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The Endocannabinoid System and Clinical Endocannabinoid Deficiency

We spoke exclusively to Ethan Russo who believes that many common diseases stem from clinical endocannabinoid deficiency.

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Clinical Endocannabinoid Deficiency

The discovery of the endocannabinoid system in the mid-1980s was a major breakthrough in modern medicine. Yet, if you looked at the curriculum for most medical schools, you might not know it. The finding would not have been possible without the help of the cannabis plant, which remains illicit in most countries around the world. After wide-spread legalization of medical cannabis and over three decades of research, knowledge about the endocannabinoid system and its associated pathologies, like clinical endocannabinoid deficiency, remain sorely overlooked.

The Endocannabinoid System: The Find of the Century?

Two decades before the discovery of the endocannabinoid system, a team of scientists led by Dr. Raphael Mechoulam, a professor of medical chemistry a the Hebrew University of Jerusalem, had finally isolated the primary psychoactive constituent of the cannabis plant—tetrahydrocannabinol (THC). After the discovery, researchers around the globe began the quest to figure out exactly how the compound worked.  A group led by Dr. Allyn Howlett, a neuroscientist then with St. Louis University, finally cracked the mystery: THC produced its psychoactive effects through engagement with specialized cell receptors.

A cell receptor can be thought of as a lock that is embedded on the surface of a cell membrane. These locks only respond to specific chemical keys. In this case, THC was the key that engaged a cannabinoid receptor. As research would soon reveal, cannabinoid receptors are part of a larger endocannabinoid system (ECS), a neurotransmitter and cell signaling network like none other.  Made up of receptor sites, their respective chemical activators, and the enzymes that deactivate these compounds, scientists quickly unveiled that the ECS was ubiquitous throughout the human body. Cannabinoid receptors are nearly everywhere — connective tissue, the brain, the spinal cord, internal organs, the digestive tract, the skin, and immune cells.

After what surely was many long hours in the lab, Howlett and her team landed on something big. Why on earth would these receptors be found in so many places? Nearly three decades down the line, scientists are still exploring the wide-reaching ramifications of the endocannabinoid system, Howlett included. In the time since its first discovery, the ECS has been found to be a potent regulator of brain activity, hormonal function, and immune response, linking the three main regulatory systems together. It’s this pervasive modulatory network that responds to THC and other cannabis constituents. When a person consumes intoxicating forms of cannabis, THC hijacks the cannabinoid receptor sites that are normally inhabited by compounds that the body produces naturally.

These compounds are called endocannabinoids. The prefix endo- refers to endogenous or internal cannabinoids. In contrast, the cannabinoids found on the cannabis plant are phytocannabinoids with the prefix phyto referring to plants. As it turns out, endocannabinoids are molecules that help maintain a state of equilibrium, or homeostasis, throughout the nervous, endocrine, and immune systems. Endocannabinoids play the part of harmonizers or middlemen, managing how each of these systems responds to stressful stimuli and communicates with the others.

Endocannabinoids are at least in part responsible for regulating the biological clock, managing things like hunger and sleep over the course of the day. Cannabinoid receptors are also highly concentrated in areas of the brain responsible for memory, emotion, and metabolism, giving them regulatory effects over a remarkable number of physiological functions. One endocannabinoid, called anandamide, even takes its name from the Sanskrit word for bliss Ananda thanks to its calming and relaxing effects.

With such a profound influence over so many basic bodily commands, it is now theorized that problems in the ECS may contribute to a wide variety of difficult-to-treat pathologies. These potential pathologies include ailments as diverse as migraines and autism.

Clinical Endocannabinoid Deficiency May Contribute to Disease

Howlett and Mechulam may have kicked off the first forays into the endocannabinoid system, but they are far from the only scientists who made serious contributions to this emerging arena of health and medicine. Back in 2001, Ethan Russo, a neurologist and medical researcher, first made the case for clinical endocannabinoid deficiency (CECD). Russo is currently the Director of Research and Development with the International Cannabis and Cannabinoids Institute (ICCI). His theory? That many common diseases stem from deficiencies of the endocannabinoid system.

“Many human disorders relate to deficiencies of neurotransmitter function,” Russo told Cannabis Aficionado. “We know that a lack of acetylcholine, the memory neurotransmitter, is key to dementia in Alzheimer disease and related disorders. Parkinson disease is associated with a lack of dopamine function. Depression is related to problems with serotonin.”

Now, Russo suggests that something similar could occur in the endocannabinoid system. “In 2001,” he explains, “I hypothesized that various human disorders could be related to a lack of endocannabinoids, the natural chemicals within our brain and bodies that are similar in activity to THC, the main psychoactive compound in cannabis.”

Since endocannabinoids have wide-spread functions in the body, a lack or deficiency of these signaling molecules could cause a whole host of trouble. Symptoms like seizures, mood troubles, and generalized pain, nausea, and inflammation are all possible side effects of an endocannabinoid imbalance. Further, the universal nature of the ECS means that ailments which are seemingly unrelated to each other may now be classified together under the endocannabinoid umbrella.

“The prime candidates for clinical endocannabinoid deficiency are migraine, fibromyalgia and irritable bowel syndrome,” says Russo, describing conditions that are currently thought of as distinct and separate pathologies. “All [three] have compelling evidence in the interim that there are deficiencies in endocannabinoid function. Additional evidence has accumulated to include post-traumatic stress, autism, and other disorders.”

It is the ECS that perhaps describes why conditions like migraine and irritable bowel syndrome may share so many overlapping symptoms, including changes in mood, digestive distress, pain, and fatigue. These problems may be genetic in nature or acquired over time. At least one scientist has even gone as far as to describe the endocannabinoid system as a “bridge between body and mind”, connecting the physical reality with an emotional and intellectual one.

Toward Recognition of the ECS

Researchers have been investigating the influence of the endocannabinoid system in disease pathology for the past 30 years. Despite advancements in our understanding about the ECS, however, therapies targeting the endocannabinoid system are still few and far between. While some cannabinoid-based therapies are available to select patients, medical cannabis still remains one of the primary therapies that targets the ECS.

Yet, while the herb has been immensely helpful to patients around the world, both cannabis and endocannabinoid research still suffers from underutilization and harsh political barriers to research. In fact, a 2018 study from the Washington School of Medicine found that only a meager nine percent of medical schools teach their students about medical cannabis. This is despite the fact that the medicinal use of the herb is legal in 33 U.S. states and all of Canada.

“In my opinion, the media attention [on the endocannabinoid system] is not yet sufficient,” says Russo, “as the scientific evidence behind the theory is now quite solid based on serum and cerebrospinal fluid tests and other data.” He is referring to tests conducted in patients with schizophrenia,  migraine, and epilepsy. In each of these conditions, patients exhibited a dysregulation of endocannabinoid molecules in their cerebrospinal fluid. In post-traumatic stress, scientists at the New York University Langone Medical Center made a similar finding back in 2013. Compared with controls, PTSD patients demonstrated reduced endocannabinoid circulation.

“Considering the extreme amount of suffering and economic costs associated with clinical endocannabinoid deficiency disorders, it is necessary to have better research support and clinical investigations,” he presses. Better research and support would enable medical researchers and other scientists to more efficiently establish key therapies and interventions for endocannabinoid disorders. “While it is clear that cannabis in one form or another can be very effective in treating such disorders, certain lifestyle approaches, such as low impact aerobic activity, and dietary manipulations with prebiotics and probiotics may also be effective.”

Unfortunately, nearly 75 percent of medical schools also fail to provide students with the required amount of nutrition education. In a world of quasi-legal remedies and underacknowledged illnesses, its past time that formal institutions look seriously into endocannabinoid health.

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Borneol: The Terpene That Improves Your Heart and Gut Health

This terpene Borneol offers many health benefits, including improved digestion (via the stimulation of gastric juices) and better blood circulation.

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Borneol
PHOTO | Jesse Barney

Of the 20,000 aromatic molecules called terpenes found throughout nature, roughly 200 have been discovered in the cannabis herb. As an aggregate, the most common health efficacies offered by cannabis-derived terpenes are reduced systemic inflammation, anti-cancer properties, and analgesic (pain-killing) benefits. The terpene Borneol emits an odor involving scents of camphor, earth, and menthol; its scent is sometimes described as “herbal minty.” It is found in many plants other than cannabis, including camphor, mint, and rosemary. It is a natural insect repellent and is utilized industrially in the manufacture of perfumes and colognes.

Borneol is not extremely common in cannabis. Strains of cannabis offering more significant amounts of this terpene include Hazes and K-13.

The Details of Borneol

This terpene offers many health benefits, including improved digestion (via the stimulation of gastric juices) and better blood circulation. It also effectively treats bronchial symptoms to improve lung function and ease breathing (helpful for sufferers of bronchitis and asthma). Like many of its sibling terpenes, it has been found to reduce anxiety.

Borneol also assists in the healing of wounds. Historically, it has been incorporated into topical treatments for such applications, including the treatment of hemorrhoids. Combined with other terpenes that convey sedative qualities — such as myrcene and linalool — the terpene can effectively combat insomnia. It is also antibacterial and antiseptic.

Borneol exemplifies the dynamics of the entourage effect, a theory that cannabinoids and terpenes work together, synergistically, to offer particular therapeutic and medicinal benefits to humans via supplementation of the mammalian endocannabinoid system (ECS). Borneol amplifies the permeability of the blood/brain barrier, allowing other molecules and compounds to more efficiently bind with specialized receptors in the brain and central nervous system.

When isolated, it can act as an irritant to eyes, skin, and the respiratory system. As a good demonstration of the impact of accurate and strategic titration (dosing), at large doses, it is extremely toxic and harmful if swallowed. A “probable lethal dose” is 50-500 mg/kg of body weight, which equates to between only a teaspoon and an ounce for a 150-pound human.

The Research

Multiple studies have demonstrated the wide-ranging medicinal efficacy of the terpene, including its pronounced role as an anti-inflammatory, bronchodilator, and cancer killer.

A 2017 study entitled “Terpenes from Forests and Human Health” and published in the journal Toxicological Research investigated how borneol reduced inflammation of the lungs. Concluded the researchers, “Borneol alleviated acute lung inflammation by reducing inflammatory infiltration, histopathological changes, and cytokine production.”

A 2013 study published in the journal PLOS ONE and entitled “Natural Borneol, a Monoterpenoid Compound, Potentiates Selenocystine-induced Apoptosis in Human Hepatocellular Carcinoma Cells” revealed the anti-cancer properties of this terpene.

The study’s researchers concluded, “Borneol effectively synergized with SeC to reduce cancer cell growth through the triggering apoptotic cell death. These results reveal that borneol strongly potentiates SeC-induced apoptosis in cancer cells by enhancement of cellular uptake. Borneol could be further developed as a chemosensitizer of SeC in treatment of human cancers.”

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There Needs to Be More Research on How Cannabis Affects Dreams

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How Cannabis Affects Dreams
PHOTO | Jesse Barney

Most people forget their dreams shortly after waking. As soon as the eyelids flutter open, an entire evening of vivid adventures and abstract situations shuffle to an end, often leaving only lingering traces of their presence — a fragment of a dress here, the flashing face of a stranger there. While some individuals may be adept at remembering these mysterious nocturnal encounters, for the most part, the dreaming mind remains an enigma.

For those who consume cannabis, the dreaming self may remain even more elusive. The plant, you see, may prevent the sleeping mind from dreaming. Although cannabis has long been used as a meditation aid and sleep-inducer, preliminary research suggests the trance-inducing herb may suppress some forms of sleep consciousness. Of course, however, research on how cannabis affects dreams is far too premature to make any serious assessments.

The Purpose of Dreaming

Dream science over the past several decades provides more and more hints into the true nature of the dreaming mind. While the exact purpose of dreaming is unclear and dreams are particularly difficult to study, it is generally understood that the dreaming mind is also an emotional mind. While logic and rationality dominate during the day, the unique function of the dreaming mind is to help soothe and come to terms with emotional memories.

Most dreaming occurs during rapid eye movement sleep (REM sleep). The REM cycle is the closest sleep state to wakefulness when electrical activity in the brain increases, along with heart rate and breathing. During this time, levels of bodily stress hormones drop to their lowest levels. During the day, the hormone norepinephrine increased in the bloodstream in response to everyday stressors and anxieties. At night, however, norepinephrine levels slowly decrease as the dreaming mind takes over.

Brain scans suggest that the dreaming mind is very similar to the waking mind; visual areas of the brain are highly engaged, as well as areas related to memory and conscious thinking. A primary difference, however, is that the waking mind also responds to stress signals by releasing hormones like norepinephrine for fight-or-flight response. When dreaming, even strong emotions are distanced from this fight-or-flight impulse of the nervous system.

While the content of dreams may be very different than your visual memories from everyday life, it appears that emotional memory processing is a core function of REM sleep. The situations that your dreaming self is exposed to may be abstract or downright weird, but the emotional context of the dream may be what holds real value.

How Cannabis Affects Dreams

If dreams are the brain’s way of de-escalating and filing away emotional memories, then the effects of cannabis on dreams are well worth knowing. Thus far, a multitude of preclinical and small human trials show that cannabis consumption causes a reduction in REM sleep. This reduction is most strongly correlated with THC, although animal research thus far hasn’t determined whether or not the same effect occurs with CBD.

For individuals with recurring nightmares, this could be a positive benefit. Those with post-traumatic stress disorder (PTSD), for example, often demonstrate disturbed REM sleep patterns and may consistently remember their dreams. Healthy sleep is sleep that promotes feelings of restfulness upon waking. If a person plagued by chronic nightmares, it can have a distressing impact on the next wakeful day

In PTSD, patients are unable to delete fear-based experiences from their memories. Already, preclinical research suggests that cannabis medicines may be beneficial for those with the condition, potentially helping patients extinguish fear-based memories during the waking day.

And yet, for the everyday individual, the overall effect of cannabis on dreams remains unknown. Research suggests that the plant does, in fact, reduce dreams and limits the amount of time spent in REM sleep. Given that REM sleep is when the body records and desensitizes emotional memories, it’s possible that reducing time spent in REM may have a negative effect on emotional processing.

The catch? Very little research has been conducted on the aftermath of cannabis consumption on dreaming. Although cannabis is one of the most popular illicit sleep aids in the world, no high-quality or conclusive evidence exists on the impact of cannabis on sleep. Further, the bulk of research on the topic was conducted in the 1970s and 1980s, with isolated cannabis compounds and small participant numbers. As a result, the way in which cannabis affects dreaming and the implications this may have on waking life are simply unknown.

REM Rebound

The human brain does not like to go without enough REM sleep. While quality research on cannabis and dreaming is appallingly absent from the scientific literature, what is known, however, is that dreams come back with a vengeance after a brief period of abstinence from the plant. When regular cannabis consumers abstain from the herb, one of the most common side effects of withdrawal is the resurgence of very vivid and memorable dreams. This phenomenon has a proper name: REM rebound.

During REM rebound, a person is able to reach a state of REM sleep more quickly. They’re also more likely to remain in REM sleep for an extended amount of time. This dreaming rebound most often occurs after a person experiences sleep deprivation. The brain, it would seem, opens the floodgates of emotion once you’ve finally safe to hit the hay.

In terms of REM sleep, does cannabis produce similar effects to sleep deprivation? Without more research on how cannabis affects dreams, it’s hard to say.

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Wizard Stones: The Magic of Making Cannabis Diamonds

Aaron Palmer and Graham Jennings, founders of Oleum Extracts in Washington State, talk about Wizard Stones, their THCA isolate product.

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Wizard Stones
PHOTO | Oleum Extracts

Heat, pressure, and time. The three components required to form a diamond from carbon. But what about diamonds made from cannabis? The founders of Oleum Extracts, Aaron Palmer and Graham Jennings both agree that a good diamond product ultimately comes down to the flavor provided by its terpene fraction.

Diamonds is a slang term for the crystal formations of the cannabinoid THCA. The molecule’s lattice structure builds upon itself naturally as individual molecules clump together creating the faceted formations that resemble diamond or quartz.

When most people talk about cannabis diamonds, they’re talking about THCA structures that form in their own terpene sauce. So, it’s a little different technique than other isolation methods.

Oleum —While their chemical composition is the same, the process to make them is slightly different than the traditional diamonds mined from a raw extract. Instead, they use a specially formulated solvent mix to create a solution with a composition that encourages crystallization.

Due to Washington state’s regulations, Oleum is limited in the chemical solvents they can use. So that blend is the crucial variable to isolating THCA into their Wizard Stones product.

Growing cannabis diamonds within their original terpene fraction comes down to creating an environment with the right amounts of pressure and heat to encourage crystal growth.

Within the raw extract, the terpene and cannabinoid compounds are homogenized together, but as they settle and separate the mixture “crashes” — which is the start of crystallization.

Palmer explains that it “helps to create a seed because if there’s nothing for the THCA molecules to grab onto then they have a harder time starting the diamond formation.”

There are a few ways extractors seed a solution to start diamond growth, but Oleum prefers to use freezing temperatures to solidify and then thaw their extract, helping to create small groupings of THCA for other molecules to stack off.

Another common seeding technique is to drop a previously grown crystal into the extracted mixture of cannabis compounds, giving the THCA something to grow off of.

This technique is especially useful when filming a time-lapse of the crystal growth because it gives the camera a focal point knowing where the formation will grow from.

Creating Wizard Stones

The above timelapse video wasphotographed over a four day period by Dankshire. We can see diamonds begin to form almost immediately. However, the crystallization process can take a month if not longer to complete once a raw extract is jarred and waiting to crash.

Oleum utilizes custom-built isolation vessels for their production diamond runs but admits that the jar tech allows more visibility into the process.

Jennings points out, “You see the jars, we even do the jar stuff a lot. It’s more popular… and people know what it is compared to a large isolation vessel that no one can see into it but you know it’s growing 2,000 grams of crystals.”

Each batch can present a different ratio of diamonds to sauce and it seems like everyone wants a little different combination. “We just give ‘em what it makes,” Jennings said.

That’s the beauty of isolated products like cannabis diamonds and sauce; you can mix your own cocktail of cannabis compounds and really dial in the flavors and feelings that you’re after.

Cannabis diamonds grown in their own sauce create a potent, refined, and pronounce expression of the strain they are extracted from.

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