The NCCIH division of the NIH has some helpful and objective things to say about use of marijuana for various medical conditions. Leafly.com has a good list of the major phytocannabinoids in cannabis. It is not the goal of this site to recreate their information.
. Does Cannabis Use Affect Cognitive Capacity?
The short answer from the Bloomfield review is that heavy use is a problem. Cannabis abuse is particularly damaging in the developing brains of children. [1] A problem is determining what is excessive. When we look at metabolic pathways we see the need for a health care provider to guide use.
Does Cannabis Use Decrease Motivation?
Yes, heavy cannabis use can decrease motivation, though using cannabis instead of doing school work may be considered a motivation. Decreased dopamine synthesis capacity was mentioned in this review. [1] Another review presented evidence that short term THC increases dopamine release but long term use blunts the system. [2]
Does Cannabis Use Increase the Risk for Psychosis?
At the risk of mis-paraphrasing the Volkow review, family history is a far more a predictor of schizophrenia than cannabis use. However, heavy cannabis use can make a bad situation worse in individuals with schizophrenia associated gene mutations. These mutations include [1]:
- COMT catacolamine O-methyl transferase catalyzes the metabolism of catacholamine neurotransmitters: dopamine, adrenaline, and noradrenaline. A Alanine → Serine substitution at position 72 reduces COMT activity and contributes to the development of schizophrenia.
- DRD2 is the name of the gene that codes for the dopamine receptor #2. Dopamine receptors, like CB1 and CB2, are G-Protein coupled receptors. A Serine → Cysteine substitution at position 311 may be associated with a higher risk for schizophrenia. 311 lies in the cytoplasmic domain.
- AKt1, RAC-alpha serine/threonine-protein kinase, a second messenger that plays a role in energy metabolism.
Maybe, just maybe phytocannabinoids have a lot of potential for treating conditions like schizophrenia. Things just go sort of wrong when the patient doesn’t get the right combination of phytocannabinoids and/or the dose right.
Do phytocannabinoids get metabolized differently than endo cannabinoids?
This page postulates that use of cannabis to relieve stress is really not that different than going for a run or eating “comfort food” to relieve stress. The difference is that the metabolism of phytocannabinoids is not as fine tuned and “on location.” Those with life circumstances and genetic backgrounds associated with schizophrenia do not self medicate with cannabis unless it provides some relief.
Anandamide degradation occurs on location
Fatty acid amide hydrolase, according to Protein Atlas, catalyzes the degradation of endocannabinoids anandamide and 2-AG. It is pretty much expressed everywhere but adipose tissue. Protein Atlas is a great learning tool. By centering the cursor over the Hippocampus bar we learn that the expression is high in glial and neuronal cells. In the caudate nucleus expression is low in glial cells but high in neuronal cells.
FAAH is expressed all over our bodies with notable high expression in our brains.
Δ9–THC degradation is highly restricted
Δ9–tetrahydrocannabinol metabolism is a bit more complicated. The strategy is to add hydroxyl groups and ultimately some sugars via with glucuronosyl transferases. The glucurnoide is more water soluble and easier to eliminate in the urine. This image is compiled from Protein Atlas expression data for CyP3A4 and reference [4]. Note the high expression in the stomach and small intestine. This site is not getting into smoking versus edibles for the best Δ9–tetrahydrocannabinol experience.
Δ9 often comes with CBD and terpenes, all of which have the potential to interfere with the metabolism of Δ9. In this table, botanical derived substances are those with a known concentration of minor cannabnoids and presumably a larger amount of THC.
An Italian study [5] examined the ability f phytocannabinoids to inhibit the metabolism of endocannabinoids. Botanically derived substances are the whole extract including quantified amounts of the indicated phyto cannabinoid. [5]
| DAGLα | MAGL | FAAH | NAAA | AEA uptake | |
| CBC | >100 µM | 50.1 ± 12.1 | >100 µM | >100 µM | 12.3 ± 2.7 |
| CBC-BDS | >100 µM | 91.4 ± 13.8 | 53.2 ± 11.3 | 14.2 ± 6.2 | 15.7 ± 4.2 |
| CBD | >100 µM | >100 µM | 15.2 ± 3.2 | >100 µM | 25.3 ± 1.8 |
| CBD-BDS | >50 µM | >50 µM | 30.8 ± 6.2 | >100 µM | 11.5 ± 3.2 |
| CBG | >100 µM | 95.7 ± 32.4 | >100 µM | >100 µM | 11.3 ± 4.2 |
| CBG-BDS | 65.7 ± 10.3 | 24.6 ± 8.4 | 62.9 ± 21.4 | 18.3 ± 9.4 | 14.2 ± 2.5 |
| CBDA | 19.4 ± 2.7 | >50 µM | >50 µM | 23.0 ± 1.3 | >25 |
| CBDA-BDS | 21.8 ± 1.3 | 29.6 ± 1.1 | >50 µM | >50 µM | 5.8 ± 1.3 |
| CBGA | 30.5 ± 1.4 | >50 µM | >50 µM | >50 µM | >25 |
| CBDV | 16.6 ± 4.1 | >100 µM | >100 µM | 72.3 ± 18.4 | 21.3 ± 1.8 |
| CBDV-BDS | >50 µM | >50 µM | 53.4 ± 8.3 | >100 µM | >25 |
| CBGV | >50 µM | >50 µM | >50 µM | >50 µM | >25 |
| CBGV-BDS | >50 µM | >50 µM | >50 µM | 24.4 ± 2.1 | 6.9 ± 1.5 |
| THCA | 27.3 ± 1.6 | 46.0 ± 1.2 | >50 µM | >50 µM | >25 |
| THCA-BDS | 21.8 ± 2.8 | 6.2 ± 1.2 | >50 µM | >50 µM | 9.7 ± 1.6 |
| THCV | >50 µM | >50 µM | >100 µM | >100 µM | >25 |
| THCV-BDS | >50 µM | >50 µM | >100 µM | >100 µM | >25 |
| THCVA | >50 µM | >50 µM | >100 µM | >100 µM | >25 |
| THCVA-BDS | >50 µM | >50 µM | >50 µM | >100 µM | 12.5 ± 5.2 |
| CBN | >50 µM | >50 µM | >50 µM | >50 µM | ∼25 |
DAGLα is in simple terms an enzyme that hydrolyzes the postion 3 acyl group from the glycerol background leaving only the arachidonic acid group in the 2 position, i.e. 2-AG. While the decrease in DAGL protein amounts in PBMC was the strongest predictor of the FEP.[6].
MAGL, monoacyl glycerol lipase, is an enzyme responsible for removing the arachidonic acid from 2-AG. This protein is expressed throughout the cell. Inhibition of MAGL may be a cause for concern. An NIH study examined MRI changes in gray and white matter of heavy and light continuous and discontinuous cannabis users. They then tried to correlate these changes with the Allen Brain Altas of mRNA expression. [7] They found that the regions of gray and white matter thinning correlated with MAGL , but not FAAH expression. [7]
FAAH, fatty acid amide hydrolase, is of course the enzyme that degrades anandamide. UniProt,org tells us that FAAH is a membrane protein with the business end on the intracellular portion of the membrane. A European compared FAAH, MAGL, and CB1 mRNA and enzyme activity in post mortem brains of schizphrenia and control subjects. [8] Positive correlation of mRNA expression was found in the prefrontal cortex of controls but not schizophrenia subjects. [8] CB1 was found to functionally couple to G proteins. [8] These authors saw an increase in FAAH activity. [8]
NAAA N-acylethanolamine-hydrolyzing acid amidase degrades many fatty acid amides that include anandamide. This enzyme may be found on the cell membrane or the membranes of lysosomes. NAAA inhibition is an emerging means to treat inflammation. [9]
Anandamide uptake is a big unknown. De Petrocellis and coworkers just measured its occurrence in cultured cells. [5]
Conclusions
Can there be any when it comes to self medication with cannabis? Unmonitored self medication with any is generally recognized as unsafe. How safe is the medical community monitored use of selective serotonin reuptake inhibitors (SSRI) in combination with monoamine oxidase inhibitors (MAOI)? Psychiatrist.com offers a more optimistic overview of the myriad of drugs used to re-balance a patient’s serotonin levels. Television commercials remind us tragic side effects when things go wrong. One little cannabis flower contains CB receptor agonists, endocannabinoid reuptake inhibitors, and degradation inhibitors. If you are using cannabis for mental health reasons, there’s an opportunity to rewrite the book on plant based medicines with the help of your physician. (1) Obtain a list of phytocannabinoids in your medicine. (2) Ask your physician if genetic testing is appropriate for the condition that you are using cannabis to treat. (3) Keep a log on your symptoms and your use of medicine. (4) Ask your physician if blood tests are appropriate to ensure you are getting your dosing right. You have nothing to hide and every right in this world to ask for a guide in your use of plant based medicine.
References
- Volkow ND, Swanson JM, Evins AE, DeLisi LE, Meier MH, Gonzalez R, Bloomfield MA, Curran HV, Baler R. Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review. JAMA Psychiatry. 2016 Mar;73(3):292-7. free article
- Bloomfield, M. A., Ashok, A. H., Volkow, N. D., & Howes, O. D. (2016). The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature, 539(7629), 369–377. PMC free article
- Manseau, M. W., & Goff, D. C. (2015). Cannabinoids and Schizophrenia: Risks and Therapeutic Potential. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 12(4), 816–824. PMC free article
- Jamwal, Rohitash & Topletz, Ariel & Ramratnam, Bharat & Akhlaghi, Fatemeh. (2017). Ultra-high Performance Liquid Chromatography Tandem Mass–Spectrometry for Simple and Simultaneous Quantification of Cannabinoids. Journal of Chromatography B. 1048. 10.1016/j.jchromb.2017.02.007.
- De Petrocellis, L., Ligresti, A., Moriello, A. S., Allarà, M., Bisogno, T., Petrosino, S., Stott, C. G., & Di Marzo, V. (2011). Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. British journal of pharmacology, 163(7), 1479–1494. PMC free article
- Schurman, L. D., Carper, M. C., Moncayo, L. V., Ogasawara, D., Richardson, K., Yu, L., Liu, X., Poklis, J. L., Liu, Q. S., Cravatt, B. F., & Lichtman, A. H. (2019).
- Manza P, Yuan K, Shokri-Kojori E, Tomasi D, Volkow ND. (2020) Brain structural changes in cannabis dependence: association with MAGL. Mol Psychiatry. 2020 Dec;25(12):3256-3266. PMC free article
- Muguruza C, Morentin B, Meana JJ, Alexander SP (2019) Callado LF. Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia. J Psychopharmacol. 2019 Sep;33(9):1132-1140
- Piomelli D, Scalvini L, Fotio Y, Lodola A, Spadoni G, Tarzia G, Mor M. N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition. J Med Chem. 2020 Jul 23;63(14):7475-7490.
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