Responsibility – self care first, so able to care for others.

Becoming paralyzed or irrational and hyperexcitable from histamine excess would not allow me to be functional. Self care with genetic differences can be more complex than for standard health. Not becoming paralyzed is a goal if mine. I already have finger numbness problems and dystonia all my life.

Choices are not the same for everyone because we don’t all have the same starting points.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Starvation or addiction?

Previous post on the topic of genetic differences in the cannabinoid system: Is it Addiction or Starvation?. Excerpt:

Substance abusers likely quit using and relapsed again more times than anyone cares to count. every single time a chronic user runs out of their substance of choice they are “quitting” until they get more. 

Do you blame a hungry person for eating breakfast in the morning? Should a person just “quit eating” if they have an overeating disorder? Answer: No. 

  • Cannabinoids might help some types of eating disorders and some types of drug or alcohol addictions by providing an essential nutrient that the person might not be able to make. 
  • If the body can’t make an important substance or convert substances into active forms then it becomes an essential nutrient – essential for that specific person’s daily diet.

[…]

The problem with addiction to some substances or to eating excess food for some cases of over eating disorders is an underlying inability to make the cannabinoids but a remaining need for them and a hunger, an urge for “something,” something that is unknown however. And what people choose to consume in order to try to quench that unknown hunger varies from food and alcohol, to the rest of the drugs that are commonly abused. 

Dietary sources are needed instead. However our food supply has limited sources. Vine ripened produce or lemon oil, rich in aroma, are examples of a food containing cannabinoids or a similar group of aromatic and medicinal phytochemicals called terpenes. Chocolate and the herb rosemary are two other food sources. The spices cardamom, cloves, and nutmeg are also sources. Non-euphoric cannabinoids also exist and may have medicinal benefits depending on the patient’s condition. Copaiba oil is a food grade essential oil that can have non-euphoric cannabinoid content with medicinal benefits.

Wouldn’t it be nicer to tell starving people that they are starving rather than that they are poorly motivated? 

~~~ end of excerpt.

Wouldn’t it be nicer to hand starving people safe foods or supplements of what they need? before chronic degenerative changes occur that can’t be reversed, such as nerve paralysis?

Worse things are also said about people who use marijuana and criminal charges can occur. Reefer madness advertising and other media spread the image of marijuana being something of jazz nightclubs and black men who might be a danger to your women, along with the marijuana that would turn her wild. — It does decrease inhibition and increase sensation so the risks are greater for making reckless mistakes. Caution. Also caution about believing media distortion – it might be for political or corporate profit goals.

The marijuana culture tends to be a sharing one – people who are regular users may relate to each other through a common understanding of the body and mood relief that can occur when you really can’t make your own cannabinoids.

Mental health awareness – we are all more susceptible to reckless decisions/non-decisions, going along with other’s suggestions/ when we are overly hungry, angry, lonely, or tired. (12 step group slogan HALT).

Lessons learned the hard way can help other people avoid similar problems. Sharing strategies that have helped others can help recognize problem situations and pause a moment – HALT – and think twice about making any important decisions until better rested or calm and fed.

Sharing personal stories can help show the real world problems others have had to survive somehow.

I can make reckless mistakes just from being overly stressed, tired, hungry, or lonely. Emotionally vulnerable people are at risk, people with ADHD or on the autism spectrum, or have other social or mental skill deficits can be at risk of being taken advantage of. Survivors of child sex trauma or child abuse may be more at risk of revictimization – grooming behavior means the child is being slowly raised to think something is normal behavior and even enjoyable and a treat to look forward too. What might seem like a reckless mistake may be a combination of limited skills, lack of boundaries, and physical stressors.

Anxiety and stress or fear can be major factors in panicked decision making.

Cannabinoids affect mood as modulators – may increase appetite at low amounts and decrease appetite at large doses. The balance and amount can calm anxiety or PTSD, or an excess or imbalance might cause anxiety or paranoia. CAUTION, is reasonable, especially with the modern more concentrated strains and products.

The anxiety of cannabinoid deficiency can be quite severe, or withdrawal if the person gets withdrawal symptoms, can also be bad in an anxious jittery kind of way. Other users understand and will ‘catch you a buzz,’ knowing you or other people will share their relaxing herb with you on another day.

Reefer Madness was a movie made to instill a negative image in public opinion of the marijuana/cannabis plant. Hemp cannabis plants were also being grown and used extensively as a fiber source for making rope and paper. Paper industry ran newspaper articles and ads that added to the reefer madness narrative.

It certainly deserves some cautions and guidance, especially with the more potent modern medical strains of marijuana. Risks can include the increase in reckless behavior due to reduced inhibition (yes, cannabis was involved in the tattoo decision-making), also perception and memory can be affected. Some things may stand out vividly, important, larger than life, while other things may be a little distant and foggy, indistinct and the memories form similarly. Decision making is also impaired by slowness sometimes, something might be said and in the fogginess you let it go, but then as the words repeat in memory, you realize that you didn’t agree and might have said so if less foggy from marijuana.

Paranoia and anxiety can be mental symptoms of excess THC, and/or the imbalance of THC without the calming effects of CBD and terpenes like limonene and pinene. Real lemon or lime juice/oil or citrus peel products may help with an anxiety reaction as they are a good source of limonene.

Whole marijuana products can cause differing effects due to the different terpenes within the plant strain. Myrcene-sleepiness, pain relief; Limonene & pinene – calming, anti-anxiety.

Sleepiness is promoted by the myrcene content of some strains, it also is a terpene with medicinal effects.

Myrcene, better known as the active sedating principle of hops and lemon grass, is also found in basil, mangos, and its namesake, Myrcia sphaerocarpa, a medicinal shrub from Brazil traditionally used to treat diabetes, diarrhea, dysentery, and hypertension (Ulbricht, 2011). ” (Hartsal, et al.)

Excess THC can cause physical effects that might seem like a panic attack, but which will subside. Limonene, lemon or lime oil products, may help reduce the effects.

Physical symptoms of excess THC can include a racing heart rate which might add to a sense that there is a panic situation or something to fear, as a racing heart rate is also a part of the feeling of fear. Feeling quite cold may also be a symptom of excess THC. Hunger can occur at lower doses of THC along with the ‘munchies’ – eating way more than typical of something sweet or salty or an odd mix of foods. At higher doses of THC the opposite might occur, a lack of appetite and even nausea or vomiting.

Physical symptoms of THC can include increased libido – feeling frisky, relaxing inhibition, slowing reaction time, odd thinking leading to poor decisions – marijuana is a risk for date rape/bad experiences. It doesn’t affect the memory as significantly as a blackout drunk or ‘roofie’ type date rape drug, however it may leave incomplete or distorted memories where some things stand out and others are fuzzy impressions.

With reduced inhibitions and increased risk of impulsive behavior, caution is needed with when and where, and with who you are using medical marijuana products.

You need a safe place, and safe people around, when consuming medical marijuana in quantities that cause changes in perception. “Come on back to my place and share a bowl” – danger, going into someone’s private space may be taken as a yes for anything else that occurs, or if a yes had been said in the past it might be taken as a yes into the future. Sharing a bowl means sharing the marijuana induced reduction in inhibitions – safer to not enter private space, yet illegal substance to many people and not to be used in public view even with the legalization in some states. <shrug> Progress takes time, caution is reasonable, there can be some potential risks to avoid, including personal stupidity.

Blaming everything on use of marijuana is wrong though, personal vulnerabilities are a risk too, mentioned earlier. Hyperthyroidism is also associated with mania, grandiose thinking and reckless sexual activity, and divorce is common. I had stress, fear to a point near panic, and was placed on a new psychiatric medication at one of largest doses – all can affect decision making negatively.

Caution also though with thinking medical marijuana use is an addiction.

Type 1 diabetes patients have a need for insulin because they can’t make it for themselves – some marijuana patients genetically or due to age or other reasons can’t make endocannabinoids for themselves. Paralysis can be a long term risk of deficiency.

One of the modulating functions of cannabinoids is brain cell maintenance – support the continuing growth of frequently used cells and take away growth support for cells that aren’t being used regularly anymore (practice daily the things that you care about).

Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells.” (14)

Caution with use of marijuana – and caution thinking that it is just an addiction or the only factor in someone being vulnerable to sexual manipulation. I have made mistakes, change was needed though and the lessons I learned were needed. Dangerous things happened to me, and I am thankful that I learned more caution before worse things might have happened.

Hyperthyroidism and elevated histamine levels can also lead to mental health symptoms that include mania and increased impulsive behavior. There can be other causes too. People who seek out cannabinoids may find that it helps them to feel more stable. Cannabinoids can inhibit the mast cells which when over active can cause elevated histamine, cannabinoids can also cause a release of histamine. Balance of the different types are important. (2) Cancer tissue also can involve changes in metabolism and possibly histamine levels. (1) Cannabinoids can be helpful for preventing and treating cancer.

Cancer may involve an excess of histamine followed by too little histamine in later stages.

Cancer is frequently associated with weight loss and muscle breakdown, a condition called cancer cachexia. A team has hypothesized that histamine excess may involved in early taste, smell and sleep symptoms also seen with cancer, and a loss of appetite, anorexia, and later stages of severe tissue wasting might involve a drop in histamine. (1)

Aberrant histamine signaling not only triggers energy-consuming processes, but also anorexia. Moreover, since functions such as taste, smell, and sleep are governed by discrete structures of the brain, which are targeted by distinct histaminergic neuron populations even relatively minor symptoms of cachexia, such as sleep disturbances and taste and smell distortions, also might be ascribed to aberrant histamine signaling. In late stage cachexia, the sympathetic tone in skeletal muscle breaks down, which we hypothesize might be caused by a reduction in histamine signaling or by the interference of other cachexia related mechanisms. Histamine signaling thus might delineate distinct stages of cachexia progression, with the early phase marked by a PSNS-mediated increase in histamine signaling, increased sympathetic tone and symptomatic adipose tissue depletion, and the late phase characterized by reduced histamine signaling, decreased sympathetic tone and symptomatic muscle wasting.  ” (1)

Elevated histamine can have an excitatory effect, hyper-excitable to the point of mania or depression and even suicide – whatever the mood, it might be escalated to extremes as histamine normally has a modulating control. Cannabinoids can have an inhibiting, calming effect on the synaptic junctions between nerve cells and inhibit nerve signals, not just mast cells. “Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation.” (3) Someone with mast cell overactivity and histamine excess might be wanting cannabinoids from marijuana because it helps calm them — it might also be helping prevent early stages of cancer cachexia too if histamine excess is a factor in that. Adequate histamine is protective against colorectal cancer. (4)

Histamine and excess mast cells are also involved in pancreatic cancer.

Recent findings indicate that the activation of granulocytes and macrophages in pancreatitis results in the release of a number of cytokines and inflammatory mediators and an important inflammatory mediator, the mast cell, secretes histamine as well as other chemotactic molecules and inflammation activators (2931). Mast cells have been implicated in the pathogenesis of pain in other conditions and some have hypothesized that mast cells and histamine secretion play a role in the pain of chronic pancreatitis, which is characterized by mononuclear inflammatory cell infiltration (27,3234). Interestingly, it has been shown that humans with painful chronic pancreatitis have an increased number of pancreatic mast cells compared to those with painless chronic pancreatitis (27).” (5)

Histamine is a vasodilator, increasing membrane permeability in the brain and other organs of the body.

Histamine also increases vascular permeability in pancreatic inflammation, suggesting it would also affect brain membrane permeability.

As histamine has been confirmed to be a potent vasodilator, histamine may possibly be an important factor to study in increased vascular permeability in pancreatic inflammation (28,38).” (5)

Yes, histamine does increase permeability of the blood brain barrier: “Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening.” (6)

Cannabinoids could be helping inhibit mast cell activation, reducing histamine levels, which would decrease blood brain barrier permeability protecting against entry of more inflammatory chemicals.

Nutrients work as a team – niacin also is important for reducing vascular inflammation.

Niacin or nicotinic acid is involved in energy production within mitochondria and can help reduce inflammation by turning it into the heat of a skin flushing reaction that is similar to the reddening warmth of an allergy reaction – both involve mast cells and histamine. Plentiful supplies of niacin help the body transform the inflammatory oxidative stress chemicals into more benign forms. Niacin also helps down regulate the production of inflammatory chemicals formed via the Nf-Kb pathway. (7)

Niacin is involved in our ability to burn lipids for warmth or energy in the brown or white adipose tissue (BAT & WAT), (8), mentioned in the cancer cachexia hypothesis as possibly being overactive, adding to unwanted weight loss, and due to an increase in histamine levels. (1)

Activation of the receptor for niacin causes a decrease in breakdown of triglycerides to free fatty acids, which would lead to lower blood lipid levels: “…the orphan G protein-coupled receptor GPR109A has been identified to be a receptor for niacin.” […] “Activation of GPR109A upon binding niacin functions in a G protein-coupled manner to decrease cAMP production, resulting in decreased hormone-sensitive lipase activity and reduced hydrolysis of triglycerides to free fatty acids (11., 12., 13.).” (10)

The warmth of the skin flushing reaction of niacin involves the niacin receptor and the release of chemicals, prostaglandin D2 and E2. “Recent studies have indicated that niacin-induced flushing was mediated by GPR109A through the release of prostaglandin D2 and prostaglandin E2 (1415).” (10) Prostaglandins are made from arachidonic acid which can be part of cannabinoid molecules. It is released from the phospholipid end when the cannabinoid is released from the membrane. Elevated levels of arachidonic acid being present can suggest cannabinoid breakdown is also elevated.

“Prostaglandins and thromboxane A2 (TXA2), collectively termed prostanoids, are formed when arachidonic acid (AA), a 20-carbon unsaturated fatty acid, is released from the plasma membrane by phospholipases (PLAs) and metabolized by the sequential actions of prostaglandin G/H synthase, or cyclooxygenase (COX), and respective synthases.” (13)

The niacin receptor, GPR109A, is regulated by G-protein-coupled receptor kinase 2, (GRK2), Gi, and Arrestin3. (10) Cannabinoid receptors are also G-protein coupled receptors.

  • GRK2 also regulates Type 2 Cannabinoid receptors. (11)
  • The arrestin proteins regulate light receiving rhodopsin, a G-protein coupled receptor and may also activate cannabinoid receptors, more needs to be learned. Cancer cell types frequently have increased cannabinoid receptors, yet providing cannabinoids can help treat cancer. (12)
  • Gi are a group of G protein alpha subunits; G proteins are guanine nucleotide-binding proteins which can act as a activating switch inside of cell for other functions, that can be activated from an external receptor, such as niacin activating the G-protein-coupled receptor GPR109A; or anandamide/THC and 2-AG/CBD activating the Cannabinoid Receptors Type 1 or 2; or a photon of light activating a rhodopsin protein.

The body is a complex team of chemicals that somehow work together in a way that allows most of us to walk and talk and function – stopping cancer and fighting virus is part of that daily function.

Lack of niacin may increase risk of cancer as it leads to depletion of NAD+ and dysfunction of the mitochondria’s ability to produce energy by oxidation of glucose. (9) Mitochondria switch to producing energy by fermenting glucose or glutamate without oxygen – a change that is associated with the mitochondria in cancer cells.

Adequate niacin and cannabinoids in balance and magnesium are all involved in the phagocytosis of infected or cancerous cells or other toxic cellular debris or proteins. The nutrients are reused by the cell or detoxified and eventually excreted in a process called by a few names, autophagy and apoptosis, lysosomal engulfment of cellular debris, or phagocytosis – engulfment of a smaller cell.

Is the desire for or use of marijuana an addiction or starvation? It seems to fall into the category of conditionally essential nutrients – essential for health for some conditions – those who can’t make them internally. It might also refer to nutrients that we can make but which we need in such large amounts that some must be obtained from the diet – such as nucleotides.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Zwickl H, Zwickl-Traxler E, Pecherstorfer M, Is Neuronal Histamine Signaling Involved in Cancer Cachexia? Implications and Perspectives. Frontiers in Oncology, Vol 9, 2019, pp 1409, DOI=10.3389/fonc.2019.01409 https://www.frontiersin.org/articles/10.3389/fonc.2019.01409/full
  2. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2826.2008.01674.x
  3. McKenna M, McDougall JJ. Cannabinoid control of neurogenic inflammation. Br J Pharmacol. 2020; 177: 4386– 4399. https://doi.org/10.1111/bph.15208https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.15208
  4. Friend and foe: Histamine mediates allergies and can fight colorectal cancer. Dec 19, 2017, blogs.bcm.edu, https://blogs.bcm.edu/2017/12/19/friend-and-foe-histamine-mediates-allergies-and-can-fight-colorectal-cancer/
  5. Taylor F, Graf A, Hodges K, et al., Histamine regulation of pancreatitis and pancreatic cancer: a review of recent findings. Hepatobiliary Surg Nutr 2013;2(4):216-226. doi: 10.3978/j.issn.2304-3881.2013.08.06 https://hbsn.amegroups.com/article/view/2606/3490
  6. Abbott NJ. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol. 2000 Apr;20(2):131-47. doi: 10.1023/a:1007074420772. PMID: 10696506. https://pubmed.ncbi.nlm.nih.gov/10696506/
  7. Si, Yanhong & Zhang, Ying & Zhao, Jilong & Guo, Shoudong & Zhai, Lei & Yao, Shutong & Sang, Hui & Yang, Nana & Song, Guohua & Gu, Jue & Qin, Shucun. (2014). Niacin Inhibits Vascular Inflammation via Downregulating Nuclear Transcription Factor-κB Signaling Pathway. Mediators of inflammation. 2014. 263786. 10.1155/2014/263786. https://www.researchgate.net/publication/263710300_Niacin_Inhibits_Vascular_Inflammation_via_Downregulating_Nuclear_Transcription_Factor-kB_Signaling_Pathway
  8. Ye, L., Cao, Z., Lai, X., Wang, W., Guo, Z., Yan, L., Wang, Y., Shi, Y. and Zhou, N. (2019), Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling. The FASEB Journal, 33: 4765-4779. https://doi.org/10.1096/fj.201801951R https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201801951R
  9. Kirkland, James. (2003). Niacin and Carcinogenesis. Nutrition and cancer. 46. 110-8. 10.1207/S15327914NC4602_02. https://www.researchgate.net/publication/8945953_Niacin_and_Carcinogenesis
  10. Guo Li, Ying Shi, Haishan Huang, Yaping Zhang, Kuangpei Wu, Jiansong Luo, Yi Sun, Jianxin Lu, Jeffrey L. Benovic, Naiming Zhou, Internalization of the Human Nicotinic Acid Receptor GPR109A Is Regulated by Gi, GRK2, and Arrestin3*, J of Biological Chem, Vol 285, Issue 29, 2010, pp 22605-22618, ISSN 0021-9258, https://doi.org/10.1074/jbc.M109.087213 https://www.sciencedirect.com/science/article/pii/S0021925820602940
  11. Lu C, Shi L, Sun B, Zhang Y, Hou B, Sun Y, Ma Z, Gu X. A Single Intrathecal or Intraperitoneal Injection of CB2 Receptor Agonist Attenuates Bone Cancer Pain and Induces a Time-Dependent Modification of GRK2. Cell Mol Neurobiol. 2017 Jan;37(1):101-109. doi: 10.1007/s10571-016-0349-0. Epub 2016 Mar 2. PMID: 26935064.
    https://pubmed.ncbi.nlm.nih.gov/26935064/
  12. Duo Zheng, Ann M. Bode, Qing Zhao, Yong-Yeon Cho, Feng Zhu, Wei-Ya Ma and Zigang Dong, The Cannabinoid Receptors Are Required for Ultraviolet-Induced Inflammation and Skin Cancer Development, Cancer Res May 15 2008 (68) (10) 3992-3998; DOI: 10.1158/0008-5472.CAN-07-6594 https://cancerres.aacrjournals.org/content/68/10/3992
  13. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31(5):986-1000. doi:10.1161/ATVBAHA.110.207449 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081099/#:~:text=Prostaglandins%20are%20lipid%20autacoids%20derived%20from%20arachidonic%20acid.&text=They%20are%20generated%20from%20arachidonate,for%20inhibition%20of%20COX%2D2.
  14. Fernández-Ruiz J, Moro MA, Martínez-Orgado J. Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurotherapeutics. 2015;12(4):793-806. doi:10.1007/s13311-015-0381-7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604192/

Cannabinoids are made with the BHMT gene (and others).

Cannabinoids are complex molecules we can make when genetically and nutritionally, healthy and nourished. Various genetic differences are known that cause a deficiency in endogenously made cannabinoids – phospholipids. Lack of cannabinoids negatively effects many areas of health throughout the body and brain, the mood and decision making, and appetite, and movement are all affected by cannabinoid availability.

It is discrimination to prevent research from occurring into the medical benefits of cannabis and cannabinoids and to prevent people who need an external source from having access to it. Covid and LongCovid may be increasing the number of people who might benefit from an external source as epigenetic changes or some other effects of the viral infection may be causing dysfunction in normal production of cannabinoids or some other problem.

Cannabinoids and the Cannabinoid receptors perform many functions in the body.

Membranes and growth of tissue is affected directly as building blocks that are part of the membranes, and indirectly as messenger chemicals that help promote and guide growth.

Cannabinoids also have widespread effects on immune function in addition to brain and nerve function. Cannabinoid receptors are found throughout the brain and also on white blood cells, leukocytes. Our immune function also needs endogenous, internally made, cannabinoids, or would benefit from an external source if endogenous cannabinoids were not able to be made normally.

“In human leukocytes the expression of cannabinoid receptor mRNA has been reported to be lower than that found in brain tissue. The message has, however, been detected in all subsets of leukocytes examined. The message levels are greatest in S cells, followed sequentially by natural killer cells (NK), polymorphonuclear neutrophils (PMN), T8 cells, monocytes and T4 cells.” (11)

Leukocytes help us fight viral infections and patrol for other infectious pathogens or precancerous or cancerous cells. Nutrients work together, synergy – increased power together than any on their own. We need magnesium for leukocytes to be able to perform the killing, apoptosis, and we need niacin to help with the safe removal of debris or engulfing of virus or small cells. Cell contents that are spilt into surrounding tissue has to be removed or it causes more inflammatory damage and can lead to death of other cells.

Niacin reduces inflammation for us in some direct ways and indirectly by inhibiting the NF-kB inflammatory pathway. Deficiency may increase neurodegeneration as well as reduce immune function for fighting virus or cancer.

Reports suggest that deficiency of niacin can increase the risk of neurodegeneration, immunological disorder and inflammation stress [14]. Additionally, niacin exerts its anti-inflammatory effect by suppressing the NF-κB pathway [15].” (18)

The cannabinoid system is also involved in neurotransmitter levels.

According to previous studies, CB1r [Cannabinoid Receptor type 1] is located in the locus coeruleus (LC) and in the dorsal raphe nucleus (DRN), and it regulates noradrenaline (NA) and serotonin (5HT) release, respectively, by the modulation of GABAergic and glutamatergic terminals (117118).” (17)

Problems with the endocannabinoid system can affect mood such as changes in serotonin leading to anxiety or depression. Adequate niacin intake helps preserve our serotonin levels by sparing tryptophan.

Genetic studies pointed out interesting results regarding the involvement of polymorphisms or epigenetic modifications of CNR1 as susceptibility/risk biomarkers to develop anxiety disorders. Lazary and cols. analyzed the interaction of the promoter regions of the serotonin transporter (5HTT; SLC6A4) and CNR1 genes on anxiety. Specific constellations of CB1r and 5HTT promoters were closely associated with high or low synaptic 5HT concentrations, which could result critically in the vulnerability to experience an anxiety disorder (124). Hay and cols. employed CRISPR/CAS9 technology to disrupt a highly conserved regulatory sequence (ECR1) of the gene encoding CB1r (CNR1).” (17)

Cannabinoid system differences occur in ethnic & gender groups. We may be equal but we are not all the same.

Who has the gene differences may vary with ethnicity. “With 60 DNA samples (120 alleles) for each of the 4 ethnic groups studied, we had 90% power to detect a variant allele with a true population frequency of ≥ 2% [16]. ” “Twenty-five SNPs were observed in BHMT — 17 in AA, 8 in CA, 9 in HCA, and 10 in MA subjects (Table 1 and Fig. 2 upper panel).” (1) Number of cannabinoid receptors has been found to vary based on ethnicity and gender with people of Caucasian background having the most, people with African/black background having slightly fewer, and Asian having significantly fewer than those of people with Caucasian or African ethnicity. (11)

The relative levels of the 58 kDa CBI protein 1070 E.S. Onaivi et al. from the male volunteers were, 47.4%; 39.0% and 13.6% for the White, Black and Asian blood samples respectively as shown in Fig. 3. The relative levels of the Cl31 protein in the male and female volunteers were 49.6%, 32.2% and 18.2% for the white and black females in comparison to the black male blood samples respectively as shown in Fig. 4. Therefore in both males and females, the cannabinoid receptors appear to vary by gender and ethnicity, for example Fig. 3 show white male > black male > Asian male and Fig. 4 show white female > black female > black male.” (11)

African Americans were found to have variations in the BHMT gene almost twice as often than Caucasian and Mexican-American ethnic groups and Hans Chinese American were least likely (small group study). (1)

The BHMT gene and Endogenous Cannabinoid production & breakdown.

The BHMT gene encodes an enzyme involved in homocysteine metabolism and the production of amino acids methionine, and dimethylglycine from betaine. (2) The BHMT enzyme is visualized in a graphic of the folded shape, made up of four parts, monomers, coupled into two sets of dimers, figure C: (1.1).

The BHMT enzyme is also involved in about 60% of the glycerophospholipid production pathway (2) which means important cannabinoids may not be able to be made internally and would need to be obtained in the diet or other sources or suffer deficiency symptoms chronically. People with Cystic Fibrosis also can’t make cannabinoids however the fatty acid end of the molecule is what can’t be made normally. The BHMT gene difference would disrupt production of the glycerophosphate end of the larger cannabinoid molecule. PA, PE, PI, and PS production might be reduced or dysfunctional and breakdown of LPC and LPE which might lead to some types of cannabinoids being unavailable and others unable to be broken down and remove normally so excess might collect -unknown by me. (3)

  • Phospholipids: PA, phosphatidic acid; PE, phosphatidylethanolamine; PC, phosphatidylcholine; PS, phosphatidylserine; PG, phosphatidylglycerol; CL, cardiolipin; PI, phosphatidylinositol. (15)
  • LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine, (19)

Research in cannabinoid chemistry was limited to toxicity or addiction due to the rescheduling of marijuana by the Nixon administration as nonmedical. Since the differences in function of the endocannabinoid system varies with ethnic group it is somewhat genetic discrimination to as well as racial discrimination to target an ethnic group with a law that wouldn’t affect all ethnic groups equally. Someone unable to make cannabinoids would have more craving and physical need for a rich source of phospholipids or cannabinoids, than a person with normal ability to make cannabinoids and/or a low or normal amount of cannabinoid receptors compared to someone with many of them.

Cannabinoid receptors effect mood, & may be involved in anxiety, depression, and possibly suicide.

Lysophosphatidylcholine, LPC, can cause an increase in calcium flow into cells at an atypical cannabinoid receptor GPR55 (4, 5) which is excitatory. Over activity, excess calcium entry, might be a negative to cell health. During normal activation levels the atypical cannabinoid receptor has anti-depressant effects and may help prevent suicide as the brains of suicide victims have fewer GPR55 receptors than typical. (14)

This result, plus the observation that GPR55 increases intracellular calcium, suggests that GPR55 activation enhances neuronal excitability. These findings, together with the preferential expression of GPR55 on large-diameter DRG neurons, which can be involved in nociception, particularly in neuropathic or inflammatory pain states (2931), suggest that GPR55 may have a pronocioceptive [pain increasing] role.” (5)

So overactivity of the GPR55 receptors might be perceived as chronic pain and might affect mood and suicidal ideation. Cannabinoid receptors in the prefrontal cortex (CB1) are also known to be involved with suicide risk from research with people suffering from anorexia (17) or alcoholism and depression. (16)

Cannabinoids also can reduce oxidative stress & inflammation, and may be helpful for preventing or treating neurocognitive degeneration conditions.

Calcium can cause oxidative stress damage and would be increased during times of strenuous activity or infection or other times of increased metabolism. THC can cross the blood brain barrier and can help reduce oxidative stress and may be helpful for treatment of neurocognitive degeneration. It was found to improve glucose use within cells and improve brain function in other ways with no toxicity problems in an animal based study. (12)

In silico analysis predicted THC to be permeable across the blood-brain-barrier. THC was also predicted to have an oral LD50 and toxicity class values of 482 mg/kg and 4 respectively. These results indicate that C. sativa improves glucose consumption with concomitant suppression of oxidative stress and cholinergic dysfunction, and modulation of purinergic and gluconeogenic activities in brain tissues.” (12)

Personal experience – I have a double BHMT allele – it isn’t something I would recommend trying yourself.

I have experience of a lifetime without typical cannabinoid production and the symptoms that may cause. There is a double allele of my BHMT gene which means I can not make some endocannabinoids and can’t break down others. A double allele means both copies contain the same difference from typical. (post, see # 3 in the first list) So I can’t make the BHMT enzyme at all. I supplement with dimethylglycine and methionine since finding out and it helped. I need to continue daily though as genetic metabolic differences mean lifelong symptoms of deficiency of the nutrients that are affected, or an excess of a chemical metabolite that normally would be broken down sooner so it wouldn’t collect.

Post: Clinical Endocannabinoid Deficiency, (CED), and phospholipids. Excerpt:

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. There is too much of the anandamide, excess THC can cause schizophrenia like symptoms, and providing CBD may help patients. *See this post for more nutritional deficiencies that cause schizophrenia like symptoms, five or more may be involved, suggesting the problem is a symptom rather than a condition with a single cause – and a single cure: The voices that people with schizophrenia are hearing are probably their own inner thoughts.
  • 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). *See this post for more details about infertility and phospholipids: (Phospholipid or phosphorylation deficiency: Potential symptoms)
  • 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.

— Addition to the excerpt – the amount of cannabinoids in medical marijuana is a lot more, and more likely to be obviously helpful, than the amount of phospholipids or cannabinoids found in a few foods and spices. Sadly medical marijuana has been stigmatized and illegal for many decades. Research into medical benefits was prevented with Richard Nixon’s administration rescheduled cannabis as having no medical value. Research was only possible on addiction or toxicity. Marijuana/cannabis not only has medical value, it has been used medicinally or in other ways by humans for thousands of years. Paper and rope made from hemp fiber was also a large industry prior to making cannabis illegal.

Conditions I’ve had symptoms of which might be due to Clinical Endocannabinoid Deficiency.

The conditions/symptoms I’ve had over my life from the above list include: Migraines, Fibromyalgia; Anxiety, PTSD, Major Depression, Bipolar disorder; Anorexia & Bulimia, Irritable Bowel Syndrome; and some nerve/numbness symptoms since childhood – dystonia.

The amount of cannabinoids a human needs if they are unable to make them internally/endogenously is not readily available information due to the lack of research. The amount of medical marijuana that I find necessary to feel nerve flow in my fingers and throughout my body and to have other symptoms improve is quite a bit each day. It adds up in money to buy, and time and stigma to use.

Smoking is frowned upon by society and cannabis use is still treated as if it is just an addiction or even criminal (which it still is at the Federal level), so it frightens some people to even learn that you use it, or have used it recently. Chronic users have adapted a tolerance to it (8), and mentally may be more used to functioning with some than going without. The type of strain is important for the terpenes that provide different aroma also provide different health effects. Some can be calming for anxiety (limonene), and another sleep inducing and pain relieving (myrcene).

Daily use every 2-4 hours is what I find helpful and smoking has benefits for dosing. Edibles take longer to feel an effect and then suddenly can be too much. Inhalation effects are fairly immediate and easy to know then when enough has been absorbed. The forms of cannabinoids that are absorbed may vary too with the different intake routes, and inhalation may be more effective for some types of health problems than edible/intestinal absorption. The healthiest I’ve ever felt was when I combined eating some fresh trim or immature buds everyday or edibles along with some smoked bud.

Smoke toxins are a negative that causes the “dopey” effect of the stereotypical marijuana user. Vaping devices exist that heat the bud to a lower temperature so the burnt toxins are not created, however some of the THC conversion occurs at higher temperatures so symptoms may not be helped as much. The vape oil products may have other negative effects on the lungs due to the oil and flavorings being inhaled into the lungs where it can add to pneumonia risk.

How much THC am I getting throughout a day then? Possibly 40% of whatever was in the marijuana you smoked – a lot is lost when you burn the buds. 8 There is approximately 525 mg in an eighth of good medical grade marijuana with 15% THC. (6) That eighth ounce might cost $45-60. One gram per day of 10% THC marijuana might provide 40% of the 100 mg of THC it contains, if smoked vs made into an edible. A quarter to half of a one gram joint every 2-4 hours might be giving 10-20 milligrams of THC each time. Strains that also provide some CBD are important as the cannabinoids work together to do somethings in the body such as inhibit mast cell activation.

Eighty to hundred milligrams of THC is suggested as possibly feeling like an excessive dose all at once for someone with increased tolerance, while 25-80 range might be the typical preferred dose. (8)

I have not calculated this for myself before so it does bring up an interesting question of whether I’m getting too much, or enough, or not enough – the fact that I felt best while also eating fresh trim and other edibles regularly would suggest to me that it is not enough when only smoking and that I do need quite a bit daily.

The non-euphoric CBD has been found safe for use even at 1500 mg per day, though 20-40 mg might be more typically used. (7)

Dronabinol is a capsule form of a THC like medication and it might be prescribed at a 2.5 mg dose twice per day. That might seem like a lot to a new user and not that big of a dose to someone else, although the lack of CBD may be a problem if anxiety is a side effect.

Tolerance levels can reduce after not using for a while and then build back up again. Doses that would seem intense for a new user would not really affect a long term user. (8) Genetics may play more of a role in these differences too, lack of research leaves some questions unasked.

Genetic differences occur in the number of cannabinoid receptors which can effect tolerance for a concentrated source such as medical marijuana.

There can be genetic differences where a person doesn’t make cannabinoids well and has lots of extra cannabinoid receptors, all wanting/ready for cannabinoid activation – but with none or to little available. They might tolerate and prefer a larger dose of THC. Other people might have normal amounts of cannabinoid production and like a smaller dose or none, might not like it. For me it provides feeling throughout my body in a way that I don’t have otherwise. It helps me for muscle knots or spasms and pain. Mentally it helps me with PTSD and anxiety and prevents mast cell histamine excess and hyperexcitability.

Cannabinoids help with learning & forgetting – reshaping nerve pathways – neural plasticity. Pain signal pathways can also be remade more easily with cannabinoids.

Cannabinoids help with learning and nerve flow, and with forgetting – changing nerve pathways to build new as needed and remove the old as they are not needed (old phone number for example). Neural plasticity – changing nerve pathways and synapses between nerves is a function involving cannabinoids. Pain and movement, appetite and growth, cannabinoids affect many functions of the body and neural plasticity can affect pain pathways too – remembered pain in an amputee’s healed wound, and maybe feelings of the missing limb still being there also.

The same team noted a baseline fragility of serotonergic systems in migraine and fibromyalgia [89], plus the co-occurrence of primary headache in 97% of 201 fibromyalgia patients. In a later study [67], they supported the concept that both disorders represented a failure of serotonergic analgesia and NMDA-mediated neuronal plasticity.” (9)

Synergy – many nutrients work together to perform any action in the body. Magnesium also helps inhibit excess pain nerve signals.

Pain conditions can be caused by deficiency of nutrients or chemicals that inhibit pain sensing nerves. Magnesium is needed to inhibit them as well as cannabinoids. Migraine pain may be not responsive to opiate pain killers. (9)

A trigeminovascular system has long been implicated as integral to the pain, inflammation and secondary vascular effects of migraine, linked through the NMDA/glutamate system [49]. Cannabinoid agonists inhibit voltage-gated calcium channels, and activate potassium channels to produce presynaptic inhibition of glutamate release [50], without dissociative effects noted with other NMDA inhibitors, such as ketamine.” (9)

*Having adequate potassium and magnesium in the diet and avoiding excess glutamate in seasonings and other dietary sources can also help avoid migraines – in addition to the cannabinoids or cannabinoid receptor agonists – activators.

Diabetes pain may also not be helped by opiates unless magnesium is also provided – and providing magnesium in a larger dose helped even more! (10)

Give the body what it needs to function and it functions. Miracle!

Sunshine might be part of the miracle too – vitamin D represents a group of chemicals which may aid us in ways we don’t know yet. Supplementing with one – vitamin D, may not be providing us others that we would have made if sun or full spectrum/UVB containing light is available. (13)

We need cannabinoids too – and some of us genetically can’t make them – since birth, and potentially – epigenetic changes might be occurring that cause dysfunction in a person’s ability to make cannabinoids at some point later in their life. Is that happening in LongCovid survivors? -discussed in the last post.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Li F, Feng Q, Lee C, et al. Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization. Molecular Genetics and Metabolism. 2008 Jul;94(3):326-335. DOI: 10.1016/j.ymgme.2008.03.013. https://europepmc.org/article/med/18457970
    1. Figure 3, https://europepmc.org/articles/PMC2515933/figure/F3/
  2. BHMT Gene (Protein Coding), Betaine–Homocysteine S-Methyltransferase: BHMT Pathways & Interactions, genecards.org, https://www.genecards.org/cgi-bin/carddisp.pl?gene=BHMT#pathways_interactions
  3. Glycerophospholipid biosynthesis, reactome.org, https://reactome.org/PathwayBrowser/#/R-HSA-1483206
  4. Drzazga A, Sowinska A, Krzeminska A, Rytczak P, Koziolkiewicz M, Gendaszewska-Darmach E. Lysophosphatidylcholine elicits intracellular calcium signaling in a GPR55-dependent manner. Biochem Biophys Res Commun. 2017 Jul 22;489(2):242-247. doi: 10.1016/j.bbrc.2017.05.145. Epub 2017 May 26. PMID: 28552522. https://pubmed.ncbi.nlm.nih.gov/28552522/
  5. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105(7):2699-2704. doi:10.1073/pnas.0711278105 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268199/
  6. Understand Cannabis Weights & Calculate THC Dose, June 5, canuvo.org, https://canuvo.org/cannabis-weight-calculate-thc-dose/
  7. CBD Dosage: Figuring Out How Much to Take, healthline.org, https://www.healthline.com/health/cbd-dosage#safety-and-side-effects
  8. Barreda AR, De Leon K and Urmasa S., A simple guide to pot, THC and how much is too much. April 20, 2018, latimes.com, https://www.latimes.com/projects/la-me-weed-101-thc-calculator/
  9. Russo, Ethan. (2008). Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?. Neuro endocrinology letters. 29. 192-200. 10.1522/cla.roj.let. https://www.researchgate.net/publication/5448843_Clinical_Endocannabinoid_Deficiency_CECD_Can_this_Concept_Explain_Therapeutic_Benefits_of_Cannabis_in_Migraine_Fibromyalgia_Irritable_Bowel_Syndrome_and_other_Treatment-Resistant_Conditions
  10. M. Bujalska, H. Makulska-Nowak, S.W. Gumuka,  Magnesium ions and opioid agonists in vincristine-induced neuropathy, Pharmacol Rep. 2009 Nov-Dec;61(6):1096-104. http://www.ncbi.nlm.nih.gov/pubmed/20081245
  11. Onaivi ES, Chaudhuri G, Abaci AS, Parker M, Manier DH, Martin PR, Hubbard JR. Expression of cannabinoid receptors and their gene transcripts in human blood cells. Prog Neuropsychopharmacol Biol Psychiatry. 1999 Aug;23(6):1063-77. doi: 10.1016/s0278-5846(99)00052-4. PMID: 10621950 https://www.researchgate.net/publication/12692236_Expression_of_cannabinoid_receptors_and_their_gene_transcripts_in_human_blood_cells
  12. Erukainure OL, Matsabisa MG, Salau VF, Islam MS. Tetrahydrocannabinol-Rich Extracts From Cannabis Sativa L. Improve Glucose Consumption and Modulate Metabolic Complications Linked to Neurodegenerative Diseases in Isolated Rat Brains. Front Pharmacol. 2020;11:592981. Published 2020 Nov 24. doi:10.3389/fphar.2020.592981 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774498/
  13. Vitamin D and your health: Breaking old rules, raising new hopes. Updated May 17, 2019, Published Feb. 2007, health.harvard.edu, https://www.health.harvard.edu/staying-healthy/vitamin-d-and-your-health-breaking-old-rules-raising-new-hopes
  14. Wróbel A, Serefko A, Szopa A, Ulrich D, Poleszak E, Rechberger T. O-1602, an Agonist of Atypical Cannabinoid Receptors GPR55, Reverses the Symptoms of Depression and Detrusor Overactivity in Rats Subjected to Corticosterone Treatment. Front Pharmacol. 2020;11:1002. Published 2020 Jul 8. doi:10.3389/fphar.2020.01002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360849/
  15. Image/ Figure “General structure of phospholipids and common head groups.” source: Membrane lipids in Agrobacterium tumefaciens: Biosynthetic pathways and importance for pathogenesis researchgate.net, https://www.researchgate.net/figure/General-structure-of-phospholipids-and-common-head-groups-PLs-contain-two-fatty-acids_fig1_261605192
  16. Hungund BL, Vinod KY, Kassir SA,, et al., Upregulation of CB1 receptors and agonist-stimulated [35S]GTPS binding in the prefrontal cortex of depressed suicide victims. March 2004, Mol Psychiatry 9(2):184-90 DOI: 10.1038/sj.mp.4001376 https://www.researchgate.net/publication/8692237_Upregulation_of_CB1_receptors_and_agonist-stimulated_35SGTPS_binding_in_the_prefrontal_cortex_of_depressed_suicide_victims
  17. Navarrete Francisco, García-Gutiérrez María Salud, Jurado-Barba Rosa, et al., Endocannabinoid System Components as Potential Biomarkers in Psychiatry. Frontiers in Psychiatry Vol 11, 2020, 31 pp, DOI=10.3389/fpsyt.2020.00315 https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00315/full
  18. Li R, Li Y, Liang X, Yang L, Su M, Lai KP. Network Pharmacology and bioinformatics analyses identify intersection genes of niacin and COVID-19 as potential therapeutic targets [published online ahead of print, 2020 Nov 10]. Brief Bioinform. 2020;bbaa300. doi:10.1093/bib/bbaa300 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717147/
  19. Lysophosphatidylethanolamine, sciencedirect.com, https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/lysophosphatidylethanolamine