Neuro(b)log for Patients

History of cannabis use

Cannabis sativa is an annual plant in the hemp family (Cannabaceae). The common hop (Humulus lupulus) belongs to the same family. The taxonomic division of cannabis into three species is debatable. Cannabis is one of the ancient cultivated plants. It originates from Central Asia (most likely from the southern Caspian Sea region near Iran) and was used as a fiber plant, for example for producing textiles and hemp ropes. The oldest hemp textiles have been found in China, Japan and also in Egypt. In the 17th century, hemp was used for making ropes and sails. In our territory, the oldest preserved trace of a hemp seed was found in a Slavic settlement dated to the 8th century BC. In Mohelnice in Moravia, a hemp textile about 5,000 years old has been preserved. Hemp was cultivated in warmer regions, for example in Moravia and southern Bohemia. From it, a coarse cloth known as kanafas (checked or striped linen) was woven. Hemp seeds were also part of cattle feed. Today, hemp seeds can be found together with other seeds in feed mixes, for example for birds (parrots). Hemp oil is also produced from the seeds.

Abuse of the plant's psychoactive properties contributed to the stigmatization of patients using cannabis for medical treatment and led to bans on its cultivation and use in many countries around the world.

Active compounds in cannabis

Cannabis contains a large variety of substances, and the number of chemically identified compounds continues to grow as analytical methods and research advance. Interest in cannabis is increasing. The number of distinct chemical constituents runs into the thousands.

One important group of active compounds are terpenes (components of essential oils). They are responsible for cannabis's characteristic aroma. Together with cannabinoids they contribute to synergistic effects as well as side effects. Phytocannabinoids and terpenes can, for example, potentiate treatments for pain, inflammation, depression, anxiety, addiction, epilepsy, and certain bacterial and fungal infections. Notable terpenes include monoterpenes (limonene, myrcene, α‑pinene, linalool, etc.), sesquiterpenes (e.g., E‑caryophyllene), diterpenes, and triterpenes. Cannabinoids are biosynthesized from diterpene precursors. The particular combination of terpenes gives each cannabis variety its unique aroma.

During cannabinoid biosynthesis a phenolic moiety is joined with terpenes, producing inactive acidic forms that have pharmaceutical potential. These include cannabichromene (CBC), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabinol (CBN), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), cannabicyclol (CBL), the psychoactive Δ8‑THC (present only in trace amounts in the plant), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarin (THCV). These compounds are produced in the trichomes of female cannabis flowers. The largest proportions are typically CBDA and Δ9‑THCA. Male plants also produce phytocannabinoids, but at lower concentrations and mainly in stems and leaves.

Among both laypeople and professionals two components are primarily known: Δ9‑tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds are activated by thermal decarboxylation, which is why dried cannabis flowers usually require heating (for example when preparing capsules for oral use).

Research on cannabis

Efforts to extract active compounds from cannabis began as early as the 19th century. It was not until the 1940s that Roger Adams succeeded in isolating cannabidiol (CBD) from the plant. Subsequently, Raphael Mechoulam from Israel, often called the father of cannabis research, and his team elucidated and described the structure of cannabidiol (CBD) and later tetrahydrocannabinol (THC) in 1963.

One of the breakthrough moments for cannabinoid isolation in Czechoslovakia was a 1975 study by Hanuš and Krejčí, in which two new cannabinoid acids were isolated from Cannabis sativa L. This work, published for example in Acta Univ. Olomuc., Fac. Med. (volume 74, pages 161–166), represented one of the first scientific attempts to separate and describe specific cannabinoid compounds with potential for later medical use.

In the 1980s it was discovered that an endocannabinoid system exists in the human body. The identification of cannabinoid receptors CB1 and CB2 and the growing understanding of the endocannabinoid system's function in organisms, including humans, led to recognition of cannabis's therapeutic effects. Researchers described the molecular mechanisms that regulate the activity of endogenous cannabinoids.

Endocannabinoids or the endocannabinoid system

Endocannabinoid receptors are located in both the central and peripheral nervous systems, and plant‑derived phytocannabinoids from cannabis interact with and bind to these receptors. The entire network — CB1 and CB2 receptors, endogenous ligands, and the enzymes responsible for their synthesis and degradation — is referred to as the endocannabinoid system (ECS). Growing scientific evidence supports a significant role for endocannabinoids in modulating neurotransmitter release and neuroplasticity.

Neuroplasticity and cannabinoid receptor distribution

Neuroplasticity is the brain's ability to change its structure and function in response to stimuli, experience, and learning. Neurons generate new cells (neurogenesis), reorganize, and prune their connections (synapses and neural networks), allowing the brain to adapt to changing internal and external conditions. Cannabinoid receptors are highly expressed in brain regions linked to executive functions and memory — notably the hippocampus, amygdala, and prefrontal cortex — and are also present during certain stages of brain development.

It was once believed that most structural brain changes occurred only during early development. We now know that a substantial degree of plasticity persists into adulthood, which is exploited in rehabilitation after injuries or stroke. Cannabinoids can modulate anxiety but may also induce psychosis‑like states in some cases. Preclinical models show that cannabis and its signaling pathways regulate neuronal communication (neurotransmission).

Roles in brain processes and potential drug interactions

Cannabinoids play important roles in brain processes including neuroinflammation, neurogenesis, neural cell migration, synaptic budding, and the development of white matter. Experimental data indicate that cannabinoids can influence the activity of various isoforms of cytochrome P450 enzymes and uridine 5'‑diphospho‑glucuronosyltransferases (UGTs), both of which participate in hepatic metabolism of many substances. Consequently, interactions may occur with drugs such as warfarin, antiarrhythmics, sedatives, and antiepileptics, potentially altering their effective blood levels.

CB1 and CB2 receptors

The best‑known psychoactive compound, THC, acts on CB1 and CB2 receptors. Below is an outline of where these receptors are located in the nervous system and how they function to our benefit.

CB1 receptors are found in both the peripheral and central nervous systems. In the peripheral nervous system they are present on sympathetic nerve endings and on sensory neurons. In the central nervous system they are predominantly located on the presynaptic membranes of excitatory and inhibitory neurons and regulate the release of vesicles containing dopamine, GABA (gamma‑aminobutyric acid) and glutamate. CB1 receptors in the CNS are the reason cannabis produces psychoactive effects (often undesirable), while at the same time mediating beneficial effects such as reduced transmission of pain signals.

CB2 receptors are expressed mainly in the immune system (for example on macrophages, B and T lymphocytes) and in microglia. Activation of CB2 receptors leads to a controlled reduction in the release of inflammatory mediators and cytokines, thereby dampening immune responses that could otherwise damage tissue. This property is important in treating chronic inflammatory conditions such as rheumatoid arthritis or chronic neuropathic pain. Synthetic compounds that selectively target CB2 receptors are being investigated as potential therapeutics that might relieve pain or inflammation without the psychotropic side effects associated with CB1 activation.

By contrast, cannabidiol (CBD) attenuates some of THC's negative effects and can act in certain respects as an antagonist. Current uses of THC and CBD in various extracts or in the plant itself show synergistic effects, which depend on the THC:CBD ratio in extracts and in the plant. Beyond modulating CB1 receptors, CBD acts more broadly at the intracellular level on various other receptor types and ion channels. It has notable antidepressant, antiepileptic, anxiolytic, neuroprotective, antinociceptive, and anti‑inflammatory properties.

In addition to plant‑derived phytocannabinoids (from cannabis, echinacea, Sichuan pepper, magnolia, turmeric), the body synthesizes endogenous cannabinoids (e.g., anandamide), which then activate cannabinoid receptors.

Effects of lesser‑known compounds from cannabis

It is appropriate to mention other cannabis compounds here whose potential effects are still under investigation.

Monoterpenes

α‑Pinene and β‑pinene inhibit acetylcholinesterase activity in the brain. Acetylcholinesterase (AChE) breaks down acetylcholine, a neurotransmitter that is very important for memory and learning. In cognitive disorders such as Alzheimer's disease, acetylcholine levels are reduced. Some drugs used to treat Alzheimer's work by slowing the breakdown of acetylcholine. It is therefore assumed that these two monoterpenes may help improve memory and reduce cognitive dysfunction seen with THC intoxication, and they may have potential for treating cognitive disorders. They smell of pine and may have antiseptic properties. β‑Myrcene stimulates the release of endogenous opioids by acting on α2‑adrenergic receptors, and together with THC and CBD contributes to pain relief. It also appears to have antioxidant and anticarcinogenic effects. Its aroma is described as musky or like hops.

By contrast, limonene, together with CBD, increases serotonin and dopamine levels, producing anxiolytic and anti‑stress effects. The floral scent of linalool may be useful in treating anxiety in aromatherapy.

β‑Caryophyllene is the most abundant sesquiterpenoid in cannabis extracts and in the whole plant. It is an agonist at CB2 receptors, is non‑psychoactive, and exerts anti‑inflammatory, gastroprotective and analgesic effects. It also shows antifungal, antibacterial, antidepressant, antiproliferative, analgesic, anxiolytic and neuroprotective properties.

Different cultivars, plant parts and environmental conditions are reflected in the terpene composition and aroma of cannabis. Moreover, it is hypothesized that varying proportions of terpene combinations in a given cannabis variety may produce different therapeutic effects for pain and other conditions. This could explain why different cannabis strains affect the same patient differently. This theory still needs scientific verification, ideally in clinical trials.

Δ8‑THC has attracted interest for its potential therapeutic properties, which are partly similar to those of the better‑known Δ9‑tetrahydrocannabinol (THC) but with milder psychoactivity. The most commonly suggested therapeutic areas include treatment of chronic pain and inflammatory conditions, particularly when conventional analgesics are insufficient or cause undesirable side effects. Reduction of anxiety and stress: because of its lower psychoactive effect, Δ8‑THC may be an alternative for people with anxiety disorders. Some users report reduced feelings of stress and anxiety without some of the intense side effects associated with Δ9‑THC. Like other cannabinoids, it can stimulate appetite and help with nausea, an effect valuable for patients undergoing chemotherapy or suffering from other conditions that reduce appetite. Its mild sedative effects may also improve sleep quality for some patients, which is important in treating insomnia or sleep disorders.

It must be emphasized, however, that although these therapeutic effects are often mentioned based on preliminary studies and anecdotal reports, extensive clinical research to confirm the safety and efficacy of this compound is still ongoing. Future study results will be crucial for determining optimal dosing regimens and for understanding in which clinical indications this cannabinoid may be most effective.

I hope the topic of cannabis as a medicinal plant has interested you. I am very interested in research on active compounds and their potential therapeutic uses. In my practice, among the steadily growing group of patients using cannabis for medical purposes, I mostly observe positive effects, and I am curious about exactly how it works in the body.

MUDr. Petra Mištríková, MBA

References for further study:

Historie pěstování konopí v Česku, dostupné z www.marijanka.cz

Sommano SR, Chittasupho C, Ruksiriwanich W, Jantrawut P. The Cannabis Terpenes. Molecules. 2020 Dec 8;25(24):5792. doi: 10.3390/molecules25245792. PMID: 33302574; PMCID: PMC7763918.

Schilling S, Melzer R, McCabe PF. Cannabis sativa. Curr Biol. 2020 Jan 6;30(1):R8-R9. doi: 10.1016/j.cub.2019.10.039. PMID: 31910378

Hanuš L., Krejčí Z.: Isolation of two new cannabinoid acids from Cannabis sativa L. of Czechoslovak origin. Acta Univ. Olomuc., Fac. Med. 74, 161-166 (1975)

Karlíčková J., Potenciální léčebné využití kanabidiolu (CBD) z konopí setého; Prakt. lékáren. 2019; 15(4): 227-230