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Factors that May Increase/Decrease Cannabinoids

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Note that each number in parentheses [1, 2, 3, etc.] is a clickable link to peer-reviewed scientific studies. A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract.

Marijuana

Marijuana isn’t the only factor that activates the cannabinoid system. Science suggests that there are other natural factors that may help activate this system.

Natural Factors that May Increase Cannabinoid Activity

No clinical evidence supports the approaches listed below to increase cannabinoid activity.

The best way to increase your natural “bliss” cannabinoids and feel peaceful is to live a healthy lifestyle, decrease stressors, address underlying health problems, and get a good night’s sleep.

If you believe that you are already ticking all of those boxes and you still struggle with anxiety or other mental health problems, talk to your doctor about any complementary strategies that could be right for you.

You may try the complementary approaches listed below if you and your doctor determine that they could be appropriate for your health. Do not make any major changes to your lifestyle or supplements regimen before speaking to a doctor.

Additionally, remember that none of the approaches listed below should ever be done in place of what your doctor recommends or prescribes.

1) Stress Reduction

Some scientists think that emotional stress decreases CB1 receptors [1], including social defeat stress [2].

Animal research suggests that prolonged exposure to elevated glucocorticoids (cortisol), such as those induced by chronic stress conditions, significantly reduces hippocampal CB1 receptors [3], leading to lower cannabinoid function.

A recent genetic association study suggested that certain polymorphisms in the CB1 receptor gene (CNR1) are linked to the effects of stress due to childhood physical abuse on anhedonia (inability to feel pleasure) and anhedonic depression. Future studies should clarify this link [3].

2) Exercise

Exercise is good for your overall health. In experimental animals, it increased the CB1 receptor sensitivity [4] and anandamide, which is the body’s natural CB1 activator [5].

3) CBD Oil

Cannabidiol or CBD is a non-psychoactive compound from hemp and cannabis plants. Scientists think CBD actually blocks the CB1 receptor and has the opposite effects of THC in some ways. They suggest CBD has more of an indirect effect by increasing CB1 receptors [6] and inhibiting FAAH [7].

However, CBD oil can cause side effects and it’s not legal in all parts of the world. Consult your healthcare provider before supplementing.

Other Research

The effects of the following factors on cannabinoid activity and/or anandamide levels in humans are unknown. Clinical evidence is completely lacking to support any of them.

Nutrition & Lifestyle

Researchers explored the potential cannabinoid-related mechanisms of the following nutrients in animals or cells:

  1. Extra Virgin Olive Oil [8]
  2. Resistant starch and butyrate on CB1 gene expression and as HDAC inhibitors/histone acetylation [9, 10]
  3. Calcium on CB1 activity and transport of CB1 receptors in rats [11]
  4. Potassium on CB1 activity and transport in rats [11, 12]
  5. Folate on CB1 expression in mice [13]
  6. Vitamin A on CB1 expression [14, 15]
  7. Arachidonic acid on anandamide and cannabinoids in the brains of piglets [16]
  8. Fish Oil on cannabinoid synthesis and CB1 and CB2 receptors [17]
  9. Caffeine on stress – induced decreases in CB1 receptors [18]
  10. Cold exposure [19, 20, 21]
  11. Sun exposure via nitric oxide [22]

Cannabinoid-like Molecules

Researchers believe the following molecules may have something in common with cannabinoids:

  1. Oleamide [23]
  2. Chocolate – N-acylethanolamines (NAEs), N-linoleoylethanolamide and N-oleoylethanolamine inhibit FAAH [24]
  3. Palmitoylethanolamide

Supplements

Supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Supplements can also interact with medications.

Speak with your doctor before supplementing.

The effects of these supplements of cannabinoid activity have only been investigated in animals or cells:

  1. Tea/EGCG [25, 24].
  2. Honokiol (from magnolia bark) [26]
  3. Capsaicin (in chili) [27]
  4. Genistein [24]
  5. Kava/yangonin [28]
  6. Kaempferol, 7-hydroxyflavone and 3,7-dihydroxyflavone [24].

Most of these studies investigated the structure of these compounds, not their health effects.

Experimental Factors

This section summarizes the research behind hormonal and drug-related factors that may increase cannabinoid activity.

Do not take any of the below-mentioned substances unless prescribed by your doctor.

Some of the substances listed here can have detrimental health effects by acting on cannabinoid pathways, potentially increasing the risk of sedation or addiction.

Hormones/NTs

Scientists are looking to determine whether:

  1. Progesterone increases CB1 expression in humans [29].
  2. Testosterone and DHT increase CB1 receptors [30].
  3. Estradiol seems to increase anandamide, CB1 receptors and inhibit FAAH but increases FAAH gene expression [31, 32, 33, 1].
  4. Cortisol increases CB1 abundance in mice [34, 35, 36].
  5. Endorphins [37].
  6. Epinephrine increases CB1 activity in rabbits [38].

Do not attempt to take any hormones without a doctor’s prescription. For example, progesterone and estradiol are used as part of hormonal replacement therapy in some menopausal women under medical guidance only.

Testosterone may be prescribed to some men as part of testosterone replacement therapy.

Cortisol is a stress hormone that has negative health effects in the long run.

Drugs

Some scientists investigated whether the following drugs affect cannabinoid pathways:

  1. Aspirin [39]
  2. Tylenol [40]
  3. Benzodiazepines via CB1 receptors [41, 42]
  4. Morphine via CB1 expression [43]

Most of the above-mentioned drugs should only be used with a doctor’s prescription. Tylenol and aspirin are available over-the-counter. Talk to your pharmacist or physician before using them.

Some addictive and dangerous substances, such as alcohol and nicotine, may also affect cannabinoids. Cannabinoid pathways may also be involved in addiction. Our aim is to discuss research findings. We strictly advise against taking these substances under any circumstances.

  1. Alcohol and acetaldehyde increase expression in mice [44].
  2. Nicotine increases anandamide, which plays a role in its addictive effects [45, 46].

Mechanisms/Pathways

Researchers are studying the following pathways in animals or cells:

  • Cyclic AMP increases CB1 activity [47, 48].
  • Cytokines such as IL-1b increase the CB1 receptor [30]. IL-4 (Th2 cytokine) also increases cannabinoid receptors [49].
  • Nf-kb, RARα and CB2 activation increase CB1 receptors [50].
  • IL-4, STAT5 (Th2), STAT6 (Th2), NFAT, NF-κB, AP-1, REST, RARα/γ and ERE increase transcription of CB1 receptors [50, 51].
  • CRY1 is correlated to CB1 receptors [52].

Potential CB2 receptor agonists/factors being researched for increasing CB2 expression:

The effects of these factors and pathways in humans has not been investigated.

Factors that May Decrease Cannabinoid Activity

The best way to increase your natural “bliss” cannabinoids is to live a healthy lifestyle, reduce stress, get restful sleep, and resolve underlying health problems by seeing a doctor.

If you believe that you are already ticking all of those boxes and you still struggle with anxiety or other mental health problems, talk to your doctor about any complementary strategies that could be right for you.

Below are some factors that, theoretically, may decrease cannabinoids in cell culture or lab animals. That doesn’t mean they reduce cannabinoid activity in humans. The effects of these factors on cannabinoids in humans are unknown.

Lifestyle and Supplements:

Drugs:

Most of the above-mentioned drugs should only be used with a doctor’s prescription. Ibuprofen is available over-the-counter. Talk to your pharmacist or physician before using it

Pathways:

The effects of these pathways in humans have not been investigated.

About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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