Medical cannabis contains more than 100 phytocannabinoids, the best known being the psychotropic tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD). However, the more than 500 plant constituents also include other biologically active substances, especially terpenes and flavonoids.
Numerous studies and experiences of many cannabis patients show that preparations from the whole cannabis plant, so-called full-spectrum preparations (cannabis flowers, full-spectrum extracts), are often more effective and tolerable than isolated cannabis medicines such as dronabinol (synthetic or semi-synthetic THC). The positive interaction between the different plant constituents is known as the entourage effect. The interaction between cannabinoids and terpenes is being intensively researched, and there are also initial studies on the role of flavonoids. We provide an overview of the benefits of full-spectrum preparations for pain, epilepsy, and affective disorders (depression, bipolar disorder, anxiety disorders).
What is the entourage effect?
The entourage effect was first discovered in 1998 by Israeli chemist Raphael Mechoulam and describes synergistic effects between different cannabinoids as well as other plant constituents . The intra-entourage effect refers to interactions between different cannabinoids. For example, the combination of THC with the non-psychotropic CBD can enhance the bioavailability of THC and reduce the psychotropic effect. Inter-entourage effects are referred to as interactions between cannabinoids and other plant constituents such as terpenes and flavonoids .
Full spectrum, broad spectrum, isolates – what is the difference?
Medical cannabis is used in different dosage forms. Depending on the composition of cannabinoids and other plant constituents, a distinction is made between full-spectrum cannabis medications and isolated cannabis medications :
Cannabis flowers are crushed and inhaled with a vaporizer. Temperatures between 180 and 210 degrees Celsius are recommended . At these temperatures, not only the cannabinoids evaporate, but also the terpenes, whose boiling points are often lower. For example, monoterpenes such as limonene and pinene boil between 150 and 185 degrees Celsius . Cannabis patients benefit from the entourage effect when inhaling cannabis flowers or ethanolic cannabis extracts.
Medicinal cannabis extracts are obtained with solvents such as liquid carbon dioxide, ethanol, or olive oil. Depending on the processing method and composition, a distinction is made between isolated cannabinoids, broad-spectrum extracts, and full-spectrum extracts :
- Cannabinoid isolates: pure phytocannabinoid such as THC or CBD
- Broad-spectrum extracts: cannabis extract low in THC, from which THC has been almost completely removed
- Full-spectrum extracts: In addition to THC and CBD, they also contain traces of cannabinoids, terpenes, flavonoids, and other plant constituents
Due to the entourage effect between cannabinoids and other plant constituents, broad-spectrum extracts, and full-spectrum extracts are considered more therapeutically beneficial .
In addition, synthetic cannabinoids are used in medicine. Dronabinol – a synonym for THC – is obtained semi synthetically or fully synthetically. Nabilone, a fully synthetic THC derivative approved in the United States, is used for nausea, and vomiting during chemotherapy and for anorexia in HIV or AIDS patients . Synthetic cannabinoids contain only one pure substance and therefore have no entourage effect.
When are full-spectrum preparations unsuitable?
Despite medical advantages, broad-spectrum preparations or full-spectrum preparations are not suitable in certain cases: These include, for example, intolerances to terpenes. Contact allergies are known for oxidized limonene and linalool . Competitive athletes or other individuals who regularly undergo drug testing should only treat CBD with isolates, as full-spectrum CBD preparations contain small amounts of THC that can lead to positive drug test results . These products are also generally not suitable for pets, as the terpenes can cause intoxication. For example, limonene and linalool are toxic to cats .
Pain and inflammation
The beneficial effects of cannabis on pain and inflammation are well studied. However, to date, the focus has been on pure THC and CBD, while full-spectrum extracts have been little studied. In addition to THC and CBD, other cannabinoids such as cannabinol (CBN) and cannabichromene (CBC) may help with pain. In addition, the terpenes myrcene, alpha-pinene, beta-caryophyllene, and D-limonene have supportive effects.
Entourage effect between cannabinoids (especially THC and CBD) and terpenes for pain and inflammation:
Full-spectrum extracts in the form of the finished pharmaceutical Sativex, an oral spray containing THC and CBD, have been studied in numerous clinical trials in patients with multiple sclerosis (MS). The cannabinoids were used either alone or as an adjunct to other MS medications. The oral spray relieved numerous symptoms: Less neuropathic pain (nerve pain), muscle stiffness and spasticity, and better sleep quality. The studies confirm that full-spectrum preparations can effectively address these symptoms. Sativex is approved for the treatment of spasticity in patients with multiple sclerosis.
In contrast, a German study published in 2017 found no significant effect of dronabinol versus placebo in MS patients with nerve pain. On the downside, pure THC medications are often less well tolerated, leading to a higher incidence of side effects such as cognitive impairment and palpitations (tachycardia) .
Pain patients prefer full-spectrum preparations
In a review paper, London-based researchers summarized findings on the role of the synergy effect and entourage effect in pain. According to the paper, pain patients clearly prefer full-spectrum preparations because they provide better pain relief with better tolerability. The analgesic effect of THC is supported by CBD: In patients with nontumor-related pain, CBD has a good safety profile, significant analgesic effects, and reduced use of opiate analgesics. The psychotropic effects of THC are attenuated by CBD. Therefore, THC/CBD-balanced preparations could be a well-tolerated and effective pain treatment .
Pain and migraine patients prefer indica-dominant cannabis strains
Terpenes, except for beta-caryophyllene, do not bind to cannabinoid receptors but have analgesic effects via other targets (such as other receptors, ion channels, and enzymes). Cannabis flowers contain completely different compositions of cannabinoids, terpenes, flavonoids, and other secondary plant compounds, depending on the chemovar. This combination may explain why many sufferers prefer full-spectrum preparations over single substances. Pain and migraine patients prefer THC-dominated cannabis flowers with low CBD content, containing beta-caryophyllene and myrcene as main terpenes .
Different ratios of major and minor cannabinoids and terpenes may explain these differences in effects. Certain cannabis flowers are particularly suitable for daytime use due to their mood elevating effects, while sedative varieties are preferred for evening use.
Synergistic effects have also been described between cannabis and other analgesics. Thus, the two endogenous systems for pain inhibition, the endocannabinoid system, and opioid systems, are interconnected. Endocannabinoids influence endogenous opioids and vice versa. In pain models, cannabis enhanced the analgesic effects of opioids and reduced opioid dependence. Cannabinoids may also support the analgesic effects of non-opioid analgesics such as diclofenac. Cannabis therapy may allow dose reduction of opioids and other analgesics and thereby reducing side effects such as gastrointestinal discomfort or dependence .
In a meta-analysis published in 2018, Brazilian researchers examined 199 publications on CBD-based medications involving a total of 670 sufferers with treatment-resistant epilepsy. The outcomes of this literature review have been very encouraging: almost two-thirds of sufferers (399 of 622 individuals, 64%) have been capable of scale back their seizure frequency with CBD. Full-spectrum preparations were significantly superior to pure CBD medications: Under CBD-dominated full-spectrum extracts, nearly three-quarters (318 of 447 subjects, 71%) reported fewer seizures. In contrast, seizures decreased under pure CBD treatment in nearly half (81 of 175 subjects, 46%) [14,15].
Full-spectrum CBD extracts better tolerated
In addition, the required CBD dose was lower with the full-spectrum extract: while 6 mg/kg/day was sufficient with the CBD-dominant full-spectrum extract, much higher doses of 25.3 mg/kg/day were required for seizure control with the CBD isolate. Thus, cannabinoids can be saved by using full-spectrum extracts. Another advantage was the better tolerability of full-spectrum products: While 76 percent suffered from mild side effects and 26 percent from severe side effects under CBD isolate, these adverse effects were less common under full-spectrum CBD extract, at 33 percent and 7 percent, respectively.
In addition, 11 clinical trials involving epilepsy patients, mostly children, were evaluated: Five studies examined pure CBD and six studies examined full-spectrum CBD-rich extracts. The best result came from an Israeli study published in 2016 of children treated with CBD-rich extracts at Sheba Medical Center’s Department of Pediatric Neurology: 89 percent of the 74 participants had fewer seizures. In fact, when all 11 studies were analyzed, seizure frequency was reduced by more than 70 percent in about one-third (83 of 311 subjects, 27 percent) of those affected [14,15].
CBD full extract improves accompanying symptoms in patients with epilepsy
In addition, a full-spectrum CBD extract also alleviated other symptoms in epileptics: Attention, sleep quality, mood, behavior and aggression, language and cognition, and motor functions improved. Such positive effects were not observed in studies with CBD alone. A limitation is that not all studies examined concomitant symptoms, and any concomitant medication with antiepileptic drugs may also have reduced seizures. CBD is considered to be similarly safe to other antiepileptic drugs based on current scientific evidence, but it is still not without risk. The most common side effects were appetite changes, insomnia, gastrointestinal upset and diarrhea, weight changes, fatigue, and nausea. Less common, severe side effects included thrombocytopenia and altered liver enzyme levels occurred [14,15].
Preclinical Study: Cannabidiol Acid (CBDA) enhances the anticonvulsant effects of CBD
A team of U.S. researchers has shown that cannabidiol acid (CBDA), the non-decarboxylated precursor of CBD, enhances anticonvulsant effects in a preclinical study in rats published in 2021. The researchers studied three cannabinoid preparations and compared anticonvulsant effects.
- CBDA-rich partial spectrum extract (chylobinoid): contains 74.5 percent CBDA as well as other cannabinoids
- High-purity crystalline CBDA stabilized with magnesium ions (Mg-CBDA): contains 92.8 percent CBDA, contains no other cannabinoids
- Cannabidiol isolate (CBD): pure CBD without other cannabinoids
All three cannabis preparations, i.e., both CBD and the precursor CBDA, protected animals from experimental seizures in a dose-dependent manner. It is interesting to compare the two CBDA-containing preparations, chylobinoid (74.5 percent CBDA) and magnesium-CBDA (92.8 percent CBDA): chylobinoid contains less CBDA than high-purity magnesium-CBDA, but other cannabinoids. For an anticonvulsant effect, a lower CBDA dose was sufficient for chylobinoid. It is possible that other cannabinoids present in chylobinoid enhance the anticonvulsant effect of CBDA. Overall, the animal model shows that CBDA-rich cannabis extracts have similar anticonvulsant effects to CBD. The results support the entourage effect .
Affective disorders and anxiety disorders
Affective disorders include e.g., depression, anxiety disorders, and bipolar disorder (manic-depressive illness). Medications such as antidepressants alleviate these by affecting the neurotransmitters norepinephrine, serotonin, and dopamine. These neurotransmitters control emotions and behaviors such as mood, vigilance (alertness), motivation, fatigue, and psychomotor agitation. Current medication therapies alleviate mood disorders in only 60 to 70 percent of sufferers, which is why cannabinoids THC and CBD in particular are coming into focus as a new treatment option.
The anxiety-relieving and antidepressant effects of CBD are based on a kind of “entourage effect” between the endocannabinoid system (ECS) and other receptor systems: Endocannabinoid system, norepinephrine system, and serotonin systems are known to interact with each other. CBD activates presynaptic cannabinoid-1 receptors, causing the sympathetic nervous system to release less of the neurotransmitter acetylcholine .
Survey in Canada: Anxiety patients prefer cannabis strains with specific terpene and cannabinoid profiles
A Canadian study published in 2018 conducted a survey examining different cannabis strains for anxiety. It surveyed 442 people between the ages of 40 and 59 who use cannabis products from a licensed dispensary. More than half (60 percent) reported using cannabis to relieve anxiety. A diagnosed anxiety disorder was present in 15 percent of respondents. Participants rated anxiety-relieving effects on a 10-point Likert scale, with higher scores indicating better treatment outcomes. Cannabis was effective in relieving anxiety: 260 respondents who reported anxiety as a reason for their use rated cannabis as effective (8.03 on the Likert scale).
To clarify which cannabis strains were most effective, participants were asked to select the most and least effective strains from 25 cannabis strains, with multiple selections possible:
- Most effective strains: Bubba Kush, Skywalker OG, Blueberry Lamsbread, Kosher Kush
- Less effective strains: Chocolope, Blueberry Lamsbread, CBD Shark, Tangerine Dream
The research team then analyzed the cannabinoid and terpene profiles of these strains to determine the relationships between chemotypes and anxiety-relieving effects:
- The best anxiety-relieving strains are predominantly Kush varieties (Bubba Kush, Skywalker OG , Kosher Kush) with similar terpene profiles: Trans-nerolidol, beta-caryophyllene, alpha-pinene, and D-limonene. Genetically, they are derived from landraces from the Kush mountains in Central Asia. The presence of trans-nerolidol was significantly associated with better relief of anxiety. The anxiety-relieving effects of alpha-pinene and D-limonene, known from previous studies, were also confirmed.
- Less anxiety-relieving varieties exhibited a divergent terpene profile: Terpinolene, Guaiol, Myrcene, Beta-Caryophyllene, and D-Limonene. According to the evaluation, guaiol and terpinolene may have anxiety-increasing effects: Three-quarters of the most ineffective strains contain guaiol, while it is absent in effective strains. Chocolope, the only strain with terpinolene, a terpene with more stimulant, anxiety-increasing, and anti-analgesic (pain-increasing) effects, received the most “negative votes.”
- Blueberry Lamsbread, a myrcene-rich variety, was rated differently by participants for anxiety. Different symptoms and biochemical characteristics of those affected may play a role, the research team said.
In summary, trans-nerolidol is the most important terpene in better, anxiety-relieving cannabis strains. In less potent strains, myrcene is the most common terpene. Guaiol and terpinolene may exacerbate existing anxiety. More anxiety-relieving strains contain more THC and less CBD. Despite similar symptoms, different cannabis strains affect each person differently.
Controlled studies are needed to better understand how different strains work for anxiety. This will make it easier for patients to find the best strain for them. Research should also be done to understand why some people respond with increased anxiety .
Full-spectrum preparations contain not only cannabinoids, but also terpenes, flavonoids, and other plant constituents. Their interaction is known as the entourage effect and plays an important role in effect and tolerance. Many cannabis patients prefer cannabis flowers and full-spectrum extracts to single agents such as Dronabinol.
Clinical studies and surveys show that people with pain, inflammation, or anxiety use cannabis strains with specific cannabinoid and terpene profiles. Studies of epilepsy patients receiving CBD medications also showed better seizure control with better tolerance of full-spectrum preparations. Studies in rats have shown that CBDA, a precursor to CBD, also has anticonvulsant effects. Unlike THC, CBD has no psychotropic effects, making CBD-rich or THC/CBD-balanced cannabis strains particularly suitable for the beginning of treatment.
Currently, there are few studies of the entourage effect. Future clinical trials with full-spectrum preparations will provide more information on the advantageous active ingredient ratios between cannabinoids, terpenes, and flavonoids in specific disorders. This will facilitate strain selection for patients. However, trial and error are essential because even with the same THC, CBD, and terpene content, cannabis affects each person differently. Cannabis patients should therefore pay attention to their body’s signals to work with their doctor to find the optimal cannabis preparation that will provide the best symptom relief with the fewest adverse effects.
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