Coffee and the Endocannabinoid and Endorphin Systems

Our endogenous opioid system communicates via endorphins released from the pituitary gland, blocking pain and contributing to our ability to experience pleasure, relaxation, and euphoria. Endocannabinoids confer similar effects, but are released throughout the nervous system. 

One endocannabinoid, the omega-6 arachidonic acid-metabolite anandamide, etymologically means bliss-amide, and is an ingredient in the neural generation of pleasure and motivation. A Scottish woman, Jo Cameron, has a constant elevation of anandamide in her blood due to lacking the expression of the enzyme that degrades anandamide (fatty-acid amide hydrolase). She has reportedly never been able to experience physical pain, anxiety, or fear (Habib, et al., 2019).

The cinnamoylquinides formed by the isomerization of chlorogenic acids during coffee roasting, particularly 4-caffeoyl-1,5-quinide, act as endorphin-antagonists at the mu opioid receptor, strong enough to prevent morphine from working in mice (Paulis, et al., 2004). Coffee also seems to lower anandamide, as the metabolites of it and other similar molecules were reduced in a metabolomic analysis of coffee drinkers (Cornelis, et al., 2018). 

However, caffeine itself sensitizes GABAergic synapses to the calming effects of cannabinoids (Rossi, et al., 2009). The cortisol induced by psychoemotional stress greatly impairs the ability of cannabinoids to calm us through GABA synapses, and caffeine’s defense and restoration of this ability is one reason caffeine heightens resilience to stress and maintains motivation (Rossi, et al., 2008), making this issue complex and contextual.

Coffee’s cinnamoylquinides may play a significant role in the stereotypical side effects of irritability, jitteriness, and overstimulation, separate from caffeine’s adrenergic and glutaminergic properties.

The dicinnamoylquinides in coffee, particularly 3,4-diferuloyl-1,5-quinolactone (DIFEQ), inhibit the adenosine transporter, which prevents the inhibitory neurotransmitter adenosine from entering the cell, prolonging its calming effects in the synapse, so the DIFEQ creates a contradiction against caffeine’s widely known adenosine-blocking stimulatory effects (Paulis, et al., 2002). 

Increasing beta-endorphins, for example via exercise, has proven effective against sleep-related movement disorders like Restless Legs Syndrome and Periodic Limb Movement Disorder (Franco, et al., 2019), but coffee’s compounds like 4-CQL directly inhibit the endorphin system and therefore may nullify endorphin release enough to disrupt sleep and exacerbate existing movement-overstimulation disorders, which has been anecdotally reported by patients who connected their coffee habit with a worsening of their RLS and PLMD, even with decaf (Whittle, 2014).

A brain deficiency of mu-opioid receptor proteins is found in anxiety, depression, schizophrenia, fibromyalgia, and chronic pain, particularly in the amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices (Harris, et al., 2007; Ashok, et al., 2019; Nummenmaa, et al., 2020). It seems in some, caffeine’s dopaminergic and adrenergic effects may be a net positive that masks the opioid-antagonism, but for others it can become troublesome, and counterintuitively so.

If one wants to experiment or avoid coffee’s anti-cannabinoid and anti-opioid effects while still reaping the benefits of caffeine, cold brew coffee, tea, or caffeine tablets seem the most convenient options, but it’s still not that simple. Cold brews contain significantly less cinnamoylquinides than hot brews, though they’re still present (Rao and Fuller, 2018).

Some people, myself included, notice a significant difference between the altered consciousness of coffee vs. pure caffeine, at the same or similar doses. Coffee significantly changes my perception of time whereas caffeine does only slightly or not at all. Caffeine tablets on their own create a cleaner stimulation with less “haze”, whereas pure coffee, even within a few sips, initiates a hyperfocus but with overall greater mental “entropy”. On the horizon is experimentation with brands and fermentations of cold brews, to compare them with usual hot coffee, plus an enjoyment of their deliciousness.

Caffeine, Cytokines, and Thymus Cells

T-helper cells can differentiate into regulatory T (Treg) or Th-17 cells. T-helper conversion decides if our immune systems impose a relaxed anti-inflammatory or activated pro-inflammatory environment on our tissues.

Th-17 cells are pro-inflammatory immune cells that secrete cytokines in response to noxious substances, or to the body’s own tissue in the case of autoimmunity. Inflammation is appropriate as an acute injury-protection process, such as but chronic inflammation leads to long-term degeneration of the brain and nervous system, for example in multiple sclerosis, where the inflammation is directed at neuronal myelin sheath, the protective gel insulating nerve axons.

An excess of Treg cells calms down the immune system’s response, which is a good thing for chronic inflammation, allergen desensitization, and organ transplants, but possibly dangerous during cancer, where we need the immune system to recognize and destroy cancer cells (Curiel, 2007). Therefore, there are contexts where T-17 cells are desirable over Treg cells, but generally we want less T-17 and more Treg, or to remove whatever insult is causing an upregulation of Th-17 cells.

For T-helper cells to become Th-17 cells, the cytokines interleukin 6, interleukin 21, interleukin 23, and transforming growth factor beta are needed. Suppression of those cytokines and of Th-17 differentiation, and a shift in favor of Treg cells occur with certain probiotics, vitamins D and A, DHA (omega-3), exercise, nicotine, and coffee (Lowder, et al., 2010; Wang, et al., 2010; Issazadeh-Navikas, et al., 2012; Elsen, et al., 2013).

Specifically, coffee suppresses interleukin 6’s and IGF-beta’s contribution to Th-17 differentiation, and stops IL-6 from phosphorylating STAT3, a transcription factor essential for Th-17 differentiation. Mice drinking coffee, normal or decaf, had overall less Th-17 cells (Okamoto, et al., 2016).

Amplification and Emotion Under Coffee

As with adrenaline—but in coffee’s case there are many factors—there’s a general amplification of all stimuli, so that intrigue, enjoyment, and anger are induced more easily and experienced more severely. Simultaneously, a contextual resilience coincides with the altered consciousness; for example, the sweetness of foods is significantly enhanced after a coffee, and the bitterness is decreased (Fjaeldstad and Fernandes, 2020).

Caffeine seems to lower emotional intelligence or exacerbate emotional distortion, owing to a study on college students, with one group drinking coffee vs. one not. The students drinking coffee scored higher for alexithymia—the difficulty in identifying and regulating one’s inner feelings—frontal lobe dysfunction, and anxiety (Lyvers, et al., 2014).

That only establishes positive correlation, and it’s common for those with ADHD, mood disorders, or trauma to experience hypoarousal and self-medicate with stimulants like caffeine.

Emotional intelligence accurately predicts the level of psychological and biological resilience to stressful situations. Of 56 test subjects, those with the highest emotional intelligence scores had the lowest subjective stress and salivary cortisol when public speaking (Mikolajczak, et al., 2007). The threshold between coffee assisting or worsening emotional intelligence and therefore stressful situations must be carefully considered.

Indeed, the glutaminergic, adrenergic, dopaminergic, and opioid-antagonizing properties of coffee lends credence to the idea that the altered consciousness of caffeination is one of productivity and explosive dynamism, a haze of busybodying, of “zoning-in” on otherwise monotonous processes, or the enhancement of already stimulatory experiences. But this state sacrifices the holism of mindfulness. Coffee—it’s a beautiful thing, but it facilitates extended attention span on one task and blurs awareness of the wider picture. It is a precedent at times to reassess what’s altering our consciousness on a daily basis, and I’ve long been a proponent of cycling habits in such a way that they do not take too consistent of a hold, disconnecting us from life’s tranquility. 

Further reading

Recommended coffee

Recommended caffeine

Works Cited

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Curiel, Tyler J. “Tregs and Rethinking Cancer Immunotherapy.” Journal of Clinical Investigation, vol. 117, no. 5, 2007, pp. 1167–1174., doi:10.1172/jci31202.

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Whittle, Robin. “Beyond Caffeine: Coffee Contains Opioid Antagonists.” Journal of Caffeine Research, vol. 5, no. 1, 2015, pp. 1–2., doi:10.1089/jcr.2014.0024.

2 thoughts on “Coffee Part Trois: Cinnamoylquinides, Endorphins, Immunity, Amplification

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