Clinical Endocannabinoid Deficiency, (CED), and phospholipids.

During normal health we make cannabinoids internally – endogenously, hence the term endocannabinoids in contrast to cannabinoids found in plants such as cannabis/marijuana/hemp. Most cannabinoids do not cause euphoria even though the group may be best known for that affect.

Anandamide (AEA) is the endocannbinoid that is chemically similar to the euphoria causing cannabinoid found in marijuana known as THC, tetrahydrocannabinol. Cannabidiol, CBD, is a non-euphoria causing cannabinoid found in some strains of marijuana. It is chemically similar to the endocannabinoid known as 2-AG which in times of normal health is found in greater concentration within the body than anandamide.

Cannabinoids within the body are found as a structural part of cell membranes. They also can be released from the membranes and used as signaling chemicals within the brain and peripheral nerves, affecting many things including memory, appetite, sleep, movement, and fertility. The cannabinoids when released from the cell membranes can also be modified into another type of signaling chemical that is important in immune health (eicosanoids).

Due to genetic changes or other issues with metabolism or health some people may not be able to make cannabinoids internally and would need an external source to maintain health. Due to marijuana having been listed as a controlled substance considered to have no medicinal value research has been limited to studies about toxicity and addiction. Research on the role cannabinoids plays in health is becoming more available but is still in early stages considering the many functions they have within the brain and body.

Conditions that may involve Clinical Endocannabinoid Deficiency, (CED):

Conditions that may involve a deficiency in cannabinoids chronically may include symptoms of pain, muscle spasms, nerve numbness, mood disorders, movement disorders, digestive and appetite problems, appetite and growth failure in infants or colic, menstrual problems and infertility/miscarriages and hyperemesis prenatally.

  • Pain/inflammation: Migraines, Fibromyalgia.
  • Mental health: Anxiety, PTSD, Major Depression, Bipolar disorder, Motion Sickness, The balance of cannabinoids (2-AG ~ noneuphoric CBD and anandamide ~ euphoric THC) is a problem in schizophrenia.
  • Nervous system: Multiple sclerosis, Diabetic Neuropathy, Brachial plexopathy, Causalgia, Phantom limb pain, Glaucoma, Huntington’s, Parkinson’s, Cystic Fibrosis,
  • Appetite/digestive system: Anorexia & Bulimia, Neonatal Failure to Thrive, infantile Colic, Irritable Bowel Syndrome.
  • Fertility/reproductive system: Dysmenorrhea, Hyperemesis, repeated miscarriages (Russo 2016), (anandamide is needed for implantation of a fertilized egg in the uterus and development of the placenta to occur normally, too much or too little can disrupt the process, Fonseca 2013), male infertility due to sperm motility problems is associated with low levels of anandamide (AEA) (Amoako 2013), (too much can also negatively affect male or female fertility).
  • Other food sources of cannabinoids exist in addition to marijuana or hemp however the amount provided is in lower concentrations so you might need a large salad that includes several sources at one meal, and other sources in beverages, supplements, or at other meals.
Conditions that may involve Clinical Endocannabinoid Deficiency (CED)

Food sources of cannabinoids or phospholipids (a precursor chemical):

Cannabinoids, can be found in smaller amounts in foods than in medical marijuana or synthetic THC medications. Good sources include:

  • Chocolate, dark cocoa powder.
  • Seeds: hemp kernels, pomegranate, seeds & peel, pumpkin, sesame, flax, fennel, cardamom, cumin and coriander;
  • Grains: amaranth, rice bran, sorghum, buckwheat, wheat;
  • Beans/legumes;
  • Coconut/Nuts: pine nuts, peanuts, cashews, almonds;
  • Green plants: lettuce, spinach, mustard greens, leek greens, asparagus, avocado fruit and dried kernel, celery, carrots, onion, garlic. Squash, cucumber and okra seeds, butternut squash, pumpkin, sweet pototo or yams, parsnip root, Jerusalem artichoke root.
  • Herbs: Rosemary, Gingko leaf, Wormwood/Artemisia;
  • Grapefruit and citrus juice with the pulp.
Good Food Sources of Cannabinoids and/or Phospholipids

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.

Nrf2 and Nf-Kb pathways – one restorative, one inflammatory

Many phytonutrients and other chemicals have been found to promote the production of the Nrf2 gene and its encoded Nrf2 protein, both of which have varying impacts on other genes causing an increase in immune strength and in our own production of antioxidants. Other research has focused on nutrients and chemicals that inhibit or promote the inflammatory Nf-Kb pathway – a chemical cascade of reactions starting outside the cell and ending in the cell with an increase in the cell’s production of inflammatory cytokines and Tumor Necrosis Factor (TNF).

The foods and chemicals often interact with both pathways but in opposite directions, promoting one and inhibiting the other. The reason is unlikely to be a coincidence, the night/day rhythms of circadian biology also tend to promote one and inhibit the other. The Nrf2 growth/repair/detoxification system is more active during sleep/dark and the NF-kB action/inflammation pathway is more active during the wake/light hours. See 1.4, 1.41, 1.42 in this draft book to read more: Preventative Health for Multifactorial Disorders.

Nrf2 Promoting Foods & Phytonutrients:

See G10: Nrf2 Promoting Foods, effectivecare.info for the reference in the graphic (Sun 2017) and more food ideas and information.

Nrf2 Promoting Foods and Phytonutrients

Neurotransmitters also vary in activity level due to the circadian cycle and can affect whether the Nrf2 or the NF-kB pathway is more active.

The neurotransmitters and neuromodulators mentioned in the last post are part of the circadian biology rhythms. Acetylcholine, attention and memory neurotransmitter, (Pepuo 2004), is more active during the day and GABA the calming neurotransmitter is more active at night. It is inhibitory, reducing activity of other neurotransmitters such as norepinephrine and serotonin that are active during wakefulness helps the body move into sleep. Low levels of GABA are associated with insomnia and disrupted sleep (Siegel 2004), and with anxiety, chronic stress, depression, difficulty concentrating and memory problems, muscle pain and headaches, and substance use disorders. (3 AmazingBenefits of GABA/PsychologyToday)

GABA which is known to have antioxidant and anti-inflammatory benefits may achieve it in part due to increasing the Nrf2 pathways growth, repair, and detoxification activity and by inhibiting the NF-kB and Caspase 3 pathways. (Zhu 2019) Resveratrol was found to help protect endothelial cells in animal models of Type 2 Diabetes and aging. It reduces oxidative stress by increasing the Nrf2 pathways, “improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring Caspase 3 activity and DNA fragmentation). (Ungvari 2010)

Lycopene is a phytonutrient that can help reduce inflammation by promoting the Nrf2 and inhibiting the NF-kB pathways.

The antioxidant lycopene was used in a study for use as a food additive in animal feed to help reduce oxidative stress caused by heat stress. The research team were concerned about the negative effects of heat stress on the Nrf2 and Nf-Kb pathways, causing decreased activity of the Nrf2 and increased activity of the Nf-Kb pathway. A brief description of the roles in the body is in the abstract: “The transcription entity nuclear factor-kappa light chain enhancer of B cells (NF-κB) controls the expression of genes involved in a number of physiological responses, including immune inflammatory responses, acute-phase inflammatory responses, oxidative stress responses, cell adhesion, differentiation, and apoptosis. The nuclear factor-2 erythroid related factor-2 (Nrf2), the redox-sensitive transcription factor, plays a key role in regulating induction of phase II detoxifying or antioxidant enzymes.  “ (1)

Several carotenoids in addition to lycopene also reduce inflammatory pathways and increase beneficial ones.

Lycopene is a carotenoid, one of a group of red and yellow colored antioxidants found in carrots, cantaloupe and other fruits and vegetables that tend to be orange or red in color, The best known carotenoid is beta-carotene, a form of vitamin A that is made with two of the vitamin A retinol molecules. Other carotenoids, including beta-carotene, lutein, alpha-cryptoxanthin, and zeaxanthin, also can inhibit the NF-kB pathway and increase the Nrf2 pathways, reducing inflammatory cytokine production and increasing beneficial antioxidant production. Other phytonutrients that also increase the Nrf2 and inhibit the NF-kB pathways include:

Other phytonutrients that inhibit inflammatory and promote anti-inflammatory pathways:

  • sulforaphanes and I-3-C, from broccoli sprouts, broccoli, kale, mustard greens, turnips and other cruciferous vegetables,
  • andrographolides (and other diterpenoids – found in Gingko biloba, sage, rosemary, (sciencedirect/diterpenoids)), andrographolides are found in the medicinal plant Andrographis paniculata, (Okhuaroba 2014),
  • quercetin found in “leafy vegetables, broccoli, red onions, peppers, apples, grapes, black tea, green tea, red wine, and some fruit juices“, (integrativepro.com) ,
  • curcumin from turmeric,
  • silymarin, an extract from milk thistle, a medicinal herb,
  • genistein from soy,
  • chlorophyll, the green pigment in plants, and
  • resveratrol, found in “grapes, wine, grape juice, peanuts, cocoa, and berries of Vaccinium species, including blueberries, bilberries, and cranberries.” (lpi.oregonstate.edu)
  • (See 1.42, Preventative Health for Multifactorial Diseases)

That list is a start, there are other beneficial phytonutrients that decrease inflammatory pathways and increase anti-inflammatory pathways, including: ginger/zerumbone/gingerol, green tea/EGCG/gallic acid, garlic/aged garlic extract, hot pepper/capsaicin, fish oil/omega 3 fatty acids, black pepper/piperine, Hops/xanthohumol, Plumbago auriculata/plumbagin, a medicinal herb used for lead poisoning. (de Paiva 2005) (Sun 2017) (Gupta 2010)

Protecting health over the long term and every day can be as simple as adding more variety of herbs and spices to your meals, along with more colorful fruits and vegetables and whole grains, nuts, beans, and seeds.

That list is a start, there are other beneficial phytonutrients that decrease inflammatory pathways and increase anti-inflammatory pathways, including: ginger/zerumbone/gingerol, green tea/EGCG/gallic acid, garlic/aged garlic extract, hot pepper/capsaicin, fish oil/omega 3 fatty acids, black pepper/piperine, Hops/xanthohumol, Plumbago auriculata/plumbagin, a medicinal herb used for lead poisoning. (de Paiva 2005) (Sun 2017) (Gupta 2010)

Protecting health over the long term and every day can be as simple as adding more variety of herbs and spices to your meals, along with more colorful fruits and vegetables and whole grains, nuts, beans, and seeds.

Colorful and flavorful foods can help keep the body more in the restorative Nrf2 pathways and reduce the inflammatory NF-kB pathway. The same nutrients or chemical groups effect both because the pathways are coordinated by the light/dark wake/sleep circadian cycle and share a need for the same type of protein – as if both need the same tool – they both can’t use it exactly at the same time. (CREB protein, see section 6: Li, 2008)

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual health guidance. Please see a health care professional for individualized healthcare guidance.

References

  1. Sahin K, Modulation of NF-κB and Nrf2 pathways by lycopene supplementation in heat-stressed poultry, World’s Poultry Sci J Vol 71, Issue 2, June 2015 , pp. 271-284 https://www.cambridge.org/core/journals/world-s-poultry-science-journal/article/modulation-of-nfb-and-nrf2-pathways-by-lycopene-supplementation-in-heatstressed-poultry/4E2AFAAFDF88B0B438BE3A19A1FB0A9B

The Cholinergic System

The cholinergic system is the network of acetylecholine receptors clustered within certain brain regions which the activation of or inhibition of in total effects most of our actions. More specifically effecting the cholinergic system might cause symptoms of “dry mouth, tachycardia or bradycardia, drowsiness, sedation, and short-term memory loss,” – all potential symptoms that may occur with varying doses of THC, the euphoria causing cannabinoid found in marijuana. (1) Tachycardia is a very rapid heart rate and bradycardia is a very slow rate.

Olanzapine, one of the anti-cholinergic medications mentioned in the last post, causes cannabinoid receptors in the prefrontal cortex to be overactive which would cause a similar effect to that of taking a large dose of THC – a cannabinoid that activates cannabinoid receptors in the prefrontal cortex.

What else does the cholinergic system do?

Acetylcholine has been found to have a large role in memory consolidation – forming memories. Low levels can cause memories to be retrieved (possibly significant in Traumatic Brain Injury, TBI, 3) and high levels facilitate the formation of new memories. Low acetylcholine levels might cause symptoms of perseveration, continuing an action repetitively, not being able to stop an action at the typical time. Damage to the medial septum/vertical limb of the diagonal band (MS/VDB) portion of the cholinergic nerve pathways might also cause perseverative behavior. (2)

Acetylcholine levels are involved in the processing of information for considering uncertainty, possibly for helping with decision making.. The new sensory information is compared to past memories, comparing incoming sensory data to stored memory data , (2) for the purpose of identifying danger or dinner – is the shape seen in the distance more like a tiger to run away from or a gazelle to pursue?

Movement involves a couple neurotransmitters for different aspects of an action. The ability to move requires acetylcholine and the motivation to move involves dopamine. (4) Dopamine is known as the reward neurotransmitter while acetylcholine is more of an action one. Should I start running towards the distant figure or away? Is it a dopamine rewarding delicious dinner of gazelle or a fear inducing tiger? Creeping slowly close enough to be able to tell without startling a gazelle or alerting a tiger would be a dopamine motivated and courageous action to take, acetylecholine would be involved in the decision to take the risk and move closer. Noradrenaline, another neurotransmitter, might also be involved in a decision involving the tradeoff between danger and reward. The neurotransmitters work as a team, see the excerpt included later. (2)

The ability to decide to move closer and to do so would be negatively effected by problems with acetylcholine, noradrenaline, or with dopamine.

What does the Dopaminergic System do? – Parkinson’s Disease & Dopamine.

Parkinson’s Disease is a degenerative disease that may involve epigentic changes in DNA, (4) – some are turned on or off with the removal or addition of methyl groups along the length of the DNA molecule.

  • Methyl groups are small, an oxygen and a hydrogen atom, and might also be thought of as a key blocking a door lock so that no other keys can be used to open the door- to activate the DNA for replication into RNA and protein molecules.

Symptoms of Parkinson’s Disease include muscle tremors and difficulty controlling or initiating movements. Walking can be slow and jerky, and hand writing very shaky. The primary degeneration within the brain involves an area that produces dopamine which may then activate dopamine receptors elsewhere in the brain along a dopaminergic network. (2) As the cells that would typically produce dopamine are damaged the body becomes less able to send the dopaminergic nerve signals that would motivate motion. The ‘fight/flight/freeze’ fear response may also be involved, becoming overactive with chronic stress and eventually leaving the body in the ‘freeze’ response. (4)

The problem from having the fight/flight/freeze response in a chronic state of ‘on’ is that it shifts the body into more inflammatory chemical pathways and turns off more restorative toxin removal and growth chemical pathways. One theory about a cause of Parkinson’s Disease (PD) suggests this overactive fear response and resulting underactive detoxification pathways leaves the body with too much of a toxic waste product from dopamine breakdown called dopal, an aldehyde. (4)

PD may result from protective negative feedback loops – the body purposely inhibiting the dopamine producing cells in the brain involved in Parkinson’s Disease in order to stop the increased levels of dopal – or the increasing levels of dopal build up most in the dopamine producing cells and cause their damage or death sooner than in other cells throughout the rest of the body. (4)

Current treatments for Parkinson’s Disease are focused on increasing dopamine levels rather than trying to break down levels of dopal – which may be worsening the degenerative problem overall. (Eckert, thesis 2012, 4) Pesticides may also be a causative factor in PD by causing malfunction of the enzyme (aldehyde dehydrogenase , ALDH) that in normal health would quickly breakdown the toxic dopal aldehyde into less toxic metabolites of the chemical. Some people with Parkinson’s Disease may have a genetic difference making them unable to make a functional form of the enzyme ALDH, so their levels of the aldehyde dopal would be chronically elevated. (4)

Patients with Parkinson’s Disease also tend to have gastrointestinal symptoms and dopamine is also produced in the GI tract. Food sensitivities to other aldehydes can also be common for patients with PD. Perfumes and other chemical scents also contain aldehydes and may also increase symptoms of pain, muscle rigidity, and brain fog (a non-scientific term for cognitive symptoms where thinking may feel fuzzy or clouded compared to normal – I would make a decision if I could get the thought from here to there through this feeling that I’m swimming through molasses, but that seems too exhausting, I will just rest here treading molasses instead). (4)

Brain fog is also a common complaint for people with chronic Candida yeast infections which can be in the GI tract or elsewhere in or on the body. Chronic yeast growth may be involved in risk for Parkinson’s Disease as they generate aldehydes during their growth or decomposition an use up nutrients that the human would need to detoxify aldehydes. (4)

The methylated active form of the B vitamin Folate is needed for detoxification of aldehydes. Someone with a genetic variation that prevents normal methylation could have increased risk for degenerative diseases that involve epigenetic changes which require methyl groups to be added or removed from DNA; and/or be at increased risk for degenerative changes caused by toxin buildup. Folic acid is an unmethylated, not bioactive, form of folate that is used in most supplements and fortified foods instead of folate, the form that would be found naturally occurring in folate rich foods such as beans, peas, and asparagus.

Formaldehyde is a neurotoxin found in smog or smoke and in the diet as a metabolite, produced during aging of the product or during digestion.

Formaldehyde is an aldehyde that is a known toxin. It is a common environmental pollutant in smog or smoke, either from a fire, candle flame, or cigarette. Formaldehye also is released during offgassing of volatile chemicals from vinyl plastic products – i.e. ‘new car smell.’ And it can be found in foods. Formaldehyde is produced chemically during the break down of some food products as they age. Older packages of shelf stable juice can contain a significant amount of formaldehyde. It is also created during the breakdown of the artificial sweeteners called aspartame and Neotame. Aspartame (brand names include Nutrasweet TM or Equal TM) is required to be listed on food labels while Neotame, slightly more concentrated form, is not required to be listed on processed food labels, whether ‘conventional’ or ‘organic’. See a previous post for more guidance about avoiding formaldehyde: Formaldehyde: Heath Risks, Environmental and Dietary Sources, (effectiveselfcare.info).

Returning to the cholinergic system – part of the neurotoxic effects of formaldehyde is due to it having an inhibitory effect on acetylcholine activity. Increased formaldehyde levels leads to an increase in levels of the enzyme that breaksdown acetylcholine, resulting in less of the neurotransmitter being available for stimulating the acetylcholine receptors of nerve cells. (5)

Neurotransmitters work together as a team.

The neurotransmitters also work together as a team in many ways, so problems with one are likely to negatively affect the other’s functions too. All of them are involved in attention abilities and novelty seeking, (2) : knowing where to pay attention – to see if the distant figure is a tiger or a gazelle, and being able to follow its motion; and in looking for newness such as changes in the environment – or is it a lion in the distance and another one just joined the first?

Other neurotransmitters, or neuromodulators as they are called in the following excerpt, include serotonin and noradrenaline. There are other neurotransmitters that do not also function as neuromodulators and other chemicals that act as neuromodulators but are not also neurotransmitters. (

It is difficult to pinpoint a specific function for each neuromodulator. It has been suggested that dopamine is related to positive value, serotonin to risk aversion, noradrenaline to vigilance, and acetylcholine to attentional effort (Krichmar, 2008). Another theory posits that dopamine is related to reward prediction, while serotonin is related to temporal discounting, and that noradrenaline regulates the exploration/exploitation tradeoff, while acetylcholine controls learning rate (Doya, 20022008).”

(Avery, 2017) (2)
  1. Domino E.E. (1999) Cannabinoids and the Cholinergic System. In: Nahas G.G., Sutin K.M., Harvey D., Agurell S., Pace N., Cancro R. (eds) Marihuana and Medicine. Humana Press, Totowa, NJ https://link.springer.com/chapter/10.1007/978-1-59259-710-9_22
  2. Avery MC, Krichmar JL. Neuromodulatory Systems and Their Interactions: A Review of Models, Theories, and Experiments. Front Neural Circuits. 2017;11:108. Published 2017 Dec 22. doi:10.3389/fncir.2017.00108 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744617/
  3. Sherin JE, Nemeroff CB. Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues Clin Neurosci. 2011;13(3):263–278. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182008/
  4. Dopamine: Aldehyde Poisoning and Parkinson’s Disease, On Thinking Parkinson’s, June 20, 2018, http://www.outthinkingparkinsons.com/articles/dopamine-aldehyde
  5. Zendehdel R, Fazli Z, Mazinani M. Neurotoxicity effect of formaldehyde on occupational exposure and influence of individual susceptibility to some metabolism., Environ Monit Assess. 2016 Nov;188(11):648. Epub 2016 Oct 31. parameters.https://www.ncbi.nlm.nih.gov/pubmed/27796833