Why Full-Spectrum CBD Has Little to No Effect on Some People

CBD (cannabidiol) has surged in popularity as a natural remedy for pain relief, anxiety, sleep disorders, and inflammation. However, while many people report positive experiences, others find little to no noticeable effect, even when using high-quality full-spectrum CBD.

This can be frustrating, especially when CBD is marketed as a game-changing wellness supplement. If CBD works for some people but not for others, what’s causing the difference?

The reality is that CBD is not a one-size-fits-all compound. A variety of factors influence how well CBD works, including:

• Differences in the endocannabinoid system (ECS)
• Genetic variations in cannabinoid receptor sensitivity
• Differences in metabolism and liver enzyme activity
• The quality and formulation of CBD products
• The role of THC and the entourage effect
• Existing tolerance to cannabinoids

This comprehensive article explores why some individuals may not experience noticeable effects from full-spectrum CBD and what scientific research suggests about these differences.

1. Understanding the Endocannabinoid System (ECS) and Its Variability

What is the ECS?

The endocannabinoid system (ECS) is a biological system that helps regulate a wide range of physiological processes, including:

• Pain perception
• Mood and stress response
• Inflammation and immune function
• Appetite and metabolism
• Cognitive function and memory
• Sleep-wake cycles

The ECS consists of:

1. Endocannabinoids – Naturally occurring cannabinoids in the body, including anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
2. Receptors – CB1 receptors (primarily found in the brain and nervous system) and CB2 receptors (found in the immune system and peripheral tissues).
3. Enzymes – Responsible for synthesizing and breaking down cannabinoids (e.g., FAAH breaks down anandamide).

How CBD Works with the ECS

Unlike THC, which directly binds to CB1 receptors, CBD does not activate CB1 or CB2 receptors in the same way. Instead, it modulates receptor activity, inhibits the breakdown of anandamide, and interacts with serotonin (5-HT1A) and TRPV1 receptors.

Why Some People May Not Respond to CBD

CBD’s indirect mechanism means that its effects are highly dependent on the individual’s ECS function. If someone has:

• A naturally low density of CB1 and CB2 receptors, they may not respond strongly to cannabinoids.
• An already well-balanced ECS, their body may not need external cannabinoids for regulation.
• Higher natural endocannabinoid production, they may not require CBD supplementation to achieve homeostasis.

Research suggests that endocannabinoid tone (the level of endocannabinoid activity in the body) varies from person to person. People with high natural levels of anandamide may experience little to no effect from CBD, as their ECS is already functioning optimally (Di Marzo et al., 2015).

2. Genetic Variations and CBD Responsiveness

Genetics and the ECS

Genetics plays a major role in how the body interacts with cannabinoids. Individual genetic differences can affect cannabinoid receptor sensitivity, enzyme function, and endocannabinoid production.

Key genetic factors influencing CBD effectiveness include:

1. Variations in CB1 and CB2 Receptor SensitivityThe CNR1 gene, which encodes CB1 receptors, has multiple variants that affect receptor sensitivity (Watson et al., 2000).Some people have less responsive CB1 receptors, reducing CBD’s impact.
2. Natural Differences in Endocannabinoid Levels FAAH enzyme activity determines how quickly anandamide is broken down.Individuals with high FAAH activity have lower anandamide levels and are more likely to benefit from CBD.Those with low FAAH activity already have high anandamide levels and may not need CBD.
3. CYP450 Gene VariabilityThe CYP450 family of liver enzymes metabolises CBD.Genetic mutations in CYP2C19 and CYP3A4 can affect how fast or slow CBD is broken down.

3. Metabolism and CBD Absorption

How CBD is Metabolised

CBD is fat-soluble, meaning it needs to be absorbed into fat before entering the bloodstream. The liver metabolises CBD using cytochrome P450 enzymes (CYP450), which play a role in breaking down a wide range of substances, including:

• Pharmaceutical drugs
• Caffeine and alcohol
• Other cannabinoids

Why Some People Metabolise CBD Too Quickly

• Fast metabolisers (people with highly active CYP450 enzymes) break down CBD too quickly, meaning it leaves their system before taking effect (Miller, 2018).
• Slow metabolisers may experience longer-lasting effects but require higher doses to feel an impact.
• Metabolic rate is also influenced by age, liver health, diet, and genetics.

4. The Entourage Effect and the Role of THC

What is the Entourage Effect?

The entourage effect refers to the way multiple cannabinoids, terpenes, and flavonoids interact to enhance each other’s effects. Full-spectrum CBD contains:

• CBD (cannabidiol)
• THC (tetrahydrocannabinol, in small amounts)
• CBG, CBN, CBC, and other minor cannabinoids
• Terpenes like myrcene, limonene, and linalool

Why Some People Need THC to Activate CBD’s Effects

CBD alone does not bind strongly to CB1 receptors, but THC does. Some individuals may require higher THC content for CBD to work effectively.

In Australia, CBD products must contain less than 0.3% THC to remain legally available. This means that the entourage effect may be weaker, potentially leading to reduced effectiveness in some individuals.

People who do not respond well to low-THC CBD products may find THC-inclusive products more effective (where legal).

5. Tolerance and Cannabinoid Desensitisation

Some individuals develop tolerance to cannabinoids, reducing CBD’s effectiveness over time.

What Causes CBD Tolerance?

1. CB1 Receptor DownregulationFrequent CBD use can lead to CB1 receptor desensitisation, making the body less responsive.
2. High Natural Anandamide LevelsSome people already produce high amounts of anandamide, making external cannabinoids less necessary.
3. Cross-Tolerance from THC or Other CannabinoidsHeavy cannabis users may require higher doses of CBD due to cross-tolerance effects.

How to Reset Cannabinoid Tolerance

A CBD tolerance reset (1-2 weeks without CBD) may help restore receptor sensitivity.

Conclusion

CBD affects people differently due to a combination of genetic, metabolic, and biological factors. If full-spectrum CBD isn’t working, the issue may stem from:

• Variability in ECS receptor density
• Genetic differences in cannabinoid processing
• Fast metabolism of CBD
• The lack of THC in legal CBD products
• Tolerance buildup

Understanding these factors can help individuals make more informed decisions about their CBD use.

References

• Bonn-Miller, M. O., Loflin, M. J. E., Thomas, B. F., Marcu, J. P., Hyke, T., & Vandrey, R. (2017). Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA, 318(17), 1708-1709. https://doi.org/10.1001/jama.2017.11909
• Di Marzo, V., Stella, N., & Zimmer, A. (2015). Endocannabinoid signalling and the deteriorating brain. Nature Reviews Neuroscience, 16(1), 30-42. https://doi.org/10.1038/nrn3876
• Iuvone, T., Esposito, G., De Filippis, D., Scuderi, C., & Steardo, L. (2009). Cannabidiol: A Promising Drug for Neurodegenerative Disorders? CNS Neuroscience & Therapeutics, 15(1), 65-75. https://doi.org/10.1111/j.1755-5949.2008.00065.x
• Miller, J. (2018). Cytochrome P450 and Drug Metabolism. Pharmacology Weekly, 10(2), 21-30.
• Millar, S. A., Stone, N. L., Yates, A. S., & O'Sullivan, S. E. (2020). A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Frontiers in Pharmacology, 11, 569. https://doi.org/10.3389/fphar.2020.00569
• Russo, E. B. (2011). Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects. British Journal of Pharmacology, 163(7), 1344-1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
• Watson, S. J., Benson, J. A., Joy, J. E. (2000). Marijuana and Medicine: Assessing the Science Base. National Academies Press.