THCV and CBDV: The Next Generation of Cannabinoids

While THC and CBD dominate public discourse, so-called "minor cannabinoids" are increasingly coming into the focus of research and the cannabis industry. Two particularly promising representatives are THCV (tetrahydrocannabivarin) and CBDV (cannabidivarin) – structural relatives of THC and CBD with surprisingly different effect profiles. This article provides a comprehensive overview of current research, therapeutic potentials, and practical aspects of these emerging cannabinoids.

## The Varin Cannabinoids: What Makes Them Special?

### Structural Differences

THCV and CBDV belong to the group of so-called varin cannabinoids. The structural difference from their "big siblings" THC and CBD lies in the side chain: THC and CBD possess a pentyl chain (5 carbon atoms), while THCV and CBDV carry a propyl chain (3 carbon atoms). This seemingly small difference has remarkably large effects on pharmacological properties.

The shorter side chain changes the three-dimensional shape of the molecule and thus its interaction with receptors in the endocannabinoid system. THCV binds differently to CB1 receptors than THC – at low doses even as an antagonist rather than an agonist. CBDV has a distinctly different interaction profile at TRP channels than CBD.

### Biosynthesis

In the cannabis plant, varin cannabinoids are produced via an alternative biosynthetic pathway. Instead of geranyl pyrophosphate and olivetolic acid (which lead to THC and CBD), divarinic acid is used as a precursor, which in turn is derived from geranyl pyrophosphate and divarinolic acid. This biosynthetic pathway is minimally active in most commercial cannabis cultivars, which is why THCV and CBDV typically occur only in small amounts.

## THCV: The "Sports Cannabinoid"

THCV is increasingly referred to as the "sports cannabinoid" or "diet weed" – nicknames that highlight its unique properties.

### Pharmacology of THCV

The most fascinating feature of THCV is its dose-dependent switch between CB1 antagonism and CB1 agonism.

**Low Doses (below 10 mg):** THCV acts as a CB1 antagonist or inverse agonist. It blocks the CB1 receptor and inhibits the action of endocannabinoids and THC. This leads to appetite-suppressing effects (opposite of THC-induced munchies), a clearer, more focused state of consciousness, possible support of energy metabolism, and no psychoactive effect.

**Higher Doses (above 10–15 mg):** At higher doses, the pharmacological profile shifts and THCV begins to act as a CB1 agonist – similar to THC but with a shorter, more energetic high. The psychoactive effect of THCV is often described as clear, focused, and stimulating – in contrast to the relaxing, sedating high of THC. The duration of effect at one to two hours is considerably shorter than THC (three to six hours when inhaled).

At the CB2 receptor, THCV is a partial agonist and shows anti-inflammatory properties that exist independently of CB1 status.

### Appetite Suppression and Metabolism

The appetite-suppressing effect of THCV is one of its best-researched effects and has generated considerable commercial interest.

**Preclinical Evidence:** Animal studies show that THCV reduces food intake, diminishes weight gain on high-fat diets, improves insulin sensitivity, and inhibits hepatic lipogenesis (fat formation in the liver). A study by Wargent et al. (2013) showed in ob/ob mice (a genetic obesity model) that THCV lowered fasting insulin levels, improved insulin tolerance, and reduced liver triglycerides.

**Clinical Evidence:** A placebo-controlled double-blind study (Jadoon et al., 2016) examined the effect of THCV (10 mg twice daily) in 62 patients with type 2 diabetes. The results were encouraging: THCV significantly lowered fasting blood glucose, improved beta cell function (measured by HOMA-2B), and reduced plasma concentrations of apolipoprotein A and adiponectin. However, the effect on body weight was not significant in this study, suggesting that the metabolic effects of THCV may work through direct cellular mechanisms rather than primarily through appetite reduction.

### THCV in Diabetes

Diabetes research on THCV is particularly promising and has attracted pharmaceutical industry interest.

**Mechanisms:** THCV likely improves insulin sensitivity through multiple pathways: CB1 antagonism in the liver reduces gluconeogenesis (glucose formation) and lipogenesis. CB2 agonism in adipocytes promotes fat oxidation and reduces inflammation in adipose tissue. Direct effects on pancreatic beta cells could improve insulin secretion. GPR55 antagonism (another cannabinoid-sensitive receptor) could influence glucose homeostasis.

**Comparison with Rimonabant:** The history of rimonabant – a synthetic CB1 antagonist that was approved as an anti-obesity drug and subsequently withdrawn from the market due to severe psychiatric side effects (depression, suicidality) – is relevant to THCV research. THCV differs from rimonabant in important ways: THCV is a partial inverse agonist (not a full inverse agonist like rimonabant), suggesting milder effects. THCV has a shorter half-life and does not accumulate systemically. THCV has additional CB2-agonistic and possibly 5-HT1A-agonistic properties that could have mood-stabilizing effects.

### THCV and Energy

The energizing effect of THCV is one of the reasons for its growing popularity in the wellness scene. Users report increased alertness and mental clarity, improved focus and concentration, a "clean" energy boost without jitteriness, and improved athletic performance (anecdotal). The pharmacological basis for these effects may lie in CB1-antagonism-mediated modulation of dopaminergic signaling pathways. CB1 receptors in the basal ganglia and prefrontal cortex influence dopamine signaling, and their blockade could produce activating effects.

### THCV in Neurological Diseases

Preclinical studies show promising neuroprotective properties of THCV.

**Parkinson's Disease:** Garcia et al. (2011) showed in a rat model of Parkinson's disease that THCV protected dopaminergic neurons in the substantia nigra from degeneration. The mechanism appears to be mediated through CB2 activation and antioxidant effects. THCV also improved motor performance in treated animals.

**Epilepsy:** Although the evidence for THCV in epilepsy is less strong than for CBD, some preclinical models show anticonvulsive properties of THCV. The CB1-antagonistic effect at low doses could be antiepileptic by modulating the excitatory-inhibitory balance in the brain.

## CBDV: The Underestimated Varin Cannabinoid

While THCV is receiving increasing attention, CBDV remains relatively overlooked – unjustifiably so, as its therapeutic potentials are remarkable.

### Pharmacology of CBDV

CBDV, like CBD, has no psychoactive effect. It does not bind, or binds only minimally, to CB1 and CB2 receptors. Instead, CBDV acts through other pharmacological targets:

**TRP Channels:** CBDV is a potent agonist at TRPV1, TRPV2, and TRPA1 channels. The activation and subsequent desensitization of these channels (tachyphylaxis) is the likely mechanism behind CBDV's anticonvulsive and analgesic properties. Interestingly, CBDV shows higher potency at TRP channels than CBD.

**GPR55:** CBDV antagonizes the GPR55 receptor, discussed as a possible third cannabinoid receptor. GPR55 antagonism could mediate anticonvulsive, anti-inflammatory, and possibly antitumoral effects.

**Diacylglycerol Lipase (DAGL):** CBDV inhibits DAGL, an enzyme involved in the biosynthesis of the endocannabinoid 2-AG. This could have indirect effects on endocannabinoid signaling.

### CBDV in Epilepsy

The anticonvulsive effect of CBDV is its best-researched therapeutic potential.

**Preclinical Data:** Several studies in different epilepsy animal models show that CBDV reduces seizure frequency and severity. Hill et al. (2012) demonstrated that CBDV was significantly anticonvulsive in both pentylenetetrazol-induced and pilocarpine-induced epilepsy models. Amada et al. (2013) showed that the anticonvulsive effect of CBDV is likely mediated through TRPV1 desensitization rather than cannabinoid receptors.

**Clinical Studies:** GW Pharmaceuticals (now Jazz Pharmaceuticals) has conducted several clinical studies on CBDV in epilepsy. A phase 2 study in focal epilepsy (GWP42006) yielded mixed results – the primary endpoint (reduction in seizure frequency) was not significantly achieved, but subgroup analyses showed promising trends for certain seizure types. Further studies are planned or ongoing.

### CBDV and Autism Spectrum Disorders (ASD)

One of the most exciting research areas for CBDV is autism spectrum disorder.

**Preclinical Evidence:** Zamberletti et al. (2019) showed in a valproic acid-induced autism mouse model that CBDV improved social interaction deficits, reduced repetitive behaviors, improved cognitive flexibility, and corrected endocannabinoid dysregulations.

**Clinical Studies:** A placebo-controlled crossover study (GW Pharmaceuticals) examined CBDV in 34 adults with autism spectrum disorder. The study measured changes in brain activity using functional magnetic resonance imaging (fMRI). Preliminary results showed that CBDV modulated the excitatory-inhibitory balance in brain regions typically altered in autism (particularly the basal ganglia and prefrontal cortex). CBDV increased glutamate levels in the basal ganglia region, which was interpreted as normalization of the hypofunction observed in ASD.

**Mechanistic Rationale:** The possible efficacy of CBDV in ASD is supported by several observations. TRPV1 channels are involved in synaptic plasticity, which is altered in ASD. Endocannabinoid dysregulations have been documented in autism patients (altered blood anandamide levels). The excitatory-inhibitory imbalance in the brain – a core feature of ASD – could be addressed by CBDV through TRP channel modulation and endocannabinoid system influence.

### CBDV as an Antiemetic

CBDV shows remarkable antiemetic properties.

**Animal Studies:** Rock et al. (2013) showed in a shrew model that CBDV significantly reduced nausea and vomiting. The effect was comparable to ondansetron, a standard antiemetic. The mechanism appears to be mediated via 5-HT1A receptors rather than cannabinoid receptors.

**Clinical Relevance:** The antiemetic effect of CBDV could be significant for chemotherapy-induced nausea, motion sickness, morning sickness in pregnancy (provided safety is confirmed), and postoperative nausea. The advantage over THC as an antiemetic lies in the absence of psychoactive effects.

### Further Potential Applications of CBDV

**Inflammatory Bowel Disease:** Pagano et al. (2019) showed in a mouse colitis model that CBDV reduced intestinal inflammation and improved gut barrier function. The mechanism appears to be mediated through TRPA1 modulation and regulation of the intestinal endocannabinoid system.

**Duchenne Muscular Dystrophy (DMD):** A preclinical study by Iannotti et al. (2019) showed that CBDV improved the condition of muscle cells in a DMD model. CBDV promoted autophagy (cellular self-cleaning) and reduced chronic inflammation in muscle tissue.

## Cannabis Strains with High THCV and CBDV Content

### THCV-Rich Strains

THCV naturally occurs in higher concentrations in cannabis strains with African genetics, particularly from the regions of Malawi, South Africa, and the Congo. Well-known THCV-rich strains include Durban Poison (African sativa with THCV levels up to 1–2%), Doug's Varin (specifically bred for THCV, up to 6% THCV), Pineapple Purps (hybrid cross with elevated THCV), Jack the Ripper (sativa-dominant with moderate THCV), and Pink Boost Goddess (bred for high THCV content). In practice, THCV levels above 3 percent in natural strains are rare. Most commercial THCV products therefore use THCV isolate obtained synthetically or through selective extraction.

### CBDV-Rich Strains

CBDV-rich strains frequently originate from Indian landrace populations, particularly from the North India and Nepal region. In commercial strains, CBDV is rarely found in high concentrations. The highest CBDV levels (up to 1–2%) have been found in certain indica landraces from the Himalayan region. Breeding programs, particularly by GW Pharmaceuticals, have developed strains with elevated CBDV content, though these are primarily intended for pharmaceutical production rather than the consumer market.

## Availability and Products

### THCV Products

THCV products are available in a growing market, though availability varies significantly by region. In the US, THCV gummies, tinctures, and vapes are available in many legal cannabis markets. In Europe and Germany, availability is considerably more limited. THCV products are more expensive than THC or CBD products due to more complex production. Quality differences are significant, and independent laboratory analyses are particularly important.

### CBDV Products

CBDV products are less widespread than THCV products. They are found mainly as CBDV oils, CBDV capsules, and in combination products with CBD. The pharmaceutical development of CBDV (as GWP42006 by Jazz Pharmaceuticals) could lead to approved CBDV medications in the long term.

### Quality and Purity

For both cannabinoids, the same quality requirements apply as for other cannabis products: independent laboratory analyses (CoA) are essential. Products should be tested for residual solvents, pesticides, heavy metals, and microbiological contaminants. The declared cannabinoid content should be confirmed by laboratory analyses. Particular caution is warranted with THCV products, as some may contain significant THC quantities.

## Legal Situation

### THCV

The legal classification of THCV is complex and varies by region. In Germany, THCV as a THC derivative potentially falls under KCanG regulations. The exact legal assessment depends on the origin (industrial hemp vs. high-THC cannabis) and the THC content of the final product. Consumers should inform themselves about the current legal status before purchasing. In the US, the legal situation is also inconsistent – some states allow THCV from hemp (below 0.3% delta-9-THC), while others classify it as a controlled substance.

### CBDV

CBDV is legally less problematic than THCV, as it has no psychoactive effect and does not fall under narcotics laws. In the EU, however, it is classified as a novel food, which restricts its sale as a dietary supplement. Pharmaceutical approval of CBDV-based medications could change the regulatory situation.

## Research Outlook

### THCV

THCV research is focusing on several promising areas: phase 2 and phase 3 studies in type 2 diabetes and metabolic syndrome, investigations of weight management efficacy, exploration of neuroprotective properties in Parkinson's and Alzheimer's disease, combination with GLP-1 receptor agonists (such as semaglutide) for synergistic metabolic effects, and development of THCV-selective controlled-release formulations.

### CBDV

CBDV research is still in its early stages, but several directions are promising: expanded clinical trials in autism spectrum disorders, epilepsy studies with specific seizure types, investigations in inflammatory bowel disease, development of topical formulations for muscle and joint conditions, and exploration of effects in Duchenne muscular dystrophy.

## Summary

THCV and CBDV represent a new class of cannabinoids that fundamentally differ from THC and CBD. THCV impresses with its unique dose-dependent profile – appetite-suppressing and clarity-enhancing at low doses, briefly psychoactive at higher doses – and its promising metabolic effects in diabetes. CBDV shows remarkable therapeutic potential in epilepsy, autism spectrum disorders, and as an antiemetic. Both cannabinoids are still in the early stages of clinical investigation, but the data so far suggest they could significantly expand the palette of cannabinoid-based therapies.