In 2012, French scientists reported the presence of cannabinoid receptors on the membranes of mitochondria, the energy-generating organelle within cells. This discovery laid the groundwork for subsequent investigations into the role of the endocannabinoid system in regulating mitochondrial activity, which is critical to how cells function. Defects in mitochondria have been linked to a wide range of neurodegenerative, autoimmune and metabolic disorders.
A growing body of scientific data indicates that cannabidiol (CBD) can affect mitochondria, both directly and indirectly. It turns out that many of the biological pathways that involve mitochondria — including energy homeostasis, neurotransmitter release, and oxidative stress are modulated by endogenous and exogenous cannabinoids.
But research on cannabinoids often seems to be riddled with contradictions. Cannabinoids are notorious (in science and lived experience) for exerting opposite effects in different situations. How is CBD able to balance physiological excess as well as a deficiency? Why does a small dose of hemp oil stimulate while a large dose tends to sedate? Examining the role of mitochondria sheds light on these questions and other perplexing aspects of the endocannabinoid system.
What are mitochondria?
Mitochondria are universal energy adaptors that exist in the cells of every multicellular organism, including humans. The number of mitochondria in an individual cell can vary greatly depending on the organism and tissue type. (All human cells, except for red blood cells, contain mitochondria.) One of the main functions of mitochondria is to take high-energy molecules – such as sugars and amino acids – and convert them into a form of energy, called adenosine triphosphate (ATP), which the cell can use. For the cell, ATP is like a battery.
The process of extracting small bits of energy from high-energy molecules can be quite dangerous. Imagine trying to power a car by simply lighting the fuel tank on fire. A cell can’t handle the microscopic equivalent of an explosion, so the cell must use finesse to harness this energy. Individual electrons are extracted from high-energy molecules by a process known as cellular respiration and their energy is gradually released.
This gradual release of individual electrons allows the cell to synthesize ATP from its precursors, adenosine diphosphate (ADP) and inorganic phosphate (Pi). The cleavage of ATP back into ADP and Pi releases a small amount of energy, which powers the proteins that allow each cell to function and communicate. ATP is the main energy source for the majority of cellular functions. While commonly referred to as the cell’s powerhouse, mitochondria are also involved in other metabolism-related functions, but the goal is always the same; homeostasis the maintenance of a stable internal environment despite external fluctuations.
Originally, mitochondria were separate from other cells. At some point, one-and- a-half to two billion years ago, a cell engulfed an evolutionary precursor to a mitochondrion. But instead of digesting the mitochondrion, the two living entities formed a symbiotic relationship. The host cell would provide nutrients and a safe place for the mitochondrion to exist, and the mitochondrion would perform the dangerous process of cellular respiration, giving the host a more useable form of energy. The result was so evolutionarily fundamental that this symbiotic relationship preceded the occurrence of multicellular organisms. All plants, animals and fungi are endowed with mitochondria.
This theory of how two different self-organized living systems began to collaborate symbiotically is supported by the fact that mitochondria have retained their own genome that is separate from the host cell’s DNA. Mitochondria and the host cell replicate independently; they also have separate cellular membranes. Two other organelles are thought to have developed in a similar way: the chloroplast, which enables photosynthesis in plants, and the nucleus, which holds the cellular DNA and acts as a kind of coordinator of the cell.
Mitochondrial diseases can be caused by inherited mutations in mitochondrial DNA or defects in the nuclear genes that encode proteins that regulate mitochondrial division and DNA replication. Mitochondrial disorders can also develop due to the adverse effects of drugs, infections, environmental toxins or unhealthy lifestyle habits. Mitochondrial diseases are most severe when the defective mitochondria are present in muscle, brain or nerve tissue, as these cells require more energy.
Free Radicals & Phytocannabinoids
Although mitochondria allow energy to be accessed at a measured pace in relatively small quantities, the process of cellular respiration, whereby cells extract energy from nutrients, still can be damaging. High-energy electrons offload their energy in a multitude of complicated steps until the lower-energy electron is finally released onto an oxygen molecule. Ideally, the oxygen molecule will interact with hydrogen and form water, which is very stable.
But sometimes the ionized oxygen, called superoxide, can escape, resulting in oxidative stress. Similarly, other unstable molecules like peroxide and hydrogen peroxide can form and escape. These unstable, renegade molecules are called reactive oxygen species (ROS) or free radicals. Free radicals cause damage by interacting with DNA, cell membranes, proteins, or other organelles.
By effectively neutralizing free radicals and mitigating oxidative stress, antioxidants confer a broad range of therapeutic benefits. CBD is a potent antioxidant, according to the U.S. government, which filed a patent on the antioxidant and neuroprotective properties of cannabinoids based on research from 1998.
Autophagy & Apoptosis
Oxidative stress is a natural byproduct of mitochondrial activity. The creation of oxidative stress is necessary for obtaining energy and sustaining cellular function. Inevitably this will take its toll on an organism. But oxidative damage can be repaired to a certain extent through an adaptive process known as autophagy, whereby faulty cell parts – misfolded or aggregated proteins, dysfunctional mitochondria, etc. – are removed and replaced by newer, better- working components. Cell survival is dependent on this ongoing regenerative mechanism.
Oxidative stress is not exclusively bad. At low levels, reactive oxygen species act as signaling molecules. Damaged neurons can shed their worn-down mitochondria, which neighboring cells interpret as an SOS. Immune cells in the brain, called astrocytes, respond by donating some of their own mitochondria to the impaired neurons. Lung cells can also secrete healthy mitochondria for damaged cells to use.
Low levels of oxidative stress may stimulate a necessary cellular housecleaning, but high levels of oxidative stress are an indication that something is going wrong in the cell. Too much oxidative stress is a signal for the cell to destroy itself in a regulated way, a process called apoptosis. It’s as if there’s a tipping point when oxidative damage exceeds the capacity of a cell to repair itself, so the cell pivots from survival mode and commits suicide for the betterment of the team. The fate of a cell – whether survival via autophagy or death via apoptosis – is contingent on the kind of stress it encounters and its duration.
While oxidative stress in moderation can be used by the cell, the dysregulation of oxidative stress results in illness. Disruption of the delicate interplay between autophagy and apoptosis allows free radicals and damaged cells to accumulate, which can lead to a wide range of pathologies. Mitochondrial dysfunction is involved in virtually all disease, especially age-related neurodegeneration. Since neurons use a tremendous amount of energy to transmit information throughout the body, they require highly active mitochondria, which means greater oxidative damage. This slowly leads to a loss of functioning and symptoms of age-related decline.
According to a 2016 report in Philosophical Transactions of the Royal Society (London), “Cannabinoids as regulators of mitochondrial activity, as antioxidants and as modulators of clearance processes protect neurons on the molecular level… Neuroinflammatory processes contributing to the progression of normal brain aging and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the aging process on the system level.”
Ageing, neurodegeneration, and metabolic disorders are all linked to mitochondrial activity — or lack thereof. But how do cannabinoids improve cognitive function? How do they interact with mitochondria?
Mechanisms of action — receptors and membranes
There are three major ways that plant and endogenous cannabinoids can directly modulate mitochondrial function: