Can cannabinoids and particularly CBD be an adjunct therapy for Colorectal Adenocarcinoma?

Adenocarcinoma is the most common type of colorectal cancer.

The inhibition of the cancer cell proliferation and induction of apoptosis in cancer cells by CB1 and CB2 activation has been reported. In a recent study by Cerretani et al., they demonstrated that CBD-induced cytotoxicity in HT-29 cells occurs through a CB1 and CB2 receptor-independent mechanism.

Cytotoxic effects on the cellular viability of HT-29 cells exposed to IC50 of THC, CBD, and CB83 in the presence of AM251 (CB1 antagonist) 1μM and AM630 (CB2 antagonist) 1 μM. The results are expressed as % of control. Data are representative of three independent experiments. Data were statistically evaluated. * p < 0.05 and ** p < 0.01 vs. control.
Source: Int. J. Mol. Sci. 2020, 21(15), 5533

No sign of oxidative stress was evident when CB1 or CB2 agonists were used. CBD increased ROS production which led to apoptotic cell death.

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Does CBD inhibit FAAH?

FAAH inhibition by phytocannabinoids

Source: Matthew W. Elmes et al. J Biol Chem. 2015;290(14):8711-8721.

CBD is proposed to inhibit FAAH, which could result in increased anandamide levels thereby, activating CB1, CB2, and TRPV1 receptors1&2. However, more recent research by Elmes et al. demonstrated that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting Fatty acid-binding proteins (FABPs) with no effect on FAAH3. The fatty acid-binding proteins (FABPs) have been shown to be intracellular transporters for AEA. Anandamide requires transport from the membrane to intracellular FAAH for degredation3.

“THC and CBD did not reduce the proportion of intracellular AEA that is hydrolyzed following uptake, suggesting that the cannabinoids block the delivery of AEA to FAAH but do not affect AEA hydrolysis by FAAH”.

This study also showed that THC inhibits the cellular uptake and catabolism of AEA by targeting FABPs3.

THC and CBD interact with FABP3, FABP5, and FABP7 and bind with similar affinities as endocannabinoids AEA and 2-AG. CBD and THC inhibit both rat and mouse but not human FAAH3.

CBD impact on Acute lymphoblastic leukemia (ALL) of T lineage (T-ALL)

Acute lymphoblastic leukemia (ALL) of T lineage (T-ALL) occurs in 15% of childhood and 25% of adult ALL cases. It represents a highly aggressive cancer that is resistant to chemotherapy and has an increased risk of relapse with long-term remission failure of  ~20% in children and 40% of adult patients.

Cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, has been shown to be highly sensitive to CBD.

Olivas-Aguirre et al. demonstrated that CBD effects do not depend on cannabinoid receptors or plasma membrane Ca2+-permeable channels. CBD directly targets mitochondria and alters their capacity to handle Ca2+. CBD causes mitochondrial Ca2+ overload, stable mitochondrial transition pore formation, and cell death.

CBD at 30–100 μM induces cell death, while at 10 μM the cells remained alive, but did not proliferate. At low (1 μM) concentration, CBD stimulated cell proliferation and prevented cell death.

Contrasting effects of low and high CBD concentrations justifies further research to better understand CBD effects and its potential role as an adjunct treatment in T-ALL.

References:

  1. Nguyen K, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group Study. Leukemia. 2008;22:2142–2150. doi: 10.1038/leu.2008.251.
  2. Pui CH, Yang JJ, Bhakta N, Galindo C. Global efforts toward the cure of childhood acute lymphoblastic leukemia. Lancet Child Adolesc. Health. 2018;2:440–454. doi: 10.1016/S2352-4642(18)30066-X.
  3. Olivas-Aguirre M, Torres-López L, Valle-Reyes JS, Hernández-Cruz A, Pottosin I, Dobrovinskaya O. Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia. Cell Death Dis. 2019;10(10):779. Published 2019 Oct 14. doi:10.1038/s41419-019-2024-0.

What do we know about CBDA?

CBDA is one of the cannabinoid acids produced in the trichomes of the cannabis plant. CBDA  can easily be decarboxylated to CBD if exposed to heat. Due to its low stability, synthetic analogs of CBDA have been developed to address this challenge.

CBDA inhibits anandamide cellular uptake. CBDA does not display significant activity as either an agonist or an inverse agonist at the CB1 receptors.

CBDA has shown to inhibit nausea-induced behavior in rats by enhancing the activation of 5-HT1A receptors. CBDA demonstrates 100-fold greater affinity for the 5-HT1A receptors.

Anxiolytic effects of CBDA may require the presence of a specific stressor. Rock et al., reported no anxiolytic effects in rats without a prior explicit stressor however, administration of CBDA (0.1-100 μg/kg) or CBD (5 mg/kg) prevented the FS-induced anxiogenic-like responding.

CBDA shares the capability of CBD to activate the transient receptor potential (TRP) cation channels, TRPV1 and TRPA1, and to antagonize TRPM8, however, it produces these effects with significantly less potency than CBD.

CBDA shows promise as a potential treatment for anticipatory nausea and vomiting and anxiety.

References:

  1. De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-1494. doi:10.1111/j.1476-5381.2010.01166.x.
  2. Bolognini D, Rock EM, Cluny NL, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013;168(6):1456-1470. doi:10.1111/bph.12043.
  3. Bagdy G, Kecskemeti V, Riba P, Jakus RJ Neurochem. 2007 Feb; 100(4):857-73.
  4.  Rock EM, Limebeer CL, Petrie GN, Williams LA, Mechoulam R, Parker LA. Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats. Psychopharmacology (Berl). 2017;234(14):2207-2217. doi:10.1007/s00213-017-4626-5 .

Does CBN help with insomnia?

CBN or cannabinol is a non-enzymatic oxidative by-product of THC.

It has a lower affinity for CB1 and CB2 receptors compared to THC (10% of the activity of Δ9-THC at the CB1 receptors).

CBN has been promoted to assist patients that are suffering from insomnia but this claim has not been substantiated by any clinical trials.

Research by Musty et al., reported that oral ingestion of 50 mg CBN did not induce dizziness or drowsiness in human subjects.

“It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used”.

As the result of the low affinity of CBN to cannabinoid receptors and limited available evidence, CBN shall not be claimed to be a sedative.

Adequate clinical trials focused specifically on the sedative effects of CBN are required to further evaluate potential other mechanisms that may be responsible for reported anecdotal claims by users.

References:

  1. Health Canada. (2018). Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids. Ottawa: Health Canada.
  2. Merzouki A, Mesa JM. Concerning kif, a Cannabis sativa L. preparation smoked in the Rif mountains of northern Morocco. J Ethnopharmacol. 2002;81(3):403-406. doi:10.1016/s0378-8741(02)00119-8.
  3. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008 01;153(0007-1188; 0007-1188; 2):199-215.
  4. Izzo AA, Borrelli F, Capasso R, Di M,V, Mechoulam R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009 10;30(1873-3735; 0165-6147; 10):515-27.
  5. Evans FJ. Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med. 1991;57:S60–S67.
  6. Musty RE, Karniol IG, Shirikawa I, Takahashi RN, Knobel E. Interactions of delta-9-tetrahydrocannabinol and cannabinol in man. In: Braude MC, Szara S, editors. The Pharmacology of Marihuana. Vol. 2. New York: Raven Press; 1976. pp. 559–563.

THCA and its potential pharmacological effects

THCA is generally referred to as an inactive precursor of THC, but research has demonstrated that this chemical compound may have potential therapeutic properties.

Δ9‐THCA is produced naturally in the cannabis plant. It is a non‐psychotropic cannabinoid and its potential to bind to CB1 receptors is still debated.

A more recent study by McPartland et.al. showed that freshly prepared and highly pure Δ9‐THCA (98%) has a low binding affinity for CB1 and CB2 receptors1.

THCA-A has shown to inhibit the release of TNFα in a dose-dependent manner and, weakly inhibit cyclooxygenase enzymes (COX-1 and COX-2) in a high concentration range (mM), compared with nonsteroidal anti-inflammatory medications (NSAIDs)2.

The anti-inflammatory activity of Cannabis extracts on colon epithelial cells of an IBD model is suggested to be derived from THCA3. This study suggested that the anti-inflammatory activity of THCA was at least partially mediated by GPR55 receptor agonism.

It is suggested that Δ9‐THCA enters the CNS and PPARγ is the major target responsible for its neuroprotective and anti‐inflammatory activity4&5. THCA-A binds and activates PPARγ with higher potency than THC5.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731255/figure/bph14019-fig-0001/

Δ9-THCA-A is a partial and selective PPARγ modulator, empowered with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoclastogenic effects in hMSC4. It is proposed that Δ9-THCA-A as a low adipogenic PPARγ agonist, may be capable of improving the symptoms of obesity-associated metabolic syndrome and inflammation4.

Δ9‐THCA has been shown to be neuroprotective in mice treated with 3‐NPA, improving motor deficits and preventing striatal degeneration. It attenuates microgliosis, astrogliosis, and up‐regulation of pro-inflammatory markers induced by 3‐NPA in mice5.

Δ9‐THCA shows potent neuroprotective activity, which warrants its consideration for the investigation of treatments of Huntington’s disease and other neurodegenerative and neuroinflammatory conditions.

REFERENCES:

  1. McPartland JM, McDonald C, Young M, Grant Phillip S, Furkert DP, Glass M (2017). Affinity and efficacy studies of tetrahydrocannabinolic acid A at cannabinoid receptor types one and two. Cannabis Cannabinoid Res 2: 87–95.
  2. Ruhaak LR, Felth J, Karlsson PC, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34:774–778.
  3. Nallathambi R, Mazuz M, Ion A, et al. Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts. Cannabis Cannabinoid Res. 2017;2(1):167–182. Published 2017 Jul 1. doi:10.1089/can.2017.0027.
  4. Palomares B, Ruiz-Pino F, Garrido-Rodriguez M, et al. Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity. Biochem Pharmacol. 2020;171:113693. doi:10.1016/j.bcp.2019.113693.
  5. Nadal X, Del Río C, Casano S, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017;174(23):4263–4276. doi:10.1111/bph.14019.

Finnish Food Authority has pulled CBD products from the market

European Union has designated Cannabidiol(CBD) as Novel Food. Novel Foods are not allowed to be placed on the market without authorization. In 2019 a German court’s ruling classified CBD as either a prescription medicine or Novel Food and most recently the Finnish Food Authority has issued a recall of extracts containing cannabinoids, such as CBD-A. Availability of products containing CBD in the EU market is changing.

Medical cannabis will be more readily available at a lower cost in Czech Republic

The Czech Republic Ministry of Health submitted an amendment to the Act on Addictive Substances for interdepartmental comment procedure. The amendment introduces completely new conditions to issue licenses to grow cannabis plants for medical use. The goal is to increase the number of cultivators and increase availability of cannabis for medical use, while at the same time reducing its price for Czech patients through commercial competition.

“We want more access to cannabis treatment to help patients who are no longer taking normal medications to treat chronic pain. Therefore, we decided to change the existing system and open the possibility of growing more subjects. For the first time, we will also open the possibility of exporting medical cannabis, which will reduce its price on the Czech market. In addition, as of 1 January next year, patients will receive 90% reimbursement for medical cannabis. Newly, the supplement will be only a few hundred, as with other drugs for chronic diseases. Patients who have so far had to pay high amounts for medical cannabis and have been very burdensome for them will be greatly relieved, ” said Minister of Health Adam Vojtěch.

Medical Cannabis coverage is a significant step forward to reduce barriers to access for patients.

The role of endocannabinoid system in the bone

Bone undergoes continuous destruction and formation. In healthy individuals, the two processes are in fine balance, maintaining a constant, homeostatically controlled amount of bone.

Bone diseases are very common across the globe. Osteoporosis is the main cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, iron overload, glucocorticoid (GC) treatments, hyperthyroidism, and chemotherapies.

Bone cells express CB1 and CB2 receptors and TRPV1 channels. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) as well as the enzymes involved in their synthesis and degradation are present in bone cells. AEA and 2-AG seem to modulate osteoblast and osteoclast differentiation.

CB1 and TRPV1 stimulation produces osteoclastogenic effects, while CB2 stimulation has an anti-osteoclastogenic effect.

CB1 activation produces age-dependent effects on bone mass by regulating the differentiation of osteoclasts and Mesenchymal Stem Cells (MSCs) into osteoblasts and adipocytes. Cannabidiol (CBD) is suggested to inhibit osteoclast and stimulate osteoblast differentiation by blocking GPR55.

The pharmacological modulation of these receptors contributes to the maintenance of bone mass by stimulating stromal cells and osteoblasts and by inhibiting monocytes and osteoclasts. Endocannabinoid system may be a pharmacological target in the prevention and treatment of bone diseases such as osteoporosis.