures, double-blind, randomized-order, crossover design to test the effects of CBDV on brain neurochemistry in adults with and without ASD. The main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites — markers of the brain's primary excitatory and inhibitory system — in both the 'typical' and autistic brain. CBDV had no significant impact on Glx in the dorsomedial prefrontal cortex, or on GABA+ in either voxel in either group. Findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the basal ganglia but not in frontal regions.
A subsequent pilot study published in Molecular Autism (2021) examined resting-state functional MRI. To examine this in a small pilot study, researchers acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study, using a seed-based approach to compare striatal functional connectivity (FC) and examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout. Compared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions; they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level.
Researchers provided preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms. An important limitation: findings should be considered in light of several methodological aspects, in particular the participant group (restricted to male adults), which limits the generalizability of findings to the wider and heterogeneous ASD population.
A 52-week open-label safety and tolerability trial (NCT03849456) studied CBDV in children and young adults with ASD: it was a 52-week, open-label trial to evaluate the safety and tolerability of GWP42006, with participants starting at a dose of 2.5 mg/kg/day and titrating to a target dose of 10 mg/kg/day or 800 mg/day, whichever is smaller, during the first 4 weeks of treatment. The study was terminated due to enrollment challenges during the COVID-19 pandemic. A separate 12-week randomized, double-blind trial (NCT03202303) comparing CBDV to placebo in 100 children with ASD (ages 5–18) focused on irritability as the primary endpoint: this study aimed to examine the efficacy and safety of CBDV with a primary aim of studying its effect on irritability in children with ASD and used a 12-week randomized, double-blind design of CBDV vs. placebo in 100 child and adolescent subjects.
Evidence strength for ASD: imaging biomarker studies are preliminary and do not measure clinical outcomes; the larger interventional RCTs have not yet reported definitive efficacy results. All available clinical evidence is exploratory.
Animal model work is substantial. Systemic treatment with CBDV (2, 20, 100 mg/kg ip for 14 days) rescues behavioural and brain alterations in MeCP2-308 male mice, a validated RTT model. The CBDV treatment restored the compromised general health status, the sociability and the brain weight in RTT mice. A partial restoration of motor coordination was also observed. In October 2017, CBDV received orphan designation from the European Medicines Agency for use in Rett syndrome and again in February 2018 for the treatment of fragile X syndrome. Evidence for non-epileptic RTT symptoms: preclinical (animal model) only; the Phase 1 trial (Hurley 2022) found no significant change in non-epilepsy-related symptoms of RTT.
Rock et al. (2013), published in British Journal of Pharmacology, evaluated whether CBDV produces the inverse agonism symptoms at CB1 receptors that cause nausea in rats. The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists. As well, these compounds may have therapeutic potential in reducing nausea. Specifically, CBDV reduced LiCl-induced conditioned gaping as is observed with THC and HU-210. Evidence strength: preclinical (rat model) only; no human data are available specifically for CBDV and nausea.
A study published in PMC (2022) demonstrated that in cell-based systems, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbens. This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management. Additionally, a hot plate test showed that CBDV potentiated morphine-induced antinociception. CBDV alone showed no analgesic activity as tested by the hot plate assay while CBDV showed analgesic effects in both the acute phase and tonic phase as measured by the formalin test. Evidence strength: in vitro and animal model evidence only; no human clinical data available.
CBDV oral solution (50 mg/ml) was prescribed and titrated to 10 mg/kg/day in the Rett syndrome Phase 1 trial. Patients began CBDV treatment at 2.5 mg/kg twice per day. If no side effects were reported, the dose was increased by an additional 2.5 mg/kg every week up to a maximum dose of 10 mg/kg per day.
In the Phase 2 focal seizure RCT, participants titrated from 400 to 800 mg CBDV twice daily (b.i.d.) or placebo over 2 weeks, followed by 6 weeks stable dosing (at 800 mg b.i.d.).
In the ASD open-label safety trial (NCT03849456), participants started GWP42006 at a dose of 2.5 mg/kg/day and titrated to a target dose of 10 mg/kg/day or 800 mg/day, whichever is smaller, during the first 4 weeks of treatment.
In the human neuroimaging (fMRI) pilot study of striatal connectivity in ASD, pharmacological probing used 600 mg CBDV or matched placebo.
There is not enough reliable information to know what an appropriate dose of cannabidivarin might be outside the context of specific clinical trials or supervised research settings. No standardized dose has been established for any indication.
Like Δ9-THC, CBDV has low water solubility and poor oral bioavailability (~6% in humans), making oral administration an unfavourable method of delivery. Significant first-pass metabolism by the liver results in erratic absorption from the GI tract, low bioavailability, and unreliable pharmacokinetics.
CBDV has relatively rapid absorption with peak concentrations seen around 2 hours after oral administration in animal pharmacokinetic studies. Orally administered CBDV in mice was found to have a plasma Cmax of 0.47 μg/mL and Tmax of 30 minutes, and a brain Cmax of 0.94 μg/mL and Tmax of 60 minutes. Due to its lipophilicity, CBDV has been shown to cross the blood-brain barrier. Orally administered CBDV in mice was found to have a plasma elimination half-life of 222 minutes, and a brain elimination half-life of 204 minutes.
Clinical studies indicate that CBDV is well-tolerated, but its efficacy remains limited due to poor systemic exposure and a lack of optimized formulation strategies. The solubility of CBDV is poor, which may limit the therapeutic applications of CBDV by its low bioavailability. Incorporating CBDV into a novel drug delivery system is proposed to boost its bioavailability, prolong its half-life, and enhance the therapeutic effect.
The most detailed human safety data derives from the Brodie et al. (2021) Phase 2 RCT in focal epilepsy. Overall, 59 (72.8%) of participants in the CBDV group and 39 (48.1%) in the placebo group had ≥1 treatment-emergent adverse event (AE); the 3 most common were diarrhea, nausea, and somnolence. The incidence of serious AEs was low (3.7% in the CBDV group vs. 1.2% in the placebo group). There was little or no effect of CBDV on vital signs, physical examination, or electrocardiogram findings.
Hepatic Safety Signal: Elevations in serum transaminases (alanine aminotransferase or aspartate aminotransferase) to levels >3× upper limit of normal occurred in three participants taking CBDV (two discontinued as a result) and one taking placebo; however, none met the criteria for potential Hy's Law cases. This transaminase elevation parallels the known hepatic signal observed with pharmaceutical CBD (Epidiolex) in epilepsy trials, particularly when co-administered with valproate.
In the Rett syndrome Phase 1 trial: hypersomnolence and drooling were the only identified drug-related adverse events. No serious adverse events reported were related to CBDV.
The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists, which would be expected if CBDV produced psychoactive or dysphoric effects via that mechanism. CBDV is a non-intoxicating psychoactive cannabinoid found in Cannabis — meaning it may affect brain function without producing the intoxicating "high" associated with THC.
No specific, well-characterized drug-drug interaction data for CBDV as a standalone agent has been published in peer-reviewed clinical literature as of the sources available. In the Phase 2 focal seizure trial, participants were receiving one to three concomitant antiseizure medications alongside CBDV. Eligible participants had seizures despite prior treatment with at least two ASMs and were receiving one to three concomitant ASMs. The transaminase elevations observed in that trial, though not meeting Hy's Law criteria, suggest caution regarding hepatic enzyme monitoring in polypharmacy contexts, particularly given that the structurally related compound CBD is known to interact with CYP3A4 and CYP2C19 enzymes. By structural and metabolic analogy, similar interactions may occur with CBDV, but this has not been directly characterized in published clinical studies.
In October 2017, CBDV received orphan designation from the European Medicines Agency for use in Rett syndrome and again in February 2018 for the treatment of fragile X syndrome. It is not scheduled by the Convention on Psychotropic Substances. No CBDV-based medicine has received full regulatory approval (FDA or EMA) for any indication as of the date of the sources reviewed here.
Clinical studies indicate that CBDV is well-tolerated, but its efficacy remains limited due to poor systemic exposure and a lack of optimized formulation strategies. The available evidence positions CBDV as a pharmacologically promising cannabinoid that remains underexplored.
The weight of evidence currently available on CBDV is as follows:
Health conditions that Cannabidivarin may help support.
Body systems that Cannabidivarin may help support.
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