Before we discuss relevant animal research on CBD that CBD targets differ between humans and animals. and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Apart from updating the literature, this article focuses on clinical studies and CBD Besides, gelsemine above μM triggered toxic effects in animals and. The document may not be reviewed, abstracted, quoted, . Adverse Reactions in Humans. . an update and extension of the pre-review on cannabidiol, that was . would produce physiological relevant effects in humans. . Across a range of measures in humans and animals, CBD had been shown to.
Cannabidiol: of S Data Review A Relevant Side Update Effects of Safety Animal on Clinical and An and
Detailed clinical observations were conducted once per day. An ophthalmologic examination was conducted during the acclimation period and prior to test termination on day Measurements of body weight were conducted twice during the acclimation period, on the first experimental day prior to treatment, and then twice weekly. Food consumption determinations coincided with body weight measurements.
Gross pathological examinations were conducted and selected absolute organ weights liver, kidneys, testes, epididymides, uterus with fallopian tubes, thymus, spleen, brain, heart, adrenals, and ovaries were measured and relative organ weights were calculated on all animals.
Complete histopathological examinations were conducted on the preserved organs and tissues adrenals, aorta, bone marrow of the femur, cerebrum, cerebellum, pons, medulla, eyes, mammary gland, gonads, heart, kidneys, large intestines, liver, lungs, submandibular and mesenteric lymph nodes, quadriceps muscle, esophagus, nasal turbinates, pancreas, pituitary, prostate, submandibular salivary glands, sciatic nerve, seminal vesicle, skin, small intestines, spinal cord at three levels, spleen, sternum, stomach, thymus, thyroid and parathyroid, trachea, and urinary bladder of all animals of the control and high-dose groups.
When no significant heterogeneity was detected, a one-way analysis was carried out. When significant heterogeneity was found, the normal distribution of data was examined by Kolmogorov-Smirnov test. If there was a positive result, the intergroup comparisons were performed using the Mann—Whitney test. A day repeated dose oral toxicity study was conducted in Hsd. Han Wistar male and female rats in order to evaluate the possible health hazards likely to arise from repeated oral exposure to the test article during postweaning maturation and growth well into adulthood.
The main study was followed by a day recovery period in which two satellite groups 5 additional animals per sex per group in the control and high-dose groups were observed in order to assess reversibility, persistence, or delayed occurrence of potential toxic effects.
The test article was formulated in the vehicle sunflower oil just prior to administration. Animals assigned to the satellite groups were treated identically up to day 90 and then observed without treatment for four weeks.
Healthy male and female Hsd. Han Wistar rats aged 42—52 days and weighing — g and — g, respectively, were acclimatized for seven days and randomly divided according to stratification by body weight into four groups numbers include the satellite animals: All animals were observed twice daily for mortality.
General cage-side observations for clinical signs were made twice during the acclimation period, once daily after administration of the test article during the treatment period and the recovery period.
Detailed clinical observations were conducted on the day prior to the first treatment and once weekly thereafter during both the treatment and recovery periods. A functional observation battery FOB was performed during the final week of the study and included evaluation of sensory reactivity to stimuli, grip strength and motor activity, general physical condition, and behavior of the animals. Individual body weights were recorded once during the acclimation period, on day 0 prior to study start , twice weekly during weeks 1—4, and once weekly thereafter weeks 5—13 and during the recovery period for satellite groups and immediately prior to sacrifice days 90, 91, and Food consumption was determined weekly to coincide with body weight measurements and food efficiency was calculated once weekly.
Ophthalmological examination was carried out on all animals prior to the experimental period and on control and high-dose group animals at the end of the treatment period. After an overnight fast approximately 16 hours following final administration of the test article on days 90 and 91 and at the termination of the recovery period on day , blood samples were collected and animals euthanized as described in the day study.
Blood samples were analyzed for hematologic, blood coagulation, and clinical chemistry parameters as listed in the day study.
Complete histopathological examinations were conducted on the preserved organs and tissues as listed for the day study of all animals of the control and high-dose groups including animals of the recovery group. The histological examination of testes and epididymides covered the stages of spermatogenesis in the male gonads spermatogonia, spermatocytes, spermatids, and spermatozoa and histopathology of interstitial testicular cell structure.
With regard to the prostate, seminal vesicle, and coagulating gland, the activity of secretion in the glandular tissue, the amount of secretions in the ducts, the average diameter of tubules, and the interstitial structures were evaluated.
The liver and adrenal glands were processed and evaluated histologically in all animals in the low- and mid-dose groups due to macroscopic findings at necropsy or organ weight changes.
Sperm analyses qualitative and quantitative were conducted on five animals from the control and high-dose groups from the treatment period due to lack of any findings, these were not conducted in lower-dose groups or the recovery group animals. One testis per animal was used for enumeration of sperm, and sperms from the ductus deferens were collected for evaluation of sperm motility and sperm morphology.
The examination was performed under a light microscope. Qualitative examinations were performed immediately after euthanasia and exsanguination of animals.
For quantitative examination, testes were frozen at necropsy and enumeration was performed on the same animals used for qualitative examinations. Statistical analysis was performed as described in the day study above.
No substantial increases in revertant colony numbers were observed in any of the five tester strains following treatment with the test article in the presence or absence of metabolic activation S9 at any concentration level see Tables 1 and 2. Sporadic increases in revertant colony numbers compared to vehicle control were observed in both experiments, reflecting the biological variability of the applied test system; however, there was no tendency of dose related increases and mutation rates remained within the historical control data range.
The concurrent positive controls caused the expected biologically relevant increases of cells with structural chromosome aberrations as compared to current solvent and historical controls. There were no statistically significant differences between treatment and the solvent control groups, and no dose-response relationships were noted see Table 3. No mortality or gender specific effects were observed in the preliminary toxicity test; therefore, the micronucleus test was conducted at the doses described above in males only.
In the main study, no mortality occurred. The mice did not exhibit any symptoms 24 and 48 hours after treatment. Because there was no mortality, bone marrow slides were not prepared on the two extra animals included in the high-dose group. The effect was not biologically significant but demonstrated exposure of the bone marrow to the test article. A large, statistically significant increase in MPCE frequency was observed in the positive control group compared to negative control. The cyclophosphamide-treated mice had MPCE counts that were slightly higher Thereafter, three males and one female died in this group on days 4 1 male , 5 1 male , and 10 1 male and 1 female.
Clinical signs were noted in all test article treated groups and no clinical signs were noted in the control group. Mean body weight gain was statistically significantly decreased in all test groups compared to controls.
Food consumption was statistically significantly reduced in animals of all test article groups throughout the study. Feed efficiency was also affected by treatment, with most animals experiencing a significant decrease; however, feed efficiency was not evaluated in some cases due to the body weight loss of the animals.
In surviving animals, the following were detected at necropsy: Statistically significant absolute and relative changes in various other organ weights were noted in all dose groups.
Histological examination of these organs revealed alveolar cytoplasmic vacuolation in the cortical zones of adrenal glands, cytoplasmic vacuolation of hepatocytes in the liver and of proximal convoluted tubules in the kidneys, accelerated involution of thymus, and lymphocyte depletion in the spleen see Figures 1 — 3.
The presence of giant cells was observed. No further signs were found in detailed clinical observations in any dose group. No alterations in behavior or in reactions to various stimuli were noted in the FOB data not shown.
No clinical signs were observed in the satellite groups during the recovery period. In the high-dose satellite group, these differences did not return to normal during the recovery period, although mean body weight gain was higher than controls in males from day 96 to the end of the recovery period with statistical significance between days 96— and days — see Table 8. These differences also did not fully return to normal in the high-dose satellite group during the recovery period.
Statistically significant lower mean food consumption compared to controls was also noted in high-dose satellite animals in recovery week 1 male and in recovery weeks 1 and 4 females. Slight, sporadic, yet statistically significant differences were noted in feed efficiency in all treatment groups data not shown. Several alterations in hematology and clinical chemistry parameters were noted during the day period compared to the control group.
Hematological differences were not found in the high-dose group at the conclusion of the recovery period; however, some differences in clinical chemistry were still present during this timeframe see Tables 10 and At the end of the recovery period, no macroscopic findings were noted in satellite group males.
Statistically significant differences with respect to control were noted in several absolute and relative organ weight measures in the test article groups during the main study. Several differences in organ weights in high-dose males and females were also identified during the recovery period see Tables 12 — Therefore, no sperm examinations were conducted during the recovery period.
A list of histopathological findings can be found in Table 15 and photos can be found in Figure 6. The current studies were undertaken to better understand the toxicological profile of this hemp extract rich in CBD in OECD compliant in vitro and animal studies. The bacterial reverse mutation, in vitro mammalian chromosomal aberration, and in vivo mouse micronucleus tests met their respective validity and sensitivity criteria and were unequivocally negative under the conditions of their respective study.
Han Wistar rats could not be established because of test article related adverse toxicological effects and histopathological findings. Thus, lower dose levels were chosen for the subchronic study. For high-dose satellite group males and females, decreased food consumption and body weights persisted throughout the recovery period. Therefore, the elevation of GGT was considered to be an adaptive response to the altered demand due to the presence of the test article, that is, the physiological response of an organism in order to maintain normal function [ 35 , 36 ].
While GGT remained statistically significantly higher in the high-dose satellite group males and females during the recovery period, the values returned to historical control ranges; therefore, the change in GGT appeared to be reversible.
CREA in high-dose satellite group females became statistically significantly lower compared to satellite controls during the recovery period. This change in significance could be attributed to the increase in the satellite control CREA at the end of recovery period In the high-dose groups, histopathological examination revealed that pale adrenal glands were accompanied by increased diffuse cytoplasmic vacuolation of the cortical cells of the adrenal glands in male and female rats.
The cytoplasmic vacuolation of the cortical cells is usually associated with increased cellular activity and may be secondary to xenobiotic treatment or due to stress [ 37 , 38 ]. These lesions were not found in the treated rats at the end of the recovery period and therefore were considered to be reversible. Histopathological examinations also revealed alveolar emphysema, which was considered to be due to the hypoxia, dyspnea, and circulatory disturbance commonly developed during exsanguination and alveolar histiocytosis, which is a common incidental finding in aging rats [ 39 ].
Dilatation of uterine horns was considered a neurohormonal phenomenon associated with the proestrus phase of the inner reproductive organs [ 40 ].
Renal findings in single animals described above cyst, mineral deposits, and focal fibrosis were judged to be individual disorders without toxicological significance [ 41 , 42 ]. In conclusion, the test article was considered nonmutagenic, nonclastogenic, and nongenotoxic in the current bacterial reverse mutation, in vitro mammalian chromosomal aberration, and in vivo mouse micronucleus tests, respectively.
The toxicological assessment that is reported herein is the first known of its kind since the Rosenkrantz et al. Given the broad physiological actions of CBD and other hemp-derived phytocannabinoids, this battery of OECD-compliant toxicological studies is a salient contribution to the literature, providing a more extensive assessment of this supercritical CO 2 extract of the aerial parts of the hemp C. Robin Reddeman, Tennille K. Clewell, and John R. Endres are employed by AIBMR Life Sciences, which was contracted by the study sponsors as an independent third party to place and monitor toxicological studies on the test article and to publish the results.
The remaining authors are employed by Toxi-Coop Zrt. Marx and Robin Reddeman contributed equally to this work. The very first use of cannabis was documented in China around BC. A very versatile plant, it was used for food, medicine, religious and spiritual rituals, industrial fiber, and, of course, recreation. From China, cannabis spread to India, the Arabian Peninsula, and then on to Europe with the spice trade. Through European colonization, use of cannabis spread to the Americas, Caribbean, and throughout the world.
How the plant was used depended on the variety of cannabis, the parts of the plant, and how the plant was cultivated. The variety of cannabis known as hemp was traditionally valued primarily for its fibers with high tensile strength, making it ideal for creating rope and textiles.
Hemp seeds and sprouts were eaten as a good source of high-quality protein and beneficial omega-3 fatty acids. The variety of cannabis known as marijuana was specifically cultivated for the euphoric properties of THC, which is concentrated mostly in the flower buds of the plant. Only recently have the unique medicinal properties of both hemp and marijuana been fully recognized. Cannabis sativa has several alter egos, but marijuana and hemp are the two best known.
Though both plants look the same, their chemical composition is quite different. The chemical difference has to do with the presence or absence of certain enzymes. Both marijuana and hemp contain a chemical substance called cannabigerol CBGA , which is concentrated mostly in the flower buds of the plant. Remember, though, that there are many varieties of marijuana and hemp plants, and their concentrations of THC and CBD vary.
Only cannabis with less than 0. There are different receptors for cannabinoid compounds located throughout the body. For instance, CB1 receptors are found in high concentrations in the brain and nervous system. CB2 receptors are located throughout the body, but predominantly within the lower body and immune system. It weakly binds to both CB1 and CB2 receptors in the brain and body, gently stimulating and blocking them at the same time.
This not only mildly activates the receptors, but is also thought to trigger the body to create more CB 1 and CB 2 receptors, a process known as upregulation. It also results in increased natural levels of anandamide. When the body experiences an increase in CB receptors, it becomes more sensitive to the natural endocannabinoids anandamide and others already present in the body.
CBD also modulates other receptors in the body. For instance, modulation of the 5-HT1A receptor involved with serotonin, a mood hormone provides mood-balancing properties: Another example is modulation of opioid receptors, which provides pain relief and tissue-supporting properties.
Cannabis plants also possess a wide spectrum of different chemical components offering a range of medicinal properties. Aside from cannabinoids, one of the most prominent chemicals in cannabis plants is terpenes, organic and aromatic compounds found in essential oils. Terpenes are beneficial on their own. For instance, research in the British Journal of Pharmacology found that terpenes are gastro-protective, suggesting they may be beneficial to people with ulcers, and that they have anti-inflammatory properties.
It also points to the importance of using a full-spectrum extract of hemp, which provides a full range of chemical components including terpenes, as opposed to purified CBD or CBD isolate, which contains only CBD. Cannabinoids, including cannabidiol CBD , work by mimicking natural endocannabinoids like anandamide described above in the body. Endocannabinoids are part of a complex messaging system in the body called the endocannabinoid system.
The endocannabinoid system oversees or regulates parts of the nervous system, endorphins, immune system functions, hormones, mood and emotions, metabolism, and many other chemical messengers in the body. Like other cannabinoids, CBD readily crosses the blood brain barrier, making it ideal for affecting central nervous system conditions.
CBD helps calm the nervous system, reduces inflammation, and is strongly neuroprotective. Not surprisingly, clinical studies evaluating cannabidiol for treatment of anxiety , post traumatic stress disorder PTSD , seizure disorders especially childhood seizures , and even schizophrenia have shown remarkable effectiveness. Management of chronic pain is another application for which CBD is ideally suited, and it works in a number of ways. It and other non-THC cannabinoids found in hemp flower-bud extracts work to block pain-conducting nerve impulses, which reduces your perception of pain.
Stimulation of CB 1 in the brain increases dopamine , which counteracts pain. Just as importantly, these same chemical substances reduce inflammation , the driving force behind pain , which allows healing to occur.
CBD and other cannabinoids also reduce pain by affecting endorphins, the feel-good chemicals we naturally produce to suppress pain. Unlike opioids heroin, narcotics , which mimic endorphins and ultimately suppress natural endorphins, cannabinoids modulate endorphins. This means, in effect, that CBD and cannabinoids increase natural endorphins.
So instead of causing dependence and addiction like opioids, CBD and cannabinoids do the opposite — so much so that CBD has proven valuable for countering narcotic and cocaine addiction. From a medicinal standpoint, the fact that CBD has the potential to relieve pain without causing euphoria, intoxication, or addiction makes it an intriguing therapeutic option — it has high potential for being at least a partial solution to the current opioid epidemic.
CBD and other chemical substances in hemp flower-bud extracts are strong immune system modulators. This means they control inflammation throughout the body, and also fine-tune the immune system for optimal performance. The wide range of benefits associated with cannabis have garnered interest for use in cancer therapy. Research suggests that cannabinoids, including CBD, may have anti-tumor effects.
While this is not enough to define cannabis as a treatment for cancer, it does make it attractive as a complement to other therapies , for both reducing symptoms and possibly enhancing the effects of anticancer drugs.
Terpenes and the wide spectrum of other chemical compounds found in hemp flower-bud extracts provide potent anti-inflammatory and antioxidant properties. This is a common source of confusion. Many people see hemp oil on grocery store shelves and assume or wonder if it contains CBD and other cannabinoids. The hemp oil you might see on grocery store shelves is made by cold pressing hemp seeds. While hemp oil is a healthful option for a salad dressing, it has no medicinal value by itself.
Cannabinoids, including CBD in hemp and THC in marijuana, are most highly concentrated in the flower buds, not the seeds. These chemical components of the plant must be extracted from the flower buds to be useful.
For medicinal use, cannabinoids are extracted from hemp and concentrated into a thick oil that, when ingested, elevates blood levels of cannabinoids for a more sustained period of time. CBD oil from hemp contains CBD and other cannabinoids, along with terpenes and other chemical components. The most common method, chemical extraction uses alcohol or hexane as solvents.
The solvent is dried off, leaving the dense oil — and possibly harmful residual solvents — behind. A newer method, CO 2 extraction is done without using chemical solvents. Instead, it uses carbon dioxide to extract the full range of chemical components from the flower buds and then distill them into dense CBD oil.
Also sometimes called thermal extraction, vapor distillation uses hot air to safely vaporize the full spectrum of chemical components at high concentration from the buds, and then the vapor is distilled into CBD oil.
This method also activates the cannabinoids by removing an extra carboxyl ring from their molecular chain a chemical reaction called decarboxylation , enabling them to interact directly with CB receptors for maximal medicinal value. I believe vapor distillation is the best method for obtaining the full range of activated chemical compounds from the cannabis plant.
This method preserves the terpenes, which are beneficial on their own, and also enhance the properties of CBD via the entourage effect. The upsides of lipid-based extraction are that the fat helps make the CBD more bioavailable easy to absorb , and there are no harsh solvents used.
Condensed CBD oil can be taken as a thick paste, but this is the least pleasant option. More commonly, the CBD oil is mixed with a carrier oil, such as hemp oil or coconut oil, to a specific concentration of CBD. The distinctive taste — which comes from the terpenes and not the cannabinoids — is often masked with chocolate, mint, or other flavorings. It typically comes in a small bottle with a dropper to administer the oil mixture.
The best way to take CBD oil mixed with a carrier oil to a specific concentration is to place a few drops or dropperfuls under your tongue for 15 seconds to access the sublingual gland. There, the CBD is absorbed directly into the bloodstream called sublingual consumption or administration for the fastest acting effects. Another method is to take a few drops or dropperfuls orally, swish the liquid around in your mouth, and then swallow it. CBD oil mixed with a carrier oil can also be taken as soft-gel capsules to avoid any taste, but absorption is only through the intestinal tract.
The average dose range is mg of CBD, one to three times per day, though much higher doses of mg sometimes required to control pain are equally well tolerated. Some people will notice benefit at the lower end of the dose range, but most people will need mg to notice any effects. Because different products provide different concentrations of CBD, the packaging usually states how much CBD is in the entire bottle as opposed to the amount in a certain number of drops or dropperfuls, so measuring can be a little tricky.
A dropperful of the medium grade product mg of CBD per fluid ounce will deliver about 15 mg of CBD — a good starting dose. And a dropperful of a high concentration product mg CBD per fluid ounce will provide about 50 mg of CBD per dropperful. CBD oil is also available as soft gel capsules. With these, the mg quantity of CBD should be designated per capsule. Because some of the chemical compounds in capsules are lost during digestion, you may find you need to take a little more to experience the benefits.
As with any medicinal herb, start at a low dose and gradually build up to a higher dose as you get used to the effects of the substance. Most people notice benefits almost immediately, but some experts suggest that full benefit does not occur until after a couple of weeks of consecutive use. CBD isolate which is CBD alone acts very differently in the body than a spectrum of hemp chemical components. Here are some quick definitions:. The cannabis plant naturally generates cannabinoids, terpenes, and other chemical compounds to serve different functions in the plant.
These functions include regulatory properties, potent antioxidants, and protection from microbes and insects. Any creature that consumes the chemicals from the plant gains these same benefits. When you consume CBD oil, you gain the benefits of all those chemical substances in natural synergy. For that reason, you get full benefit at a dose range of mg. CBD isolate is limited to that single chemical messenger. The synergy provided by the full spectrum of chemicals in CBD oil is lost.
This is likely why clinical studies using purified CBD require very high doses, in the range of mg of CBD several times daily, to see a benefit. When CBD is formally legalized at the national level, prescription drugs providing high doses of purified CBD will become available several are already in the pipeline.
Reported side effects of hemp oil with CBD are generally mild and uncommon and can include tiredness, loose stools, and mild changes in appetite and weight either increased or decreased. Both hemp oil with CBD hemp flower-bud extracts and purified CBD CBD isolate have been shown in both animal and human clinical trials to be remarkably safe and well tolerated.
Prolonged use is not associated with an increased risk of side effects. In research studies , up to mg of purified CBD per day has been used to address various medical illnesses without reported harmful effects including changes in heart rate, blood pressure, temperature, oxygen and carbon dioxide levels, electrolyte balance, gastrointestinal function, psychomotor functions, or sleep cycles.
Prolonged use at high doses has not shown potential for abuse of CBD. In fact, a clinical study published in found that recreational polydrug users did not show abuse potential with use of CBD.
The Science Behind CBD Oil: Everything You Need to Know
This review describes in vivo and in vitro reports of CBD administration in humans, controlled CBD may be safe in humans and animals. well as the CBD/ THC ratio, seem to play an important role .. to placebo in the Cannabis side effect inventory, clinical lab .. This data highlights the need for careful monitoring. An Introduction to CBD. Cannabidiol (CBD): Uses, Effects and Safety screened in lab experiments using animal cells, then tested in live animals, and finally in humans. most important properties of CBD is its ability to modulate the effects of THC. Safety and Side Effects of Cannabidiol – A review of clinical data and. The Author(s) Published by S. Karger AG, Basel However, although research into the therapeutic effects of CBD is rapidly increasing, most current uses of CBD are not (yet) supported by clinical data. . Analysis of Dutch cannabis oil samples obtained from actual patients, comparing the claimed.