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Trends in Endocrinology + Metabolism

The quest for a healthy
Endo-Cannabinoid System (ECS)
Emphasis on immunoregulation

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The ECS is a disperse system, extending throughout the body; it is in constant interplay with all other organ systems promoting homeostasis in almost every aspect. Despite that, the ECS is still neglected and not included in the curricula of medical schools. For this reason a few introductory notes are in order (Battista et al, 2012). The ECS is the regulator of cognition, mood, nociception, energy metabolism, oxidation, inflammatory processes and a disease modifier as well (Tantimonaco et al, 2014).

The ECS consists of receptors, ligands to these receptors and enzymes that synthesize and degrade these ligands. The number of known endocannabinoid receptors is still growing to more that 55; the two most outstanding receptors are CB1R, mainly distributed throughout the nervous system and responsible for the psychoactivity of cannabis, and CB2R, mainly distributed on immune cells, even those “disguised” as specialized cells within other organs. Other receptors include TRPVx, GPR55, PPaRs etc; all these receptors form dimers between them as well as heterodimers with other types of receptors, like opioid, dopamine, serotonin, adenosine, catecholamine receptors and many others, thereby promoting a universal regulatory interplay throughout the body. The ligands to these receptors are the endocannabinoids (ECs): lipids of the eicosanoid family, derivatives of arachidonic acid (AA); the latter abounds in cell membranes; five of these are well characterized to date, but two are well studied: Anandamide (AEA) and 2-Arachidonoyl-Glycerole (2AG). ECs in the nervous system act in negative feedback loops, more or less like neurotransmitters, but, unlike them, they are synthesized and degraded on demand, and not stored in micro-vesicles. Several formerly unrelated morbid conditions are now recognized as ECS deficiencies, including, among many, migraine, autism, fibromyalgia, irritable bowel syndrome, etc (Russo, 2016).

The endocannabinoid system is involved in immunoregulation through the CB2 receptor and through receptor independent biochemical pathways. The mechanisms of immunoregulation by ECs include modulation of immune response in different cell types, effect on cytokine network and induction of immunoapoptosis; in brief, ECs down-regulate the innate and adaptive immune response in most, but not all, instances. Manipulation of endocannabinoids in vivo may constitute a novel treatment modality against inflammatory disorders.

It is obvious that the health of the ECS is of great importance in many ways, including the facing of a viral infection like COVID-19. A healthy ECS depends on many factors, most importantly from proper nutrition (McPartland et al, 2014).

Dietary ω3 fatty acids seem to act as homeostatic regulators of the ECS, acting in opposite directions if consumed by obese or non-obese individuals. Little change in EC levels are seen in individuals with normal weight, not fed a high ω6 diet.

Dietary ω6 fatty acids are also essential, but should be in a balance to ω3s; suggested balance is ω3:ω6=1:1 to 1:3 for proper ECS signaling and prevention of peroxidation in general. Arachidonic acid is an essential component of the ω6 fatty acids.

Probiotics and prebiotics play a significant part in ECS health, but, for a bizarre reason, they are generally not mentioned: They up-regulate CB2Rs residing on immune cells of the gut; they also modulate CB1Rs, depending on conditions, for instance, they down-regulate CB1Rs in obese individuals and help them gain less or no fat.

Some flavonoids, like kaempferol, genistein, epigallocatechine gallate, and curcumin enhance the ECS; same happens with some anthocyanidins, like cyanidin and delphinidin, although with a different mechanism.

Phthalates, pesticides, additives to pesticides like piperonyl butoxide act as ECS disruptors, meaning that consuming organic food may be a sound protective measure, along with intake of detoxifiers, in case of health problems consistent with ECS deficiency not otherwise explained.

Chronic stress impairs the ECS by decreasing levels of AEA and 2AG, and possibly through changes in CB1R expression too. Stress management may reverse the effects of chronic stress on ECS signaling. Anecdotal reports and common experience suggest that techniques such as meditation, yoga, deep breathing exercises and practicing of sex as well, exhibit mild cannabimimetic effects, thereby balancing the system.

Exercise is also an ECS regulator: Long-term exercise leads to sustained elevations of ECs, and predictable CB1R down-regulation.

Chronic alcohol consumption and binge drinking likely desensitize or down-regulate CB1R and impair EC signaling. Alcohol is not compatible with a healthy ECS.

Nicotine is an ECS deregulator: It induces EC production in some areas of the brain, while decreasing them in others. It should be avoided too.

Caffeine, acutely administered, potentiates CB1R-mediated effects through antagonizing adenosine at the A1 receptor (AA1R). At the undisturbed state, AA1Rs tonically inhibit CB1R activity; Caffeine antagonism on AA1Rs sets CB1Rs free of inhibition, thereby enhancing ECS function, for example by letting 2AG activate CB1Rs. During chronic administration of caffeine, the effects are blurred by individual differences in adaptation. In general, CB1Rs are down-regulated.

Chocolate: Cocoa contains sm-all amounts of at least three N-acyl-ethanolamines with cannabimimetic activity, expressed either directly by activating cannabinoid receptors, or indirectly, by increasing AEA levels (di Tomaso et al, 1996).


Selected Bibliography:

Battista et al, 2012: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303140/

Tantimonacco et al, 2014: https://pubmed.ncbi.nlm.nih.gov/24526057/

(Russo, 2016): https://pubmed.ncbi.nlm.nih.gov/28861491/

(McPartland et al, 2014): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951193/

(di Tomaso et al, 1996): https://pubmed.ncbi.nlm.nih.gov/8751435/

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GRAM Mag Sets NOW AVAILABLE!

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GIVE THE GIFT OF GRAM

You can now order sets of our
printed magazines. Give the gift of
knowledge this year to your friends,
family, or yourself and only pay
the shipping and handling.

What a deal!

Set includes 9 vintage GRAM Mags
(2019-2020)

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Turmeric

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Turmeric is a root vegetable commonly used as a spice in various Indian and other cultures’ dishes. Turmeric is in the zingiberaceae family, as is ginger. The turmeric plant is native to the southeastern region of Asia and commonly harvested in places like India, Sri Lanka, China, Indonesia, and Taiwan. It is responsible for curry’s signature orange color, and its vibrant pigment will give essentially any meal an orange hue. 

Turmeric contains a substance called curcumin, and curcumin has been shown through research to offer anti-inflammatory and other therapeutic benefits. The scientific name for the turmeric plant is Curcuma Longa, and likely where the name curcumin comes from. When people are talking about the health benefits of turmeric, they are referencing curcumin so you may hear the two names used interchangeably. Curcumin is part of a group called curcuminoids, with curcumin being the most active and the most beneficial for health. Flavonoids are another substance found in various plants and give these plants their color. Curcumin is a flavonoid and is responsible for providing that bright orange color to turmeric. In addition to providing aesthetic value, flavonoids are also strong antioxidants with anti-inflammatory and immune-boosting properties.

The Journal of Biological Chemistry published a study done by Sanjaya Singh and Bharat B. Aggarwal of the Cytokine Research Laboratory at the world-renowned cancer hospital, M.D. Anderson. The study found that curcumin suppressed NF-κB, a protein complex responsible for controlling inflammatory responses. In other words, turmeric shuts off the body’s inflammatory response. Anti-inflammatories can be beneficial for many different ailments, including chronic pain and digestive disorders. A lot of CBD companies even put curcumin in their products because of its benefits. It is believed to be a synergistic pair with complementary therapeutic properties. The thought is that the two plant medicines are powerful on their own; as a combination, they can deliver even more anti-inflammatory and medicinal benefits. 

Many people simply add turmeric to their dishes as a way to easily incorporate it into their daily routine. It is pretty mild in flavor and can be added to many dishes without changing the overall taste too drastically. Some say that turmeric isn’t strong enough on its own to receive the anti-inflammatory properties that curcumin provides, and therefore recommend a curcumin supplement. Research varies on that, so in the end it is just up to personal preference and your doctor’s approval. Curcumin supplements come most available in capsules. Pregnant women can safely use turmeric as an addition to their food, but should avoid taking high-dosage supplements. Those who are interested in supplementing with curcumin products should talk with their doctor first. 

M.D. Anderson Cancer Center did another study in 2007 exploring curcumin for cancer treatment. The study found that curcumin inhibits ovarian cancer growth and angiogenesis (the development of new blood vessels). It does this by targeting and manipulating the NF-κB pathway, the same protein complex responsible for controlling inflammatory response. According to a report published by the National Center for Biotechnology Information, “The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules.”  

The trend with curcumin seems to be it’s ability to control inflammatory responses in the body. It does this by multiple pathways, but a commonly researched one is the NF-κB protein complex. Because this pathway is able to be manipulated by curcumin to encourage anti-inflammatory expressions, its potential for successfully treating various ailments is there.

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Psilocybin + Magic Mushrooms

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When many think of plant medicine, specifically those plants with psychoactive effects, they think of “magic mushrooms,” or fungi containing psilocybin and psilocin that can cause hallucinations depending on the dosage consumed. In many states, there are active efforts to decriminalize these otherwise scheduled substances, lowering penalties for their use and possession. But what value do psilocybin-containing mushrooms offer? New research suggests a range of therapeutic and psychological value ranging from the treatment of substance abuse to anxiety and depression management.  

What are Magic Mushrooms?

Magic Mushroom use dates back to 10,000 BCE and references continue throughout the era. Their modern popularity began when the term “magic mushroom” was coined by two etnomycologists who learned of a Harvard study on local doctors in Mexico using these substances, noting the substance’s ability to affect the nervous system. These findings were eventually published in Life magazine in 1957, and the term became the universal reference for psychoactive fungi and truffles, specifically those containing high concentrations of psilocybin and psilocin.

Psilocybin & Psilocin: The “Magic” in Magic Mushrooms

Psilocybin and psilocin are part of a family of psychedelic compounds found in magic mushrooms. Psilocin is pharmacologically active, and psilocybin is converted into psilocin when consumed or activated. Similar in structure to serotonin, there are more than 50 species of mushrooms and a variety of truffles that produce both the precursor, psilocybin, and the psychoactive compound, psilocin. Unlike LSD, magic mushrooms do not affect dopamine receptors, solely targeting serotonin sites

How are Magic Mushrooms used?

Magic mushrooms are often used for recreational, therapeutic and medicinal reasons. “Effects range from mild feelings of relaxation, giddiness, euphoria, visual enhancement (seeing colors brighter), visual disturbances (moving surfaces, waves), to delusions, altered perception of real events, images and faces, or real hallucinations.” Recreationally, this is often known as “tripping.” As an alternative health option, these fungi are being used for anxiety, depression, PTSD, and trauma, as well as psychological disorders such as substance abuse disorders, and science is beginning to back the potential for these applications.

Research on Mushrooms

Evaluations of currently available scientific studies suggest a growing number of therapeutic benefits and treatment options. “In the past few years, a growing number of studies using human volunteers have begun to explore the possible therapeutic benefits of drugs such as psilocybin…looking at psilocybin and other hallucinogens to treat a number of otherwise intractable psychiatric disorders, including chronic depression, post-traumatic stress disorder, and drug or alcohol dependency.”

Magic mushrooms have been respected as a “safe & natural healing sacrament for millennia throughout Mexico, Central America and the world,” and are known to be beneficial for depression, recidivism (the tendency to repeat past transgressions), and encourages openness, creativity, as well as personal and spiritual growth. UCLA and NYC have done studies on the applications of magic mushrooms in the treatment of end-of-life anxiety and other studies have backed up the use of psilocybin and psilocin in the treatment of substance use disorders, depression (especially in cases of terminal conditions like cancer as well as treatment-resistant depression), and reducing depression and anxiety overall.

Best way for people to consume?

When it comes to the consumption of mushrooms, advice on dosage is about as specific as it was with cannabis under prohibition. Consumers must purchase on the black market and are subject to whatever may be available. 

“Recreational doses range from 1–5 grams of dry mushrooms depending on the species and individual strength of the specimens… After ingestion, the psilocybin is enzymatically converted to psilocin. Absorbed from the gastro-intestinal tract, hallucinogenic effects usually occur within 30 minutes of ingestion with a duration of effect of 4–6 hours.” 

My recommendation as someone who has used magic mushrooms both for recreational and therapeutic purposes, is to grind the mushrooms into a fine powder and either encapsulate them in small increments and/or combine with lemon juice. Capsules will allow you to titrate your dosage as needed with a recognizable increment, while lemon juice will expedite onset time.  

The Legality of Magic Mushrooms

In the United States, psilocybin is a Schedule I controlled substance, with no accepted medicinal value and a high potential for abuse. In contrast, the Drug Policy Alliance states that “Physically, psilocybin mushrooms are considered to be one of the least toxic drugs known.” With that being said, local efforts such as Decriminalize Nature – Oakland and Decriminalize Denver have pushed for and successfully passed initiatives and legislation to reduce penalties and make enforcement a low priority, as was done in the early days of cannabis activism. This has spurred multiple local and international efforts to “Decriminalize Nature,” efforts that we learn more about in this month’s feature.

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