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Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. This was probably due to already elevated cholesterol in the transgenic mice.
The study observed no side effects. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD increased IL levels, which is thought to act as an anti-inflammatory cytokine in this context. After inducing arthritis in rats using Freund's adjuvant, various CBD doses 0. CBD reduced joint swelling, immune cell infiltration. CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis.
Helix-loop-helix Id proteins play a role in embryogenesis and normal development via regulation of cell differentiation. High Id1-levels were also found in breast, prostate, brain, and head and neck tumor cells, which were highly aggressive.
In contrast, Id1 expression was low in noninvasive tumor cells. Id1 seems to influence the tumor cell phenotype by regulation of invasion, epithelial to mesenchymal transition, angiogenesis, and cell proliferation. There only seems to exist one study that could not show an adverse CBD effect on embryogenesis.
An in vitro study could show that the development of two-cell embryos was not arrested at CBD concentrations of 6. Various studies have been performed to study CBD anticancer effects. CBD every 3 days for a total of 28 weeks, almost completely reduced the development of metastatic nodules caused by injection of human lung carcinoma cells A in nude mice.
The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies.
Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs' adverse muscoskeletal effects.
Two studies showed in various cell lines and in tumor-bearing mice that CBD was able to reduce tumor metastasis. CBD downregulated Id1 at promoter level and reduced tumor aggressiveness. Moreover, to carry out these experiments, animals are often immunologically compromised, to avoid immunogenic reactions as a result to implantation of human cells into the animals, which in turn can also affect the results.
Another approach was chosen by Aviello et al. After 3 months, the number of aberrant crypt foci, polyps, and tumors was analyzed.
The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt elevation caused by the carcinogen. Animal studies summarized by Bergamaschi et al. Chronic administration 14 days, 2. This effect could be inhibited by coadministration of a CB2R antagonist. The positive effects of CBD on hyperglycemia seem to be mainly mediated via CBD anti-inflammatory and antioxidant effects.
In addition, treatment increased adiponectin and liver glycogen concentrations. CBD showed inhibition of testosterone oxidation in the liver. Motor function was also tested on a rotarod, which was also not affected by CBD administration. Static beam performance, as an indicator of sensorimotor coordination, showed more footslips in the CBD group, but CBD treatment did not interfere with the animals' speed and ability to complete the test.
Compared to other anticonvulsant drugs, this effect was minimal. CBD did not lead to adverse effects. In addition, psychomotor function and psychological functions were not disturbed.
Interestingly, the CYP2C19 inhibitor omeprazole, used to treat gastroesophageal reflux, could not significantly affect the pharmacokinetics of CBD. Unfortunately, it was not mentioned whether this effect was mediated via the cytochrome P complex.
Another aspect, which has not been thoroughly looked at, to our knowledge, is that several cytochrome isozymes are not only expressed in the liver but also in the brain. It might be interesting to research organ-specific differences in the level of CBD inhibition of various isozymes. Apart from altering the bioavailability in the overall plasma of the patient, this interaction might alter therapeutic outcomes on another level.
Generally, more human studies, which monitor CBD-drug interactions, are needed. In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects.
This was followed by a single 0. This extensive tool tests, for example, 78 adverse effects divided into 23 categories corresponding to organ systems or body parts. No respiratory depression or cardiovascular complications were recorded during any test session. The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows. No effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose, in which CBD clearance was reduced.
Importantly, fentanyl coadministration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl's effects. No correlation was found between CBD dose and plasma cortisol levels.
CBD did not worsen the adverse effects e. Coadministration was safe and well tolerated, paving the way to use CBD as a potential treatment for opioid addiction.
A Dutch study compared subjective adverse effects of three different strains of medicinal cannabis, distributed via pharmacies, using VAS. The 12 adjectives used for this study were as follows: This strain showed significantly lower levels of anxiety and dejection. Moreover, appetite increased less in the high CBD strain. The review by Bergamaschi et al. This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.
Order of drug administration was pseudorandomized across subjects, so that an equal number of subjects received any of the drugs during the first, second, or third session in a double-blind, repeated-measures, within-subject design.
This effect was caused by opposite neural activation of relevant brain areas. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured. A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. The doses were selected to only evoke neurocognitive effects without causing severe toxic, physical, or psychiatric reactions.
The physiological parameters, heart rate and blood pressure, were also monitored and no significant difference between the placebo and the CBD group was observed. A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: Hepatic enzymes were also measured daily, but no effect was reported. Naturalistic studies with smokers inhaling cannabis with varying amounts of CBD showed that the CBD levels were not altering psychomimetic symptoms.
CBD might work to alleviate disorders of addiction, by altering the attentive salience of drug cues. The study did not further measure side effects. CBD can also reduce heroin-seeking behaviors e. This was shown in the preclinical data mentioned earlier and was also replicated in a small double-blind pilot study with individuals addicted to opioids, who have been abstinent for 7 days.
One hour after the video session, subjective craving was already reduced after a single CBD administration. The effect persisted for 7 days after the last CBD treatment.
Interestingly, anxiety measures were also reduced after treatment, whereas no adverse effects were described. A pilot study with 24 subjects was conducted in a randomized, double-blind, placebo-controlled design to evaluate the impact of the ad hoc use of CBD in smokers, who wished to stop smoking. Pre- and post-testing for mood and craving of the participants was executed.
Craving was assessed using the Tiffany Craving Questionnaire On day 1 and 7, exhaled CO was measured to test smoking status. Sedation, depression, and anxiety were evaluated with the MRS. At day 7, the anxiety levels for placebo and CBD group did not differ. CBD did not increase depression in contrast to the selective CB1 antagonist rimonabant. CBD might weaken the attentional bias to smoking cues or could have disrupted reconsolidation, thereby destabilizing drug-related memories.
To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. Growth hormone and prolactin levels were unchanged. Compared to the healthy individuals, the cortisol levels increased less after TSST in the 32 at-risk individuals.
The CBD group showed less reduced cortisol levels but differences were not significant. Truly chronic studies with CBD are still scarce. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.
These results are supported by another study described in the review by Grotenhermen et al. CBD was administered on average with three other drugs, including clobazam The coadministration led to an alteration of blood levels of several antiepileptic drugs.
In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study. A first pilot study in healthy volunteers in by Mincis et al. Clinical chronic lasting longer than a couple of weeks studies in humans are crucial here but were mostly still lacking at the time of writing this review. They hopefully will shed light on the inconsistencies observerd in animal studies.
Chronic studies in humans may, for instance, help to test whether, for example, an anxiolytic effect always prevails after chronic CBD treatment or whether this was an artifact of using different animal models of anxiety or depression. In a 4-week open trial, CBD was tested on Parkinson's patients with psychotic symptoms.
This led to a reduction of their psychotic symptoms. Moreover, no serious side effects or cognitive and motor symptoms were reported. No adverse effects were observed and her symptoms improved. The same positive outcome was registered in another study described by Bergamaschi et al. The respective treatment was maintained for three additional weeks. This was the case for three patients in the CBD group and five patients in the amisulpride group.
CBD treatment was accompanied by a substantial increase in serum anandamide levels, which was significantly associated with clinical improvement, suggesting inhibition of anandamide deactivation via reduced FAAH activity.
In addition, the FAAH substrates palmitoylethanolamide and linoleoyl-ethanolamide both lipid mediators were also elevated in the CBD group. CBD showed less serum prolactin increase predictor of galactorrhoea and sexual dysfunction , fewer extrapyramidal symptoms measured with the Extrapyramidal Symptom Scale, and less weight gain. Moreover, electrocardiograms as well as routine blood parameters were other parameters whose effects were measured but not reported in the study.
CBD better safety profile might improve acute compliance and long-term treatment adherence. A press release by GW Pharmaceuticals of September 15th, , described 88 patients with treatment-resistant schizophrenic psychosis, treated either with CBD in addition to their regular medication or placebo. Important clinical parameters improved in the CBD group and the number of mild side effects was comparable to the placebo group. Moreover, neurological and physiological examinations were performed, which neither showed signs of CBD toxicity nor severe side effects.
The study also illustrated that CBD was well tolerated. CBD in addition to their regular epilepsy medication. Another clinical study lasting at least 3 months with children and young adults with various forms of epilepsy, who were treated with the CBD drug Epidiolex, was presented at the American Academy for Neurology in In a few cases, severe side effects occurred, but it is not clear, if these were caused by Epidiolex. The largest CBD study conducted thus far was an open-label study with Epidiolex in patients mainly children, the average age of the participants was 11 suffering from severe epilepsy, who could not be treated sufficiently with standard medication.
Ten percent of the patients reported side effects tiredness, diarrhea, and exhaustion. After extensive literature study of the available trials performed until September , CBD side effects were generally mild and infrequent.
The only exception seems to be a multicenter open-label study with a total of patients aged 1—30 years, with treatment-resistant epilepsy. This led to a reduction in seizure frequency. It is therefore difficult to put the side effect frequency into perspective.
Attributing the side effects to CBD is also not straightforward in severely sick patients. Thus, it is not possible to draw reliable conclusions on the causation of the observed side effects in this study. This rating instrument comprised the following factors: This assessment instrument analyzes adverse medication effects, including psychic, neurologic, autonomic, and other manifestations.
Using various safety outcome variables, clinical tests, and the cannabis side effect inventory, it was shown that there were no differences between the placebo group and the CBD group in the observed side effects. The occurrence of various degrees of GVHD was compared with historical data from patients, who had only received the standard treatment. This resulted in lower resistin levels compared to baseline. The hormone resistin is associated with obesity and insulin resistance.
Compared to baseline, glucose-dependent insulinotropic peptide levels were elevated after CBD treatment. This incretin hormone is produced in the proximal duodenum by K cells and has insulinotropic and pancreatic b cell preserving effects. CBD was well tolerated in the patients. However, with the comparatively low CBD concentrations used in this phasetrial, no overall improvement of glycemic control was observed. When weight and appetite were measured as part of a measurement battery for side effects, results were inconclusive.
For instance, the study mentioned above, where 23 children with Dravet syndrome were treated, increases as well as decreases in appetite and weight were observed as side effects.
However, in the safety analysis group, consisting of subjects, 10 showed decreased weight and 12 had gained weight. Both these factors were not controlled for in the reviewed studies. This review could substantiate and expand the findings of Bergamaschi et al. First, more studies researching CBD side effects after real chronic administration need to be conducted. Many so-called chronic administration studies, cited here were only a couple of weeks long.
Second, many trials were conducted with a small number of individuals only. To perform a throrough general safety evaluation, more individuals have to be recruited into future clinical trials. Third, several aspects of a toxicological evaluation of a compound such as genotoxicity studies and research evaluating CBD effect on hormones are still scarce.
Especially, chronic studies on CBD effect on, for example, genotoxicity and the immune system are still missing. Last, studies that evaluate whether CBD-drug interactions occur in clinical trials have to be performed. In conclusion, CBD safety profile is already established in a plethora of ways. However, some knowledge gaps detailed above should be closed by additional clinical trials to have a completely well-tested pharmaceutical compound.
The study was commissioned by the European Industrial Hemp Association. EIHA paid nova-Institute for the review. Iffland K, Grotenhermen F An update on safety and side effects of cannabidiol: National Center for Biotechnology Information , U. Journal List Cannabis Cannabinoid Res v. Published online Jun 1.
Find articles by Kerstin Iffland. Find articles by Franjo Grotenhermen. Author information Copyright and License information Disclaimer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This article has been cited by other articles in PMC. Relevant Preclinical Studies Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. Open in a separate window. The reality is more complex, because CBD is lipophilic and, for example, will consequently accumulate in fat tissue. These calculations were made with the intention to give the reader an impression and an approximation of the supraphysiological levels used in in vitro studies.
CBD-drug interactions Cytochrome Pcomplex enzymes This paragraph describes CBD interaction with general drug -metabolizing enzymes, such as those belonging to the cytochrome P family.
Neurological and neurospychiatric effects Anxiety and depression Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated day administration of CBD.
Psychosis and bipolar disorder Various studies on CBD and psychosis have been conducted. Addiction CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. Neuroprotection and neurogenesis There are various mechanisms underlying neuroprotection, for example, energy metabolism whose alteration has been implied in several psychiatric disorders and proper mitochondrial functioning. Immune system Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes.
Cell migration Embryogenesis CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis. Cancer Various studies have been performed to study CBD anticancer effects.
Food intake and glycemic effects Animal studies summarized by Bergamaschi et al. Genotoxicity and mutagenicity Jones et al. Acute Clinical Data Bergamaschi et al. Physiological effects In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects. Psychosis The review by Bergamaschi et al. Addiction A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: Endocrine effects and glycemic including appetite effects To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects.
That is to say, it can inhibit or activate compounds in the ECS, which in turn can impact the amount of pain you feel or limit inflammation in the brain and nervous system.
Like all supplements, CBD has certain qualities that may be of benefit to you and your circumstances, and others that may have no effect on you whatsoever. So, how can CBD help you specifically? Studies have shown that CBD can alleviate the physical and mental effects of anxiety, as well as ease the symptoms associated with depression. The compounds found within cannabis known as cannabinoids are very similar to the ones produced naturally by our bodies.
These cannabinoids have been observed to relieve the symptoms of various conditions by attaching themselves to particular receptors in the brain, thereby blocking or boosting certain signals. This can help bring calm to an otherwise stressful situation. For example, an NIH study on social anxiety disorder found that, by giving CBD to patients, they could lower anxiety levels associated with public speaking.
CBD can also potentially help lift your spirits and improve your mood, positively impacting your behavior and reducing psychological issues in conditions related to social interactions and PTSD.
Research has suggested that CBD can be effective at reducing sleep difficulties, combating the effects of insomnia, and improving the quality of sleep. Stress is often the number-one culprit when it comes to sleep disorders.
The good new is, for many people, CBD has been observed to help reduce stress, which in turn can help improve sleep quality. Furthermore, according to studies , CBD could also increase the amount an individual sleeps. A number of studies suggest that CBD can be used to effectively manage and alleviate chronic pain and inflammation. As I mentioned earlier, when consumed, the cannabinoids found in CBD attach themselves to certain receptors in your brain and immune system.
One such receptor, the CB2 receptor, helps manage pain and inflammation in your immune system. CBD can also potentially help alleviate pain associated with joint injuries sustained while exercising, headaches, and muscle soreness. When applied topically, research indicates that CBD oil may reduce the symptoms associated with a variety of skin conditions, such as acne, psoriasis, and eczema.
It can also be used as a long-lasting moisturizer, and may even reduce the appearance of lines and wrinkles. The elements found in CBD can help soften, revitalize, and regenerate tired, dry, or inflamed skin. They also increase the elasticity of the skin and the flow of blood underneath while removing dead skin cells, which could give your skin a more youthful, healthy glow.
Although CBD can be a great option for a variety of health needs, we strongly recommend that you speak with a medical professional regarding any serious illnesses, disorders, or conditions you may have. Hemp-based CBD products come in all shapes and sizes. Do you want to feel the effects quickly? Or is it more important that they come on slower and last longer? Or is it more important that they come on slower and last longer.
Are you new to CBD and want to keep it simple? Or are you comfortable using gadgets like vaporizers and e-pens? Is the strength of CBD important to you? Or are you simply dipping your toe in the water at this stage?
To work this out, you should look at the milligrams of CBD, which should be clearly listed on the product label. In fact, it should look something like this:. The milligrams of CBD are what counts. This is similar to buying fish oil supplements. Fish oil supplements contain a certain amount of total fish oil and a certain amount of DHA and EPA the important substances in this supplement.
Likewise, knowing the total milligrams of CBD rather than the total volume of oil will help you compare products of a similar price to find out which is of better value. Sometimes only a percentage amount is listed, instead of the total milligrams.
This percentage is a ratio of total CBD to total liquid volume of the product. Fortunately, most manufacturers are phasing this out in favor of just using milligrams of CBD.
CBD has maximum efficiency when used consistently, much like a daily multivitamin supplement. This effect is due to the fact that it takes a while for your body to adjust to the chemical compounds found in CBD.
Therefore, CBD should be taken consistently for at least seven to ten days to allow its full effects to work properly. Depending on your metabolism, body weight, cannabinoid tolerance, and desired effects, you may wish to start with five milligrams instead—and you can always increase your serving size once you know how CBD will affect you. As there are no psychoactive or dangerous components present in CBD, you can safely increase your serving size at any time to find the optimal concentration for you.
Remember to talk to your doctor if you have trouble finding the right amount of CBD for your circumstances, or if you have a serious ailment or disease. Interested in trying CBD for your furry friends? By and large, CBD is very simple to use. It can be taken in many different forms and used as you would a vitamin supplement or topical balm—but some CBD products can be quite tricky. For example, using CBD vape oil requires a vaporizer, something you may be unfamiliar with, and for a beginner it can be intimidating.
This will largely depend on which products you use:. Typically, the slower CBD absorbs, the longer it lasts. Likewise, if the CBD absorbs quickly, it will usually offer immediate, short-term relief.
For some people, taste is incredibly important. If taste matters to you, there are a few things worth considering:. Finally, the price of CBD should loom large in your decision-making process. The intended effects, along with the quantity, longevity, and immediacy can all impact the cost of a particular CBD product. So, you need to consider which CBD product type will work best for you and your circumstances.
For example, when does it make sense to choose a vape oil over a tincture, or an edible over a topical? Simply spray or drop onto your tongue and swish for 90 seconds before swallowing. CBD will be absorbed sublingually under the tongue at first, and then in your stomach. Effects can be felt in ten to fifteen minutes and can last between two and six hours, depending on the strength. Tinctures are an extremely versatile product, great for beginners who need to figure out how much CBD to take.
I recommend a spray tincture for its ease of use. There are numerous CBD tincture products to choose from, with different flavors and CBD strengths, and all of them are very easy to use. Tinctures trump all other types of CBD products in terms of serving size precision, as you can easily increase or decrease your serving size by the drop tinctures typically come with a precise dropper or a spray.
This terrific and tasty CBD Oil Herbal Spray Tincture from Herbal Renewals comes in a variety of flavors, including original, vanilla, and peppermint, and contains added sweeteners to make them even more enjoyable. Simply squeeze a grain-of-rice-sized portion onto your tongue and swish for 90 seconds before swallowing. The CBD will be absorbed sublingually at first, and then in your stomach. Effects can be felt in ten to fifteen minutes and last six to twelve hours, depending on the strength.
Pastes and concentrates are great if you want a strong CBD product that will last for a long time. Make no mistake, this is strong stuff. You will only need the size of a grain of rice taken once or twice daily the equivalent of roughly 4.
With that kind of serving size, the three-gram tube will last you a few months of daily use, giving you plenty of CBD goodness. This product is also available in one-gram and ten-gram tubes, along with a six-pack of ten-gram tubes. The oil is heated by an e-pen or a vaporizer until it turns from liquid to vapor. This allows you to safely inhale and absorb the CBD through your lungs.
Exhale normally and repeat three to five times. You will feel the effects almost immediately, and they can last from one to six hours, depending on the strength. Vape oil is great if you currently use or are familiar with e-pens or vaporizers, or if you want to feel the effects of CBD as quickly as possible. The design is lightweight and portable, and the CBD oil delivers a smooth and full-bodied taste when vaped. CBD topicals are CBD-infused lotions, balms, and oils that are absorbed through the skin for the localized relief of joint pain, muscle soreness, and inflammation.
In one to two hours you should start to feel the effects of the CBD, and it can last between six and twelve hours, depending on the strength. Creams, patches, and lotions all help soothe your aches from the outside and last a long time. Hemp Salve 50mg CBD. This thick, potent, and moisturizing all-natural skin-care product brings together the incredible calming properties of CBD with an impressive mix of natural extracts, essential oils, and organic, non-GMO ingredients.
And it smells amazing! These pills typically contain higher concentrations of CBD, like 15 to 25 milligrams which is more than the normal recommended serving size of two to three milligrams. They are tasteless and odorless, and effects can last for six to twelve hours. Simply place one CBD capsule in the back of your mouth, sip on water, and swallow.
The CBD will be absorbed through your stomach. The capsules are non-GMO, vegan, and kosher—perfect for specific dietary requirements.
Simply take one to two capsules per day to enjoy between 15 and 30 milligrams of high-quality CBD. Edibles are a terrific alternative to smoking or vaping CBD, and they come in many varieties and flavors, including cookies, candies, gummies, chocolates, and more.
Eat CBD edibles as you would any other piece of chocolate, gummy, or candy. The CBD will be absorbed through the stomach. You should begin to feel the effects of CBD in one to two hours, and effects can last from six to twelve hours, depending on the strength. Available in either milk or dark chocolate, it packs 60 milligrams of CBD into a gram bar, along with a host of organic ingredients. You can easily adjust your serving size by simply eating more or fewer segments until you find the right balance for you.
This portable CBD snack allows you to enjoy the benefits of CBD anywhere, anytime, without drawing the glances of strangers. CBD pet products are specially made for pets and designed to target a long list of issues. Similar to the CBD products available to you, CBD for pets can promote a sense of calm and well-being in your pets, while also relieving pain and improving quality of life.
1. LEARN THE CBD BASICS
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