One theory is that endocannabinoids impact the amount of calcium available in cells. This is where things get complicated because there are two primary medicinal compounds in marijuana, THC and CBD. Both of these chemicals can act on the ECS, albeit in very different ways.
Another 2015 study for BioMed Research International states that THC, specifically, can negatively impact mitochondria in the brain. The authors suggest that it could harm these crucial structures and increase the risk of strokes.
In terms of how THC and CBD affect mitochondrial disease, the evidence is somewhat conflicting. One 2014 study in the American Journal of Physiology, Endocrinology, and Metabolism suggests that compounds that activate cannabinoid receptors could damage mitochondria.
Can Cannabis Help Mitochondrial Disease?
Finally, a more recent 2018 study in Frontiers in Pharmacology claims that CBD could increase the activity of mitochondrial complexes in rats. Its antioxidant and neuroprotective properties could also protect cells from damage.
Symptoms can range from mild to severe. However, several types of mitochondrial diseases follow a particular pattern.
In some types of mitochondrial disease, both parents must carry a defective gene for the condition to manifest. However, in some cases, it can be inherited from the mother alone.
THC is probably the most famous chemical in cannabis. It is known for causing the intoxicating high that recreational users seek. It also has a range of medical benefits, including relieving pain and nausea, enhancing the appetite, and improving mood.
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Over the past several years we have been using more and more THC-Acid (THC-A.) Many of you may be familiar with the differences between THC and THC-A.
Mitochondria exist in every cell in the body other than red blood cells.
As there was not much data on it, I must admit that I was somewhat dismissive of THC-A. The reason for the lack of data was because it was very difficult to make a synthetic version in the lab.
Benefits of THCA?
Mitochondria are primarily responsible for creating energy for the cell and for the body.
With COVID, we have never been more aware of critical shortages of masks, ventilators, hospital beds, etc., all leading to rationing. In this BLOG, Dr Frankel, examines how rationing in our medical care is a much bigger problem than just face masks.
Previous work from our laboratory indicated a link between CBD-induced Ca 2+ responses and intracellular Ca 2+ stores (Drysdale et al., 2006), rather than extracellular Ca 2+ sources. Thus, we next investigated a potential role of mitochondria, fundamental players in cellular Ca 2+ homeostasis, in CBD’s action. To simultaneously study mitochondrial signaling together with cytosolic Ca 2+ responses, cultures were preloaded with the mitochondrion-specific Ca 2+ -sensitive fluorescent marker, Rhod-FF, AM, followed by fura-2 AM loading ( Fig. 4 ). The fluorescence pattern and responses to FCCP (10 μ m ), an uncoupler of ATP synthesis due to its action as a protonophore, confirmed the specificity of this protocol, causing leakage of mitochondrial Ca 2+ from mitochondria accompanied by an increased cytosolic Ca 2+ concentration ( Fig. 4 ). Application of CBD (1 μ m ) resulted in an increase in cytosolic Ca 2+ , preceded by a response in the Rhod-FF fluorescence ( Fig. 5 ). Two Rhod-FF response patterns were observed, biphasic (an initial rise followed by a decrease) or a continuous decline (see sample traces given in Fig. 5 A,B). Subsequently, we confirmed that the pattern observed with CBD in this dual-fluorescence model genuinely represents a release from mitochondrial Ca 2+ stores by preapplication of FCCP (1 μ m ), applied to dual-loaded cultures (see Fig. 1 for the sites of action for this and other mitochondrion-acting compounds). At this concentration, FCCP induced an immediate reduction in Rhod-FF fluorescence in the mitochondrial compartment, and somewhat delayed in onset and progression, an increase in cytosolic Ca 2+ levels was observed. More importantly, no further responses to CBD could be induced in mitochondria ( Fig. 5 C), while raised cytosolic Ca 2+ levels recovered partially, in agreement with our previous experiments in high-K + HBS and 4AP.
Each treatment and relevant vehicle controls were run in six samples (wells) per experiment and repeated at least twice, viability was compared using the nontoxic cell viability marker Alamar Blue (Serotec). This marker was made up as a 10% solution in MEM and applied to all wells (following the removal of treatment medium) for 2 h at 37°C, 5% CO2. The plates were then run in a plate reader (either Victor 2 1420, Wallac, Perkin-Elmer or Synergy HT, Bio-Tek) and the fluorescence (excitation: 530 nm and emission: 590 nm) measured.
Effects of ER- and mitochondrion-acting drugs on CBD responses. A, B, The role of mitochondria in CBD responses were confirmed in neurons (A) and glia (B). The uncoupler FCCP prevented neuronal CBD response and largely reduce glial responses while blockade of IP3 and ryanodine receptors [by 2-APB and dantrolene (Dant.), respectively] did not significantly alter CBD responses in neurons, a sample trace of which is also shown (C). In the presence of CGP 37157 (CGP), but not in the presence of the mPTP inhibitor cyclosporin A (CsA), CBD responses were also blocked in normal and high-excitability HBS; CBD responses under high-excitability conditions no longer differed from standard HBS responses. Data are presented as %ΔF/F + SEM; n.s., not statistically significant; **p < 0.01, ***p < 0.001.
CGP may act not only upon mitochondrial NCX, but also as an inhibitor of VGCCs in dorsal root ganglion neurons (Baron and Thayer, 1997). However, our previous data with VGCC blockers (Drysdale et al., 2006) are not consistent with an effect of CBD on this target. Others have found CGP to inhibit the NCX in the plasma membrane of cerebellar granule cells (Czyz and Kiedrowski, 2003), although with an IC50 of 13 μ m , a concentration higher than that used here, and higher than CGP’s IC50 (4 μ m ) for the mitochondrial NCX in cultured rat DRGs (Baron and Thayer, 1997). Indeed, the concentration of CGP used here is in keeping with recent work by others in cultured neurons (Medvedeva et al., 2008).
Bidirectional Ca 2+ responses to CBD in hippocampal cultures. A, B, Sample traces for CBD-mediated Ca 2+ responses in neurons (black traces) and glia (gray traces) in normal (A) and high-excitability (B) HBS (double K + concentration). NMDA applications at the end of each experiment were used to confirm intact signaling in neurons. C, Mean responses of CBD in normal (ctrl) and high (high ex)-excitability HBS. Data are presented as %ΔF/F + SEM. ***p < 0.001.
Preparation of standard primary hippocampal cultures from Lister–Hooded rat pups (1–3 d old) was conducted as described previously (Drysdale et al., 2006; Ryan et al., 2006), conforming to Home Office and institute regulations. Briefly, pups were killed by cervical dislocation and the brain removed, and the hippocampi were dissected out and placed in filtered ice-cold HEPES-buffered solution (HBS, composition in m m : NaCl, 130; KCl, 5.4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 25; compounds from Sigma-Aldrich). Hippocampal tissue was finely chopped and placed in a 1 mg/ml protease solution (type X and XIV, Sigma-Aldrich) for 40 min. Graded fire-polished glass Pasteur pipettes were used to triturate the tissue a number of times. Following centrifugations, the tissue pellet was resuspended in tissue culture medium [90% minimum essential medium (MEM; Invitrogen), 10% fetal bovine serum (FBS) (Helena Biosciences), and 2 m m l -glutamine (Sigma-Aldrich)], kept in a humidified incubator at 37°C and in 5% CO2, and plated in 35 mm culture dishes (Invitrogen, coated with poly- l -lysine, Sigma-Aldrich). After 1 h, an additional 2 ml of tissue culture medium was gently added to each dish and stored in a humidified incubator (37°C; 5% CO2). After 2 d of maturation, the MEM was replaced with Neurobasal medium (Invitrogen) to reduce glial growth [composition of culture by cell-type (2:1, neurons:glia) was in keeping with that outlined in previous publications (Platt et al., 2007)], containing 2% B27, 2 m m l -glutamine, and 25 μ m l -glutamate (Sigma-Aldrich). Culture dishes were checked for uniform density and deemed suitable for imaging experiments from 5 to 10 d in vitro based on fully reproducible NMDA responses (variability: <5%), with control experiments conducted at regular intervals.
Exogenous application of hydrogen peroxide (as well as the cellular generation of this oxidative agent) has been shown to induce apoptosis in association with MAP kinase activation (Guyton et al., 1996). Thus, CBD’s neuroprotective action against H2O2 toxicity in SH cells is in line with CBD’s reported inhibition of p38 MAP kinase, although proposed to be secondary to CBD’s antioxidant capacity (El-Remessy et al., 2006), which was not apparent here. Ligresti et al. (2006) also showed protection in breast cancer cells against H2O2 toxicity at low (n m ) but not higher (μ m ) concentrations of CBD. The latter effect was suggested to involve the generation of ROS, also reported in glioma cells (Massi et al., 2006). Therefore, the possibility has been raised that CBD might have potential as an anticancer treatment (for review, see Mechoulam et al., 2007). A comparison between the antioxidant properties of CBD and BHT has been performed previously (Hamelink et al., 2005), with approximately equivalent antioxidant capacities reported for both compounds. This is surprising in the light of the data generated here where CBD, but not BHT, alone was neuroprotective against FCCP toxicity. Interestingly, the combination of CBD and BHT caused complete protection against FCCP. Previous work conducted in our lab has shown an interaction between this phytocannabinoid and BHT, with BHT preexposure (saturating antioxidant pathways) to primary rat hippocampal cultures facilitating [Ca 2+ ]i responses to a subsequent CBD application (our unpublished observations). This implies a synergy between CBD and antioxidant pathways, with the latter facilitating CBD’s effects, rather than mediating them. Since CBD showed only little protection in the peroxide model, it seems that its anti-oxidant properties are not of major relevance for its protective action. While similar protection was seen for CsA and CBD in the FCCP model, differences in efficacy between CsA and CBD and the lack of additivity between CBD and CsA in the oligomycin model (Comelli et al., 2003) suggest that the mPTP is not a major target in CBD’s action.