Endocannabinoid

Naturally occurring cannabinoids in the human body. The endocannabinoids are fatty lipids, a sensitive signaling system used by cells to communicate about almost all of the physiological processes of life. The most studied endocannabinoid neurotransmitters are anandamide & 2-AG – but others include virodhamine, noladin ether (2-AGE), lysophosphatidylinositol (LPI), and N-arachidonoyl-dopamine (NADA). Related fatty acids include PEA, oleamide (OEA), DHEA, EPEA, and 2-OG (these are not called endocannabinoids because they do not bind to the CB1 or CB2 receptors, but they do interact with other endocannabinoid lipid targets).

The endocannabinoid system seemed to have evolved very early in the history of life & has even been found in hydras, a relative of sea anemones & the first animal organism to have developed a neural network. Present in almost every complex form of life besides insects, the endocannabinoids regulate vasodilatation, thermal regulation, appetite & energy balance, painkilling, immune system modulation, a healthy stress response, exploration & social behavior, anxiety & fear, memory, sleep, synaptic plasticity, and neurogenesis – the growth of new brain cells. One of their most unique functions is retrograde transmission, in the brain, sending a message to the upstream neuron to calm down its activity, a key regulator of brain homeostasis. The endocannabinoids may also underlie the “runner’s high”.

The Endocannabinoids System (ECS)

One of the most widespread signaling systems in the human body & brain - but only first discovered in the early ‘90s. Unlike most of the classical neurotransmitters, endocannabinoid are lipids, or fats. This makes them slippery, hard to study & a supremely sensitive signaling system because of the ability of cells to detect minute changes in lipid levels & act accordingly. Intimately connected to the immune system, the neuronal system & the hormonal system, as one old scientist said to me in his cups, “If you told me that the endocannabinoid system is where the body meets the soul, I’d believe you.”

Anandamide (AEA) [Our Great White Whale]

The first endocannabinoid neurotransmitter ever discovered. Widespread in the human brain & produced ‘on-demand’ when needed. Appears quickly, broken down quickly. Often called the neurotransmitter of balance.

2-AG [Blue whale]

The second endocannabinoid neurotransmitter discovered. Only 2-AG & AEA have been well studied (thousands of research papers)

CB1 [Whale bar]

The first endocannabinoid receptor discovered. Mediates the psychoactivity (getting high feeling of THC). Most importantly, it’s the most widespread receptor of its class in the human brain.

[the bar in the membrane wall of the neuronal city where endocannabinoid whales meet with messenger fish to pass on their messages into the interior of the cellular city]

CB2 [Whale gay bar]

The second endocannabinoid receptor discovered. Found in almost every organ of the body & closely connected to our immune system. The CB2 occurs at low levels in the brain where it responds to neural insults.

[a gay bar in the membrane wall of the neuronal city]

FAAH (fatty acid amide hydrolase) [Giant squid]

The enzyme that breaks down anandamide & a frequent target of drug discovery for modulating the endocannabinoid system. If you inhibit the FAAH enzyme, it does less breaking down of AEA, and your AEA levels rise. More balance.

[the giant squid that slices sperm whales in half]

Diacylglycerol lipase (DAGL or DGL)

The enzyme responsible for producing 2-AG.

MGL (monoacylglycerol lipase - also sometimes abbreviated as MAGL) [Giant squid]

The enzyme that breaks down 2-AG. Another frequent target of drug discovery because inhibiting MGL raises 2-AG levels

[a giant octopus that eats blue whales]

Palmitoylethanolamide (PEA) [North Atlantic right whale]

An endogenous fatty acid amide whose only reason for not being labeled as a classic endocannabinoid is because it doesn’t bind to the CB1 or CB2 receptor - but it’s a hugely important neurotransmitter found in every cell of the body. A long body of work stretching back to World War 2 has found it to be an amazingly safe & effective drug for a number of things related to the immune system. Available as a dietary supplement, this is one of the best-studied cannabinoids in humans. Highly recommended.

[North Atlantic Right whale of course. Just look at that grin…]

NAAA (N-acylethanolamine acid amidase) [Giant Pacific octopus]

The enzyme for breaking down PEA, with a special function as a messenger for pain & inflammation as well as in the control of obesity.

[a giant Giant Pacific octopus that eats Right whales]

Oleamide (OEA) [Humpback whale]

An endocannabinoid related to sleep. They discovered it by keeping cats awake for 3 days & then analyzing their spinal fluid. You can buy it on Amazon. 2 scoops helps you to sleep while 6 scoops is a very pleasant psychoactive experience (Hamilton Morris has called it his favorite way to get high - which is saying something). It’s also worth considering for cancer treatment.

[Humpback whale, because it sings hippies to sleep]

Oleoylethanolamide (unfortunately, also abbreviated as OEA sometimes) [Pygmy sperm whale]

An analog of anandamide, this lipid acts via the peroxisome proliferator-activated receptor alpha (PPAR-α) receptors on the cell’s nucleus. These alter genetic transcription, a powerful method of cellular control. In animal models, oleoylethanolamide causes them to eat less food & drink less alcohol. In roundworms, it causes them to live longer. For the orphaned GPR119 receptor (a receptor that might one day be officially designated as a cannabinoid receptor), it may be the native ligand (the thing that binds to it). It’s already identified as the native ligand for hypoxia-inducible factor 3α (HIF-3α). OEA also interacts with our histamines.

[Pygmy sperm whale. Not well known, a smaller cousin to the sperm whale]

Fatty acid-binding proteins (FABPs) [Whale cars]

These transport proteins move fatty lipids such as the endocannabinoids around the body. While still mysterious, they’re thought to move anandamide between membranes as well as transporting it to be broken down by the enzyme FAAH. Several types of FABPs exist in humans. THC & CBD bind to some of them. This may explain why endocannabinoid levels tend to increase after consuming cannabinoids. As the brain ages, the levels of FABPs decrease.

Plant-based cannabinoids first found in cannabis – but now known to exist in over 70 other plant species, most notably cacao (the source of chocolate). The over 200 cannabinoids found in cannabis are made up of two or three ringed structures of carbon & oxygen with long tails. They act as intercellular lipid messengers that communicate between cells via activation of the cannabinoid receptors. The most abundant phytocannabinoids are THC (delta-9 THC) & CBD. Some of the other most studied phytocannabinoids include CBG, CBN, THCV, CBDV, and delta-8-THC. Their benefits in humans include appetite stimulation, metabolic disorders, painkilling, asthma, bone disorders, glaucoma, gastrointestinal issues, nausea, sleep disorders, anxiety & mood disorders, inflammation, autoimmune disorders, neuroprotection, and neurodegenerative diseases. The cannabinoids bind to the CB1 & CB2 receptor, other purported cannabinoid receptors like GPR55 & GPR18 as well as interacting with many of the major neurotransmitter systems including serotonin, dopamine, endorphins, adrenaline, glutamate, GABA, and the PPAR nuclear receptors that regulate genetic transcription. The cannabinoids from cannabis are theorized to beneficially interact with the terpenes, flavonoids, and fatty acids also in the plant to cause an ‘entourage effect’.

Entourage effect

The scientific concept proposed in 1998 that “the endocannabinoid system demonstrated an ‘entourage effect’ in which a variety of ‘inactive’ metabolites and closely related molecules markedly increased the activity of the primary endogenous cannabinoids, anandamide and 2-AG.” This would mean that the presence of all of the minor cannabinoids, terpenes, and fatty acids enhance the effects of THC & CBD. The entourage effect would also explain why botanical drugs are often move effective than their isolated compounds, something seen when CBD-rich full spectrum hemp extract outperforms isolated CBD. In some cases, the botanical cannabis extracts demonstrate less side effects than the isolated pharmaceutical cannabinoids.

THC (delta-9-tetrahydrocannabinol or Δ9-THC) [African elephant]

The well-known & well-studied molecule in cannabis that gets you high - and helps in a number of other fascinating ways.

[African elephant. Powerful, unpredictable, beautiful]

Low dose THC / Microdosing THC

Microdosing THC has been gaining popularity in recent years as a way to experience the potential health benefits of THC without the associated "high" or psychoactive effects. Microdosing refers to the practice of consuming small, precise amounts of THC on a regular basis, typically in the range of 2.5 to 5mg. Research suggests that microdosing THC may have a wide range of therapeutic benefits, especially for brain health. Studies have also found benefits of low doses of THC for pain, neuropathic itch, headaches, sleep apnea, cardioprotection, seizures, behavioral problems of autism, age-related cognitive impairments, Tourette's syndrome, lowering biomarkers of Alzheimer's disease, dementia, neuroinflammation, multiple sclerosis, and fibromyalgia. Microdosing THC may also have cognitive benefits, including improving focus & creativity, but this is hard to prove in scientific studies.

CBD (cannabidiol) [Asian elephant]

The cousin of THC that does not get you high but does a lot of the heavy lifting in why hemp has been such a staple of medicine since before recorded history. In most plants outside those bred for the recreational market, CBD is the most common cannabinoid. It binds to a wide swathe of receptors outside the endocannabinoid system including three serotonin receptors, two opioid receptors, a dopamine receptor as well as glutamate & GABA (the two most widespread neurotransmitters, the basic neuronal signals for excitation & inhibition, respectively)

[Indian elephant. sweet, gentle, you can work with it]

CBDA (cannabidiolic acid) [Asian elephant with a tophat]

CBDA is the most abundant cannabinoid in Nature – but there’s less than 100 total studies on it. The naturally occurring raw form of CBD that is produced directly in the plant, CBDA was first isolated in 1955. The early research focused on the sedative properties but now it’s been more widely studied for nausea, anxiety, the lowering of inflammation & pain, anti-tumor effects via changes to genetic transcription, and in a model of Alzheimer’s, working with THCA to protect the brain & rescue memory deficits. Well known for its safety, the most common use is now for gut health. The growing trend of juicing the whole cannabis plant & drinking the juice comes from the ability of CBDA to help with gut homeostasis. At the biochemical level, CBDA raises anandamide levels, activates a serotonin receptor, acts as an antioxidant, regulates genetic transcription, and inhibits the COX-1 pathway (a pathway also used by aspirin). Many patents exist for the pharmaceutical uses of CBDA.

THCA (tetrahydrocannabinolic acid) [African elephant with a tophat]

In the cannabis plant, THCA is the precursor cannabinoid to THC. Found in the raw plant, THCA decarboxylates to THC as it ages, but the process is more rapid when the cannabis is smoked or cooked. Recently, THCA has become available from dispensaries in a crystalline powder form for smoking or vaporizing. Many people report the benefits of cannabis tea, of which THCA is the main component. When taken orally, THCA does not seem to convert to THC in the body.

First discovered in 1967, THCA is now known to act as a neuroprotective in a model of Parkinson’s & Alzheimer’s disease (with CBDA), an immune system modulator, to cause relief in a model of arthritis, and may have more potent anti-nausea effects than THC. THCA also acts as an anti-inflammatory via the COX pathway (similar to the NSAIDS like aspirin & ibuprofen) as well as in colon cells via the GPR55 receptor.

Contradictions exist about the actions of THCA at the CB1 & CB2 receptors. Some studies report it binds them weakly, some that it does not bind to CB1, another that it bound to both almost as strongly as THC, and the most recent that THCA binds to CB1 & CB2 little or not at all. One hypothesis is that while THCA may bind to CB1 receptors, it cannot penetrate the blood-brain barrier & so it only activates the CB1 receptors in the body. THCA also inhibits the DAGLα enzyme that creates 2-AG, raises anandamide levels via inhibition of FAAH & the anandamide transporter, and acts via the TRP ion channels. In addition, THCA binds to the PPARγ nuclear receptors that regulate genetic transcription to cause neuroprotection.

Decarboxylation

Decarboxylation is the process of removing a carboxyl group (-COOH) from a molecule, typically through the application of heat (200-245ºF). In the context of cannabis, decarboxylation refers to the conversion of cannabinoid acids such as THCA or CBDA into THC or CBD. The acid forms of the cannabinoids occur in the raw plant & are often referred to as the “inactive cannabinoids” - but that is an incorrect definition. THC Acid & CBD Acid have their own array of effects, but they seem to not pass the blood-brain barrier into the brain to cause psychoactive effects. Decarboxylation is an important step in the production of many cannabis-based products because most consumers are looking for CBD & THC. Decarboxylation can also occur over time & increases in the presence of oxygen.

CBG (cannabigerol) [Wooly mammoth]

Known as the “mother cannabinoid”, CBG is the chemical precursor to THC, CBD, and the other cannabinoids in the plant. CBG occurs only at low levels in cannabis because it tends to be quickly converted to other cannabinoids. Binding slightly to the CB1 & CB2 receptor, it also inhibits the enzymes that break down anandamide & 2-AG, hence raising the levels of those endocannabinoids. CBG interacts with an adrenaline receptor (α-2 adrenoceptor) & a serotonin receptor (5-HT1A Receptor) as well as modulating the expression of glutamate, GABA, and dopamine via the PPAR receptors on the nucleus, controllers of genetic transcription. CBG is also active at the TRP channels involved in the sensations of temperature, pressure, pH, smell, taste, vision, and pain perception whose dysfunction are linked to neuropathic pain, inflammation, and respiratory disorders. Surveys show patients reporting help for anxiety, chronic pain, depression, and disturbed sleep. In preclinical trials, it's been studied for eye pressure, gut problems, appetite modulation, blood pressure lowering, bladder control, oral care, muscle spasms, airway inflammation, arthritis, painkilling, and most notably for brain health & neuroinflammation. In adult neural stem cells, CBG increased their viability. The breakdown products of CBG have been shown to reduce inflammation via the brain’s immune cells.

[since it’s the first cannabinoid produced, it must be the wooly mammoth]

CBGA (Cannabigerolic acid) [4-tusked primelephas]

There’s little research that’s been done on the acidic precursor to CBG. But CBGA is the very first cannabinoid produced by the plant in its synthesis process. CBGA has been shown to help with inflammation in immune cells, to lower viral replication of the virus of COVID-19 & to modulate endocannabinoid system signaling.

[As an ancestor to the CBG wooly mammoth, CBGA is the primeval 4-tusked primelephas]

CBN (cannabinol) [Aged African elephant]

A phytocannabinoid found in cannabis formed from the breakdown of THC. It tends to occur at higher levels in more aged cannabis. The first cannabinoid ever isolated from the plant in the 1880s, it was also the first to have its chemical structure solved in 1940. CBN binds weakly to the CB1 receptor & more strongly to the CB2 receptor. If taken orally, liver enzymes convert it to 11-OH-CBN, a cannabinoid with stronger activity at CB1 but weakly blocking the CB2 receptor.

With only limited modern clinical studies, little data exists in humans. The pharmaceutical company InMed claims, “using CBN at very high doses … hundreds of times higher than what would occur with topical dosing in humans [and] no adverse events were seen on central nervous system (CNS) function”. InMed is researching CBN for the treatment of glaucoma both via neuroprotection of the eye’s neurons as well as the reduction of intraocular pressure. They also announced Phase 2 clinical trials for a topical CBN cream to treat epidermolysis bullosa, a rare skin condition of fragile, blistering skin.

In animal studies, CBN works as a mild painkiller via the pain sensors & combines well with CBD to lessen pain in a rat model of facial pain. In a rat model of ALS, CBN delayed the onset of symptoms, perhaps by protection of the mitochondria (the powerhouse of the cell). In a model of seizures, CBN was the most effective of the cannabinoids tested.

In cells of the immune system, CBN protected them from cell death caused by oxidative stress. In mice, CBN increased their appetite & in mice with allergies, CBN lessened the inflammatory airway response. CBN functions as an antibiotic against MRSA (the drug-resistant form of staph infection). CBN is currently in clinical trial for insomnia as well as use by healthy adults.

THCV (tetrahydrocannabivarin) [African elephant with a short trunk]

THCV, first discovered in 1971, is similar structurally to THC because it has a tail that is just two carbons shorter but its effects are quite different. Instead of binding to the CB1 receptor, THCV seems to blocks access to the CB1 receptor while also binding strongly to the CB2 receptor although its exact effects at the CB1 receptor are still not completely understood. Early studies demonstrated its anticonvulsant effects, probably via the CB1 receptor. Another focus has been its potential help for diabetes, nausea, and obesity. In a mouse model of obesity, THCV lowered food intake & weight gain as well as helping to lessen insulin sensitivity. In humans, 10 mg of THCV caused the brain to respond less strongly to tempting foods like chocolate. It’s been looked at in humans for treating diabetes & has a pharmaceutical patent for that application. In the brain, it helps to calm neural transmission, lessens obsessive compulsive behaviors & schizophrenic behaviors in animal models, causes neuroprotection in a model of Parkinson’s & helps lessen negative side effects from the Parkinson’s treatment drug L-DOPA via antioxidant effects. THCV has also been researched for inflammatory & neuropathic pain, reduced contractions in the bladder, reduced fat levels in nonalcoholic fatty liver disease, antimalarial activity, reduced sebum production to help with acne, and protection from some of the negative side effects of THC.

CBC (cannabichromene) [Sri Lankan elephant]

Only discovered in 1966, CBC is the third most prevalent cannabinoid produced by the cannabis plant. While not as well studied as THC or CBD, CBC is known best for its potential for inflammation, pain, and neuroprotection. It strongly binds the CB2 receptor, but not the CB1 receptor, causing it to have immune system effects without the psychoactivity. One area of mystery is that CBC is often found to cause its effects by neither the CB1 or CB2 receptor & while it interacts with a number of the TRP channels, the exact mechanism of action isn’t always known. One additional pathway CBC is thought to utilize is adenosine (an important signaling molecule & a building block of RNA). In a clinical trial, CBC may have preferential absorption over CBD & THC when administered together.

Its ability to lower inflammation has been studied for decades & in rat models, CBC works via several mechanisms to lower pain & combined well with CBD in a mouse model of arthritis. When administered with THC, the two have stronger anti-inflammatory effects than when used separately. In neural stem cells, CBC increased their functioning, a mechanism of protecting the brain, as well as helping in a mouse model of depression. In a mouse model of epilepsy, it displayed anticonvulsant effects & helped with lung inflammation & oxygenation in the acute respiratory distress of COVID. CBC helps in the guts of mice with diarrhea & in their pineal glands, it reduced the output of melatonin (the sleep inducing hormone). CBC seems to be useful against acne & lowering skin inflammation as well as the production of sebum.

[Sri Lankan elephant. Little, sweet, not as well known as it should be]

CBDV (cannabidivarin) [Asian elephant with a short trunk]

CBDV is the varin form of CBD, identical except for the tail which is shorter by 2 carbons. Also not psychoactive, CBDV tends to occur in cannabis from India & Nepal. Identified for the first time in 1969, CBDV has had a Phase 2 clinical study for use in epilepsy & it seems to work via BDNF & TRPV. In animal models, CBDV acts a safe anticonvulsant & causes a significant reduction in seizures, most notably in young patients with Rett syndrome via the normalizing of neural pathways. A review on using CBDV for epilepsy & autism can be seen here. In humans with autism, CBDV helped to balance brain connectivity & regulate the levels of glutamate & GABA (the brain’s primary excitatory & inhibitory neurotransmitters) while in a rat model of autism, it helped to lessen behavioral abnormalities such as impaired sociability, short-term memory problems, and hyperlocomotion.  In assays for Alzheimer’s CBDV helps to protect the brain cells from the toxicity of the amyloid plaques. In a model of stroke, CBDV was found protective of the blood-brain barrier. In animal models, CBDV helped with nausea, bladder contractility, and in intestinal inflammation, CBDV not only lowered the signs of inflammation but also improved the gut microbiome. CBDV has antibiotic properties & can act an anti-inflammatory in various cell types. (Easter egg: the first person to email me about this easter egg will get a free copy of my Queer book once I get it printed & up on Amazon soon…)

Δ8-THC (delta-8-tetrahydrocannabinol or THC8) [The forest species of the African elephant]

The rule of thumb is that to feel the same psychoactive effects, that you need twice as much delta-8 THC versus delta-9 THC. So why are people using it?

Even though delta-8 THC has been studied as a potential treatment for the nausea of chemotherapy, glaucoma & eye injuries, according to a recent review by leading researcher, Dr. Linda Klumpers, not one good study exists on delta-8 THC’s pharmacokinetics: how it moves through the body, how it gets absorbed, where it gets distributed & how it breaks down.

The easiest way to produce delta-8 THC from CBD is a chemical process known as cyclization. If you look at the CBD molecule above, you’ll see that it has two rings. To make a third ring, you close those two tails by adding a little acid, heat, and time. Not that you should do it at home by yourself – but you could. It’s not a simple process & some researchers warn that when done poorly, the CBD to delta-8 THC conversion leads to unlabeled adulterants & unintended byproducts. If you are planning on consuming delta-8 THC, make sure to buy it from a reputable manufacturer who does third-party testing on every batch of their product.

According to a recent survey,

• “Most delta-8-THC users experienced a lot or a great deal of relaxation (71%); euphoria (68%) and pain relief (55%)
• a moderate amount or a lot of cognitive distortions such as difficulty concentrating (81%), difficulties with short-term memory (80%), and alerted sense of time (74%)
• and did not experience anxiety (74%) or paranoia (83%).”

In terms of safety, a study in 1973 found that you could safely give monkeys a gigantic amount – 9,000 milligrams orally per every kilogram of body weight. For an average sized money, that’s eating 4 ounces of delta-8 THC, basically equivalent to a baseball. To consumers, delta-8 THC is often available as gummies, edibles or in vape pens. However, because of its chemical similarity to delta-9 THC, ingesting delta-8 THC can make you fail a drug test.

[The forest species of the African elephant – smaller & more elusive]

Terpenes

The largest class of natural molecules with 55,000+ currently discovered, terpenes are the smell molecules produced by plants & insects for communication, defense, disease resistance, and the attraction of pollinators. Because cannabinoids are odorless, the source of aroma in cannabis is the terpenes. In the cannabis plant, the palette of over 150 terpenes gives rise to the wide variety of smells of the different cultivars (strains). More than the cannabinoid content, the way to differentiate different cultivars of cannabis is by their terpene profile. A genetic analysis found that between the cannabis types labeled “indica” and “sativa”, the difference between them actually came down to their genes for terpene production.

The terpenes have therapeutic properties & also alter how the cannabinoids work with our system, such as increasing cannabinoid levels in the blood. Called the entourage effect, the ability of terpenes to enhance the action of cannabinoids can affect neuroinflammation, gut inflammation & colitis. On their own, terpenes are immunomodulatory, anti-inflammatory, and painkillers.

Like the cannabinoids, the terpenes are produced in the resin glands at the end of the trichome stalks by a complex synthesis pathway that involves many different genes. Each stalk is topped by one to two dozen cells synthesizing a sticky resin made of cannabinoids (up to 80%) as well as a rich bouquet of monoterpenoids & sesquiterpenoids (up to 10% of the glandular hair). When the resin is secreted, it’s kept separate from the cells that produced it in a special cavity at the end of the trichome that swells as it fills. This protects the resin from oxidation (degradation) & enzymatic change. Terpenes can also be found in the flowers, leaves, bark, and roots of cannabis. Terpene levels fluctuate daily & are also affected by soil & weather. With evaporation occurring at temperatures as low as 75 degrees, the plant contains the most terpenes at the end of dark period.

Beta-caryophyllene (BCP) [Flying elephant]

A terpene that’s also a cannabinoid. The terpenes of cannabis give the plant its smell. Also found in oregano, black pepper, lavender & hops, beta-caryophyllene has a spicy sweet woody smell. But unique among terpenes, this one also binds to the CB2 receptor, making it a dietary cannabinoid. It shows a potential for treating inflammation, pain, anxiety & seizures. The FDA has designated it to be GRAS (generally regarded as safe) & thus it can be safely used as a food additive.

[a terpene/cannabinoid that travels through the air? That could only be a flying elephant]

Myrcene (the “couchlock” terpene)

One of the most abundant cannabis terpenes, myrcene is a sedative, a hypnotic, a painkiller, an anticonvulsant, an antioxidant, an anti-inflammatory, a neuroprotective, and it’s thought to be the terpene most responsible for the “couchlock effect” of cannabis. Myrcene gives a bitter taste to hops, a sweet earthy smell to cannabis, and also occurs at high levels in lemongrass, verbena, and black pepper. Among recreational cannabis users, there’s a trend of eating mangoes before taking cannabis in order for the fruit’s high level of myrcene to cause more of the THC to cross the blood-brain barrier into the brain, though scientific data for this is limited. Myrcene has been researched for osteoarthritis, neuropathic pain, acute pain, ulcers, heart failure, pleurisy, anti-aging effects on the skin, and protecting the liver & body from environmental toxins. Myrcene interacts with the opioid, adrenaline, and TRPV systems.

α-Pinene

One of the most common terpenes in the plant world, α-pinene is found in pine trees, rosemary, and cannabis. Its ability to inhibit the enzyme that breaks down acetylcholine makes it a booster of memory & an increaser of alertness. Its ability to strengthen binding to GABAA (the receptor used by benzodiazepines) suggests sedating & anti-anxiety effects. It’s also been used to treat respiratory infections & insomnia for centuries. It causes less anxiety, more locomotion, and it lowers the stress response.

In animal models, α-pinene is

• An antidepressant via its antioxidation effects & helpful for mood disorders via dopamine
• anti-convulsant
• antibiotic against MRSA, antifungal against candida, anti-viral, and anti-parasitic
• protective of the skin against the damages of UVA radiation such as aging
• immunomodulatory
• anti-inflammatory & antioxidative
• gastroprotective against ulcers & pancreatitis
• helpful for bone growth
• beneficial for seasonal allergies via the lowering of histamine release
• helpful for deep sleep
• neuroprotective via several different pathways including in a model of stroke
• helpful with pain, including neuropathic & inflammatory pain via the GABAA & opioid receptors

Limonene

Limonene, a major terpene in citrus as well as in cannabis, is commonly used as dietary supplement as well as a fragrance. With a strong safety profile, limonene is an anti-inflammatory, an antioxidant, an antibiotic & antifungal, an anticonvulsant, gastroprotective, cardioprotective, genoprotective, anti-stress, and a painkiller. It’s been researched for anxiety, colitis, diabetes (insulin resistance & liver protection), arthritis, heart injuries, liver fibrosis, ulcers, gallstones, protecting the kidney from chemotherapy, and immunomodulation.

Linalool (from lavender)

Best known as the terpene in lavender, linalool also occurs in cannabis as well as over 200 other plant species. The ability of the smell of linalool to lower anxiety is one of its best studied properties. Its use to relieve stress & anxiety is approved by the European Medicines Agency. With a strong safety profile, linalool has also been researched for

• a strong anticonvulsant effect
• increasing blood flow in the brain
• an amplifier of serotonin-receptor transmission that causes an antidepressant effect
• anti-anxiety effects & a decrease of conflict
• in stressed mice, increased social interactions & exploration as well as decreased aggressive behaviors (even in honeybees) via decreases in serotonin, dopamine, and norepinephrine, the inhibition of glutamate receptors (the primary excitatory neurotransmitter of the brain), and the GABAA receptor (same as used by benzodiazepines like Valium)
• neuroprotection from oxidative stress via the microglia (guardian cells of the brain)
• in a model of Alzheimer’s, help with anxiety, learning, memory, and the reduction of neuroinflammation as well as the improvement of cognitive deficits via antioxidative effects + in a mouse model of Alzheimer's, the cannabis terpenes linalool & cineol combined well with aerobic exercise to cause a protective effect
• in sleep-deprived mice, help with memory loss & behavioral impairment
• faster recovery times from a model of stroke in rats via the control of lipid levels as well as antioxidative & anti-inflammatory effects
• allergies via the lowering of histamine release
• a decreased stress response
• anti-inflammatory effects in lung cells, white blood cells, and microglia (guardian cells of the brain) & also as an anti-inflammatory when found in citrus
• topically, the healing of acne, skin burns, skin allergies, and as an antibacterial for wound dressing
• antidiabetic effects & protection of the kidneys

1,8-Cineole (Eucalyptol - thought provoking)

A major component of eucalyptus & also known as eucalyptol, 1,8-Cineole is a stimulating & thought-provoking terpene in cannabis. It also has been shown to be

• an anti-inflammatory in airway diseases
• an antioxidant
• in humans, effective against bronchitis & sinus infections
• increased lung function in asthma patients
• help patients with anxiety before surgery
• In animal models, a treatment for influenza, hypertension, brain blood loss, colitis, pancreatitis, steatosis, diarrhea, gastric injury
• Lessening inflammation in a tissue model of Alzheimer’s as well as disease prevention + in a mouse model of Alzheimer's, the cannabis terpenes linalool & cineol combined well with aerobic exercise to cause a protective effect

via a wide-range of pharmacological activities.

Nabiximols (ie Sativex®)

A pharmaceutical 1:1 CBD:THC spray produced by GW Pharmaceuticals. One of the first cannabinoid pharmaceuticals on the market, Sativex is an approved treatment for neuropathic pain, spasticity, overactive bladder & the symptoms of multiple sclerosis.

Epidiolex® (in the UK, Epidyolex®)

An isolated CBD formulation approved for treating the severe seizures of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex. Produced by GW Pharmaceuticals, the doses tend to be incredibly high – hundreds or thousands of milligrams of CBD every day in young children. But even with that, the side effects tend to only be lethargy & stomach upset.

Dronabinol (ie Marinol® & Syndros®)

A synthetic form of THC for the treatment of anorexia in AIDS patients & the nausea of chemotherapy. These tend to not be popular with patients because it’s a horse dose of THC with no modulation by the other molecules in the cannabis plant like CBD.

Nabilone (Cesamet®)

A synthetic derivative of THC approved for treating the nausea of chemotherapy patients.