Accurate Education – Marijuana (Cannabis): Terpenes – Limonene

Limonene is an aromatic terpene abundant in citrus fruits like oranges, lemons, and grapefruits, known for its fresh citrus aroma and therapeutic potential. As an antioxidant and anti-inflammatory agent, it contributes to chronic pain management, and the forces that drive it. It promotes relaxation and has been shown to improve anxiety and stress.

Limonene can be inhaled as aromatherapy using a room diffuser for rapid onset (1–5 minutes), or orally. Dietary sources include citrus fruits (~50–90% in peel oils – consider use in smoothies), but supplements (e.g., citrus peel extracts, ~90% limonene) are available that provide therapeutic doses. It can also be topically when added to a carrier oil for Miss a refreshing massage.

Limonene is safe, with minimal side effects (e.g., mild GI upset at high doses) and no significant drug interactions at therapeutic doses. Its anti-inflammatory and antioxidant benefits complement a healthy anti-inflammatory diet.

As with all nutraceuticals, consult a physician before use.

2. Systemic Inflammation, Neuroinflammation and Oxidative Stress

Any discussion relative to treating chronic pain and associated conditions must include the driving forces underlying them: systemic inflammation, neuroinflammation and oxidative stress. These three conditions contribute to chronic pain by creating a cycle of tissue damage, immune cell activation, and pain amplification.

Systemic Inflammation

While acute inflammation associated with trauma or infection is a natural part of the healing process, “systemic inflammation” is a widespread chronic inflammatory response throughout the body that can be triggered by infection, injury, stress, and other conditions. It plays a complex role in many medical and psychiatric conditions and contributes to chronic pain, anxiety, depression, fatigue and impaired thought processing (memory and cognitive function). Additional symptoms of systemic information can include decreased motivation for physical activity, and, in severe cases, organ dysfunction (e.g. pancreas and liver). Research shows that sustained inflammation underlies and drives these conditions through multiple mechanisms.

Neuroinflammation

Inflammation in the nervous system (neuroinflammation) triggers immune cells (e.g. glial cells) to release inflammatory compounds (cytokines and free radicals (ROS) that damage cells and tissues. When these processes persist, they impair nerve functioning and disrupts connectivity between nerves which contributes to symptoms of increased pain and impaired mood, energy, memory and thought processing.  By disrupting normal cellular physiology, these conditions also contribute to the development and progression of chronic diseases, including diabetes, heart disease, stroke, chronic kidney and liver disease, rheumatoid arthritis, cancer and Alzheimer’s. This process works both ways in a vicious cycle: psychological stress and mental health disorders also worsen systemic inflammation.

Oxidative Stress

When systemic inflammation and neuroinflammation persist, it causes a buildup of compounds that “oxidize,” or damage, cells and tissues which, when excessive, leads “oxidative stress.”Oxidative stress is an imbalance when the amount“antioxidants” that are obtained from food or produced by the body) are insufficient to prevent the damage to cells and tissues caused by oxidizing compounds.

Chronic inflammation and oxidative stress coexist because they mutually induce each other. Given the importance these three conditions pose in one’s health, especially those with chronic pain, it is imperative that any therapeutic approach one undertakes should always consider the choices available to prioritize reducing these conditions, whether it be one’s choices of food, nutraceutical supplements, cannabis, essential oils or other treatment modalities. This is why these conditions are emphasized in all of the nutritional and nutraceutical approaches to the management of pain and it’s comorbidities presented on this website.

3. Summary of Limonene’s Potential Therapeutic Benefit/Roles in Systemic Inflammation, Neuroinflammation and Oxidative Stress:

Quality of Evidence: Low to Moderate

Because the research currently available regarding limonene is limited to pre-clinical laboratory and animal research,the quality of evidence provides Low to Moderate confidence overall for limonene’s benefits for Systemic Inflammation, Neuroinflammation and Oxidative Stress. Two things should be noted about this however. (1) A lack of evidence does not equate to lack of benefit. While a lack of evidence for benefit for these conditions may argue against seeking limonene out as the primary argument for use, it should be noted that (2) there is reasonable likelihood of benefit and little likelihood of harm or safety concerns. Including citrus peels (a potent source of limonene)in one’s diet in a smoothie, for example, is simple, affordable and potentially beneficial, so one could certainly make the argument for their supplemental use.

• Systemic Inflammation (Moderate confidence – preclinical and human studies). Limonene combats systemic inflammation by inhibiting pro-inflammatory compounds (cytokines) via modulation of cellular pathways. Preclinical studies show reduced inflammation in arthritis models, and human trials indicate lower inflammatory markers in pain patients using citrus oils.

The Science

Limonene inhibits pro-inflammatory cytokines (e.g., IL-6, TNF-α) via modulation of NF-κB and MAPK pathways, reducing systemic inflammation. Preclinical studies show reduced inflammation in arthritis models, with human trials indicating lower inflammatory markers in pain patients using citrus oils. This supports pain reduction and disease prevention (e.g., cardiovascular, diabetes). Limonene’s anti-inflammatory effects are evident in models where it suppresses cytokine release and inhibits vascular permeability, as seen in carrageenan-induced edema studies, where D-limonene epoxide reduced paw edema and neutrophil migration.

• Neuroinflammation: (Moderate confidence – preclinical studies). Limonene reduces glial activation and cytokine production in the central nervous system, suggestingan inhibitory effect on neuroinflammation. Animal studies demonstrate decreased pain sensitivity in neuropathic models, suggesting potential benefits for neuropathic pain conditions, particularly those associated with increased central sensitization such as fibromyalgia.

The Science:

Limonene may reduce neuroinflammation by decreasing activated glial cells and suppressing production of pro-oxidation free radicals (ROS) and nitric oxide (NO has found in pre-clinical research]. Neuroinflammation is mitigated by limonene acting as an antioxidan and by it enhancing anti-inflammatory cellular defense. through Nrf2 pathways. \ oxidase, while upregulating SOD1 and HO-1 [2]. Overall, limonene’s ability to combat these conditions makes it promising for pain management.

• Oxidative Stress: High confidence (in vitro and in vivo studies) Systemic administration inhibits oxidative stress-induced pain.Oxidative stress is reduced by limonene acting as an antioxidant, neutralizing pro-oxidation compounds and enhancing cellular defenses. Preclinical data shows that limonene can reduce oxidative damage in nerve tissues, demonstrating neuroprotection benefits. Overall, limonene’s ability to combat these conditions offers promise for reducing systemic inflammation and oxidative stress.

  The reported antioxidant and free radical scavenging properties of Citrus lumia oil, which is highly-concentrated in monoterpenes (e.g., 48.9% D-limonene and 18.2% linalool), suggests an possible preventive role in oxidative stress. Overall, limonene has therapeutic potential for diseases associated with inflammatory and oxidative-stress processes.

The Science:

Oxidative stress is mitigated by limonene acting as an antioxidant, neutralizing free radicals (ROS and NOS) and by facilitating cellular defense through enhancing Nrf2 pathways. In corticosterone-induced models, limonene down-regulated MDA, NO, and NADPH oxidase, while upregulating SOD1 and HO-1.

4. Summary of Limonene’s Therapeutic Benefit/Roles

Evidence for therapeutic benefits of limonene for pain are for the most part limited to pre-clinical laboratory and animal research with few significant human studies providing direct benefit for any pain conditions. One may argue, however, that limonene’s confirmed human benefits for anxiety and stress may indirectly reduce the perceived severity of pain.

4a. Pain Conditions

Animal studies suggests that limonene reduces mechanical and thermal hyperalgesia and attenuates neuroinflammation and astrocytosis in rodent models. Supplements of limonene can offer mechanisms to enhance benefits in bioavailability when combined with other compounds.

However, although limonene shows analgesic and anti-inflammatory effects in animal models of pain, there is no substantial clinical evidence to support its use for pain management in humans and no clinical guidelines from major societies address limonene for pain management. The use of limonene to impact chronic pain by reducing systemic inflammation and oxidative stress is an area of research that has not been developed.

• Neuropathic Pain Conditions (Low confidence – preclinical studies only). Oral: Limonene’s role in neuropathic pain is supported by studies where it reduces mechanical hyperalgesia. It modulates pro-inflammatory cytokines (IL-1β and IL-10,) increases antioxidant enzymes (SOD), showing anti-inflammatory and antioxidant effects.
• Inflammatory Pain Conditions :(Low confidence – preclinical studies only). Oral: Limonene suppresses cytokines, inhibits vascular permeability and reduces neutrophil migration in edema models and ha shown systemic and peripheral analgesic effects via opioid system.
• Migraine Headaches: (Low – Moderate confidence – observational studies only). Oral: Reduces mechanical hyperalgesia, a condition that often accompanies migraines. Limonene in essential oils reduces frequency, duration and severity of migraine attacks. Surveys have shown cannabis strains with limonene are often preferred for pain relief, especially migraine headaches.
• Multiple Sclerosis: In multiple sclerosis models, limonene-containing extracts showed antimicrobial activity against bacteria triggering autoimmune responses, potentially reducing inflammation. Limonene reduces glial activation and cytokine production in the nervous system mitigating neuroinflammation, a key force in MS.
• Fibromyalgia: Low confidence (preclinical studies). Oral:: Reduces mechanical hyperalgesia in animal neuropathic pain studies, suggesting potential benefit for fibromyalgia pain.

4b. Mental Health

• Anxiety/Stress: (High confidence – human RCT studies).

Limonene provides symptom reduction with anxiety as well as promoting relaxation effects. Inhaled: Reduces anxiety associated with use of marijuana and THC products. Inhaled limonene reduces stress and studies of the use of Bergamot essential oils with limonene reduces activity of stress hormones. iAnimal studies show anxiolytic and sedative effects, with inhalation of limonene-rich essential oils improving sleep-related behaviors and increasing pentobarbital-induced sleeping time in mice.

THC and Limonene

While THC is believed to drive most of marijuana’s pharmacodynamic effects, the entourage theory asserts that other constituents in marijuana interact with THC in ways to impact its therapeutic effects.  THC is known to have the side effect of anxiety and paranoia, especially at higher doses. A 2024 study assessed whether  d-limonene reduces  these side effects of THC.

The double-blind study evaluated 20 participants when they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo. Another subset of 12 participants inhaled 30mg THC+15mg d-limonene.

When d-limonene was administered alone, outcomes did not differ from placebo. However, when d-limonene was administered with THC, anxiety effects associated with THC use decreased as the d-limonene dose increased. Administration of 30mg THC+15mg d-limonene significantly reduced ratings of “anxious/nervous” and “paranoid” compared with 30mg THC alone.The effects of d-limonene were dose related and correlated with blood levels.. D-limonene did not alter THC pharmacokinetics. Additional research is needed to determine whether this benefit extends to oral use as well.

The Science: Although.limonene reduces anxiety, this benefit is not not abolished by benzodiazepine blockers, suggesting a non-benzodiazepine mechanism. Limonene’s anxiolytic and sedative effects are mediated by modulation of GABAergic and dopaminergic neurotransmission.

• Depression: Moderate confidence (preclinical studies).

Inhaled: Reduces signs of depression in animal models and improves biomarkers of depression. A clinical study in which hospitalized depressed patients were exposed to citrus fragrance in ambient air demonstrated improved depression but more studies are needed.

• Sleep: (Moderate confidence – human RCT studies).

  The evidence for the benefits of limonene for sleep, including inhaled, oral ingestion, and topical applications, is limited and primarily preclinical, with some emerging clinical data for oral ingestion and inhalation, but no direct evidence for topical use.

Inhaled: Prolongs sleeping time. Limonene in Anshen essential oils reduced latency, increased sleeping time and sleep biomarkers (5-HT, GABA). Citrus limonene prolonged sleep. Oral: ingestion, a randomized, double-blind, placebo-controlled trial in adults with sleep disturbance using a standardized lime peel supplement (containing limonene and flavonoids) at 300 mg/day for 2 weeks demonstrated significant improvements in sleep latency, sleep efficiency, total sleep time, and reduced daytime sleepiness, with no serious adverse effects reported. In summary, oral and inhaled limonene show potential benefits for sleep based on limited clinical and preclinical evidence, but there is no evidence for topical limonene for sleep.

Systematic reviews and meta-analyses of aromatherapy (which often includes limonene-containing citrus oils) indicate that inhalation aromatherapy is effective in improving sleep quality, though most clinical data focus on lavender and mixed essential oils rather than limonene alone.

The Science:

Limonene’s anxiolytic and sedative effects are mediated by modulation of GABAergic and dopaminergic neurotransmission.[

4c. Other Conditions

• Memory/Cognitive Function: Moderate confidence (preclinical studies).

  The available literature consists primarily of preclinical studies in animal models and in vitro systems, which suggest neuroprotective, antioxidant, and anti-inflammatory properties of limonene that may theoretically benefit cognitive function and memory. The use of marijuana products and essential oils in aromatherapy that contain limonene are often described as mentally stimulating and energizing. These features have not been well studied, but are supported by popular thinking.

  However, there are no published randomized controlled trials or clinical guidelines from major societies supporting limonene for cognitive enhancement or memory improvement in human adults. The evidence from animal studies and mechanistic research is insufficient to recommend limonene as a therapeutic agent for cognitive disorders or memory impairment in clinical practice.

Oral: In pre-clinical research, limonene improves memory in dementia models and reduces memory errors in Alzheimer’s models. A study using human subjects utilized a method in which subjects consumed one of two types of capsules, which contained either 500 uL of peppermint (Mentha piperita) essential oil, or vegetable oil (control). All subjects drank 200 mL of milk one hour before the tests started. The peppermint (Mentha piperita) contained, among others, 1,8-ceneole (5.34%), limonene (2.06%), linalool (0.47%), α-pinene (0.42%), β-pinene (0.71%), and α-thujene (0.02%). In this study the subjects who took essential oils showed less fatigue to cognitively demanding tasks and showed.higher cognitive function.

The Science

Limonene has shown improvement in learning and memory impairment in rodent models of neurodegeneration and stress, with mechanisms involving reduction of neuroinflammation, oxidative stress, and acetylcholinesterase inhibition.

• Gut Health: ((Low confidence (preclinical studies).

Oral: Gastroprotective: Limonene protects the gastric mucosa lining of the stomach by enhancing mucus secretion. Recent studies have found that the terpenes in orange essential oils (i.e., limonene, linalool, and citral), enhance the microbiota in mice, especially the beneficial Lactobacillus, and limonene had the strongest impact. Studies suggest that essential oils may be involved in regulating energy homeostasis by enhancing the microbiota.

• Metabolic Health: (Low confidence – preclinical studies).

Limonene combats systemic inflammation by inhibiting pro-inflammatory cytokines via modulation of cellular pathways, with human trials indicating lower inflammatory markers in pain patients using citrus oils. This supports the potential for both pain reduction and disease prevention (e.g., cardiovascular, diabetes). Oral: has been shown to Improves lung function and it may help reduces blood pressure and cholesterol with repeated oral treatment.

5. List of Common Essential Oils Containing Limonene

Many popular essential oils used in aromatherapy, especially citrus, have a limonene content greater than 5%. Chemical compounds that constitute more than 50% of the oil are called major constituents it is not known the extent to which Minor constituents contribute to the overall therapeutic effects of an essential oil and of course will vary from compound to compound.Some terpenes that are common in many essential oils are limonene, linalool, α-pinene, β-pinene, β-caryophyllene, myrcene, 1,8-cineol, sabinene, geraniol, α-terpineol, p-cymene, linalyl acetate, and γ-terpinene.

The exact concentration of limonene in an essential oil can vary depending on factors like the plant’s variety, geographical origin, and the extraction method. Always confirm the percent content of a specific terpene before purchasing an essential oil for it’s specific terpene content content. Quality brand providers of essential oils should be able to give you that information prior to purchase.

Citrus essential oils:

• Sweet orange (Citrus sinensis): >90%, with some varieties reaching as high as 97%.
• Grapefruit (Citrus paradisi): Up to 93%.
• Bitter orange (Citrus aurantium): 68–90%, with some studies showing levels as high as 98.66%.
• Mandarin (Citrus reticulata): 51–90%.
• Lemon (Citrus limon): 39–72%, depending on variety.
• Lime (Citrus aurantifolia): 39–63%.
• Bergamot (Citrus bergamia): 32–45%.

Other essential oils:

• Artemisia dracunculus (Tarragon): 12.4%.
• Tetraclinis articulata (Sandarac tree): 7.34%.
• Lippia alba (Bushy lippia): 6.8%.
• Piper guineense (Ashanti pepper): 5.8%.
• Schinus terebinthifolius (Brazilian peppertree): 5–24%.
• Lavandin super (Lavandula hybrida): Some varieties contain small amounts of limonene.
• Pine needle (Pinus sylvestris): Some varieties contain small amounts of limonene.

7. Synergies and Additive Benefits

• Other Terpenes: Limonene may have synergistic or additive effects with BCP for anti-inflammatory effects and with linalool for anxiety reduction and sleep improvement.
• Prescription Medications: Limonene may have additive anti-inflammatory effects with NSAIDs andpotential additive effects with gabapentin for neuropathic pain.
• Cannabis and Cannabinoids: Limonene may contribute to the opioid-sparing effects sometimes attributed to THC and cannabis use but there is no evidence however, that limonene directly interacts with either CB1 one or CB2 receptors. In cannabis, terpenoid–cannabinoid interactions are commonly proposed to exert synergistic “entourage effects” but the research at this time does not support synergy, only additive benefits.
• OTC Medications: unknown
• Nutraceuticals: Limonene may amplify omega-3s anti-inflammatory effects.
• Adaptogens: Limonene enhances stress reduction and would be expected to be additive if not potentially synergistic with adaptogens such as Ashwagandha and Rhodiola.
• Acupuncture: although the mechanisms of action providing the benefits of acupuncture in the management of chronic pain, anxiety in other conditions are in completely understood, the mechanisms of limonen’s benefits for these conditions may be additive.

8. Recommended Formulations

Recommendations for use: Aside from personal preference, recommendations for use may also be based on method of use:

• Inhalation: for anxiety (rapid onset),

1. 1. Bioavailability: Moderate inhaled 20-30%, Short half-life (2-3 hours)
   2. Pharmacokinetics: Rapid response: 2-3 minutes, benefits may last up to 6 hours (dose-dependent). For in-depth review: pharmacokinetics of limonene
   3. Recommended Essential Oil Brands: (See: detailed recommendations)

• • • NOW Foods
    • Plant Therapy
    • doTERRA
    • Young Living
    • Rocky Mountain Oils
    • Edens Garden.

• Oral Ingestion:

1. 1. Bioavailability: Low oral (10-20%)
   2. Food: Ingest with fats; Supplements may be enhanced with liposomal preparations;. grinding citrus, fruit peels as part of a smoothie would provide a good source of limonene
   3. Commercial Formulations: Commercially available supplements containing compounds derived from citrus fruits, specifically limonene, include products marketed as “D-limonene” capsules, citrus essential oils (such as orange, lemon, and grapefruit oil), and nutraceutical blends containing citrus bioactives. These are widely available and often labeled for digestive health, antioxidant support, or mood enhancement. D-limonene is typically derived from orange peel oil and is available in oral capsule for systemic benefits;

• Topical: Recommend dilution with carrier oils for topical applications. Common carrier oils include coconut, avocado, argan, almond, grape seed and jojoba.

9a. Mechanisms of Action (patient-oriented)

Limonene eases pain and anxiety like a calming citrus scent. It reduces inflammation and oxidative stress, protecting nerves and improving mood/sleep.

9b. Detailed Mechanisms of Action (physician-oriented)

• The evidence supporting the use of limonene for pain management is preclinical, with no high-quality clinical trial data in humans. Pre-clinical research shows that limonene reduces hyperalgesia by modulating IL-1β, IL-10, increasing SOD and inhibiting NF-κB, cytokines (IL-1β, TNF-α).Multiple animal studies demonstrate that limonene, administered orally or intraperitoneally, has antinociceptive and antihyperalgesic effects in models of inflammatory, musculoskeletal, orofacial, and neuropathic pain, including formalin-induced pain, carrageenan-induced inflammation, chronic constriction injury, and spared nerve injury.
• Mechanistically, limonene’s analgesic actions involve modulation of inflammatory cytokines (IL-1β, TNF-α), downregulation of NFκB and p38MAPK signaling, and effects on the l-arginine/nitric oxide/cGMP/K\(_{ATP}\) channel pathway, as well as interaction with TRPA1 channels and possible involvement of opioidergic and benzodiazepine receptors.

10. Key for the reader:

Levels of Confidence are determined by the quality of research: Confidence is rated Highest (Cochrane Reviews); High (robust RCTs, meta-analyses), Moderate (small RCTs, observational), or Low (preclinical, case reports).

1. Cochrane Reviews: Highest (Gold-standard): best designed systematic reviews.
2. Systematic Reviews/Meta-Analyses: High-Highest confidence
3. Randomized Controlled Trials (RCTs): Moderate to High confidence. Randomized Controlled Trials (RCTs) involve human participants who are randomly assigned to different groups (treatment or control) to test the effectiveness of an intervention. Limitations: Short duration.
4. 4. Other Studies: Observational, preclinical (lab or animal studies; lower confidence Study limitations (e.g., small sample sizes, animal data).

For each condition: List Highest, High, Moderate, or Low confidence: based on quality of research/evidence (e.g., RCTs, preclinical studies).

11. Chemistry and usual sources of the terpene

12. References

1. Eddin, L.B.; et al. (2021). Neuroprotective Potential of Limonene and Limonene Containing Natural Products. Molecules, 26, 4535. https://doi.org/10.3390/molecules26154535.
2. Spindle, T.R.; et al. (2024). Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis. Drug Alcohol Depend, 257, 111267. https://doi.org/10.1016/j.drugalcdep.2024.111267.

Additional References

1. 1. Efficacy and Safety of Standardized Lime Peel Supplement in Adults With Sleep Disturbance: A Randomized, Double-Blind, Placebo-Controlled, Polysomnographic Study. Kim S, Um MY, Han JK, et al. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2025;139:156510. doi:10.1016/j.phymed.2025.156510.
2. 2. Central Effects of Citral, Myrcene and Limonene, Constituents of Essential Oil Chemotypes From Lippia Alba (Mill.) n.e. Brown. do Vale TG, Furtado EC, Santos JG, Viana GS. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2002;9(8):709-14. doi:10.1078/094471102321621304.
3. 3. Anxiolytic-Like Activity and GC-MS Analysis of (R)-(+)-Limonene Fragrance, a Natural Compound Found in Foods and Plants. Lima NG, De Sousa DP, Pimenta FC, et al. Pharmacology, Biochemistry, and Behavior. 2013;103(3):450-4. doi:10.1016/j.pbb.2012.09.005.
4. 4. Citrus Essential Oils Inhalation by Mice: Behavioral Testing, GCMS Plasma Analysis, Corticosterone, and Melatonin Levels Evaluation. Wolffenbüttel AN, Zamboni A, Becker G, et al. Phytotherapy Research : PTR. 2018;32(1):160-169. doi:10.1002/ptr.5964.
5. 5. The Effects of Aromatherapy on Sleep Improvement: A Systematic Literature Review and Meta-Analysis. Hwang E, Shin S. Journal of Alternative and Complementary Medicine (New York, N.Y.). 2015;21(2):61-8. doi:10.1089/acm.2014.0113.
6. 6. A Systematic Literature Review and Meta-Analysis of the Clinical Effects of Aroma Inhalation Therapy on Sleep Problems. Cheong MJ, Kim S, Kim JS, et al. Medicine. 2021;100(9):e24652. doi:10.1097/MD.0000000000024652.
7. 7. Limonene Has Anti-Anxiety Activity via Adenosine A2A Receptor-Mediated Regulation of Dopaminergic and GABAergic Neuronal Function in the Striatum. Song Y, Seo S, Lamichhane S, et al. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2021;83:153474. doi:10.1016/j.phymed.2021.153474.
8. 8. Sedative, Anxiolytic and Antidepressant Activities of Citrus Limon (Burn) Essential Oil in Mice. L M Lopes C, Gonçalves e Sá C, de Almeida AA, et al. Die Pharmazie. 2011;66(8):623-7.
9. 9. The Cannabis Terpenes, Sarana Rose Sommano 1,2,3,*, Chuda Chittasupho 3,4, Warintorn Ruksiriwanich Molecules 2020, 25, 5792; doi:10.3390/molecules25245792
10. 1. Unveiling the Anti-Inflammatory and Antinociceptive Effects of Limonene in Two Models of Carrageenan-Induced Inflammation and Formalin-Induced Pain: Role of L-Arginine/Nitric Oxide/cGMP/Katp Channel Signaling Pathways, Opioidergic, and Benzodiazepine Receptors. Fakhri S, Yarmohammadi M, Abbaszadeh F, Kiani A, Farzaei MH. Behavioural Pharmacology. 2025;:00008877-990000000-00142. doi:10.1097/FBP.0000000000000840.
11. 2. D-Limonene Exhibits Superior Antihyperalgesic Effects in a Β-Cyclodextrin-Complexed Form in Chronic Musculoskeletal Pain Reducing Fos Protein Expression on Spinal Cord in Mice. Araújo-Filho HG, Pereira EWM, Rezende MM, et al. Neuroscience. 2017;358:158-169. doi:10.1016/j.neuroscience.2017.06.037.
12. 3. Limonene, a Citrus Monoterpene, Non-Complexed and Complexed With Hydroxypropyl-Β-Cyclodextrin Attenuates Acute and Chronic Orofacial Nociception in Rodents: Evidence for Involvement of the PKA and PKC Pathway. Pereira EWM, Heimfarth L, Santos TK, et al. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2022;96:153893. doi:10.1016/j.phymed.2021.153893.
13. 4. Limonene, a Food Additive, and Its Active Metabolite Perillyl Alcohol Improve Regeneration and Attenuate Neuropathic Pain After Peripheral Nerve Injury: Evidence for IL-1β, TNF-α, GAP, NGF and ERK Involvement. Araújo-Filho HG, Pereira EWM, Heimfarth L, et al. International Immunopharmacology. 2020;86:106766. doi:10.1016/j.intimp.2020.106766.
14. 5. Limonene Reduces Hyperalgesia Induced by Gp120 and Cytokines by Modulation of IL-1 Β and Protein Expression in Spinal Cord of Mice. Piccinelli AC, Morato PN, Dos Santos Barbosa M, et al. Life Sciences. 2017;174:28-34. doi:10.1016/j.lfs.2016.11.017.
15. 6. Antihyperalgesic and Antidepressive Actions of (R)-(+)-Limonene, Α-Phellandrene, and Essential Oil From Schinus Terebinthifolius Fruits in a Neuropathic Pain Model. Piccinelli AC, Santos JA, Konkiewitz EC, et al. Nutritional Neuroscience. 2015;18(5):217-24. doi:10.1179/1476830514Y.0000000119.
16. 7. Antinociceptive Effect of the Monoterpene R-(+)-Limonene in Mice. do Amaral JF, Silva MI, Neto MR, et al. Biological & Pharmaceutical Bulletin. 2007;30(7):1217-20. doi:10.1248/bpb.30.1217.

    1. Neuroprotective Potential of Limonene and Limonene Containing Natural Products. Eddin LB, Jha NK, Meeran MFN, et al. Molecules (Basel, Switzerland). 2021;26(15):4535. doi:10.3390/molecules26154535.

    2. D-Limonene Reduces Depression-Like Behaviour and Enhances Learning and Memory Through an Anti-Neuroinflammatory Mechanism in Male Rats Subjected to Chronic Restraint Stress. Alkanat M, Alkanat HÖ. The European Journal of Neuroscience. 2024;60(4):4491-4502. doi:10.1111/ejn.16455.

    3. The Improvement ofEssential Oil on Learning and Memory Impairment of D-Galactose-Induced Mice Through Nrf2/NF-κB Pathway. Qu Y, Guo Y, Li W, et al. Frontiers in Pharmacology. 2022;13:994705. doi:10.3389/fphar.2022.994705.

    4. Related Mechanism of Limonene Improves LPS-Induced Neuroinflammation. Jiang Y, Liu G, Liu Q, et al. Journal of Microbiology and Biotechnology. 2025;35:e2411053. doi:10.4014/jmb.2411.11053.

    5. The Antioxidant Activity of Limonene Counteracts Neurotoxicity Triggered byAβ Oligomers in Primary Cortical Neurons. Piccialli I, Tedeschi V, Caputo L, et al. Antioxidants (Basel, Switzerland). 2021;10(6):937. doi:10.3390/antiox10060937.

    6. Neuroprotective Effects of Limonene (+) Against Aβ42-Induced Neurotoxicity in a Drosophila Model of Alzheimer’s Disease. Shin M, Liu QF, Choi B, et al. Biological & Pharmaceutical Bulletin. 2020;43(3):409-417. doi:10.1248/bpb.b19-00495.

    7. Components of Lemon Essential Oil Attenuate Dementia Induced by Scopolamine. Zhou W, Fukumoto S, Yokogoshi H. Nutritional Neuroscience. 2009;12(2):57-64. doi:10.1179/147683009X388832.

Cannabis Strains High in Limonene

Limonene is the second most abundant terpene in cannabis, but it is not necessarily found in all strains. Strains that have “lemon” or “sour” in their name are usually rich in limonene. The following strains are noted to have limonene as one of the most dominant terpenes and recommended for anxiety:

• Banana MAC
• Black Cherry OG*
• Chem OG *
• Chiesel
• Citral Glue
• Crescendo RBX1
• Girl Scout Cookies
• Ghost OG
• Grease Monkey
• O.G. Kush
• Lumpy Space Princess*
• Mandarin Cookies*
• Member Berry
• Member OG
• Military Chocolate
• Morockin’ Kush
• Pillow Factory*
• Super Lemon Haze
• Titty Sprinkles

* Indicates that the strain’s the most dominant terpene is limonene

Proposed Therapeutic Benefits

Proposed therapeutic benefits of limonene include  anti-inflammatory, gastro-protective, anti-nociceptive, anti-tumor, and neuroprotective activity, mood enhancement and stress reduction as well as sedation and immune-stimulation. Confirmatory evidence in humans was found in a clinical study in which hospitalized depressed patients were exposed to citrus fragrance in ambient air demonstrated subsequent normalization of depression and successful discontinuation of antidepressant medications in 9/12 patients.

Anxiety

While THC is believed to drive most of marijuana’s pharmacodynamic effects, the entourage theory asserts that other constituents in marijuana interact with THC in ways to impact its therqpeutic effects.  THC is kown to have the side effect of anxiety and paranoia, especially at higher doses. A 2024 study assessed whether  d-limonene reduces  these side effects of THC.

The double-blind study evaluated 20 participants when they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo. Another subset of 12 participants inhaled 30mg THC+15mg d-limonene.

When d-limonene was administered alone, outcomes did not differ from placebo. However, when d-limonene was administered with THC, anxiety effects associated with THC use decreased as the d-limonene dose increased. Administration of 30mg THC+15mg d-limonene significantly reduced ratings of “anxious/nervous” and “paranoid” compared with 30mg THC alone.The effects of d-limonene were dose related and correlated with blood levels.. D-limonene did not alter THC pharmacokinetics. Additional research is needed to determine whether this benefit extends to oral use as well.

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