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CBD’s in understanding importance the of The body metabolism

stewi
15.05.2018

Content:

  • CBD’s in understanding importance the of The body metabolism
  • Human Cannabinoid Pharmacokinetics
  • 2. Pharmacokinetics of Cannabinoids
  • Why is it important to understand how CBD is metabolized? Because if the cannabinoid is to be taken seriously as a drug for certain pathologies, then it is. Mar 1, Due to extensive Phase I metabolism, the pharmacokinetics of CBD is . The first demonstration of CB biotransformation in humans appears to be the study .. The understanding of the clinical significance of these abundant. Thus, it is important to understand cannabinoid pharmacokinetics and the the body, metabolism by the liver and extra-hepatic tissues, and elimination in the feces, . CBD may modify the effects of THC and reportedly may inhibit cytochrome.

    CBD’s in understanding importance the of The body metabolism

    After the initial distribution phase, the rate-limiting step in the metabolism of THC is its redistribution from lipid depots into blood [ 98 ]. However, later studies did not corroborate this finding [ 8 ][ 91 ]. More than 30 metabolites of CBD were identified in urine, with hydroxylation of the 7-Me group and subsequent oxidation to the corresponding carboxylic acid as the main metabolic route, in analogy to THC [ ].

    Other tissues, including brain, intestine, and lung, may contribute to the metabolism of THC, although alternate hydroxylation pathways may be more prominent [ 86 ][ - ]. An extrahepatic metabolic site should be suspected whenever total body clearance exceeds blood flow to the liver, or when severe liver dysfunction does not affect metabolic clearance [ ]. Within the brain, higher concentrations of CYP enzymes are found in the brain stem and cerebellum [ ].

    Metabolism of THC by fresh biopsies of human intestinal mucosa yielded polar hydroxylated metabolites that directly correlated with time and amount of intestinal tissue [ ]. In a study of the metabolism of THC in the brains of mice, rats, guinea pigs, and rabbits, Watanabe et al.

    Hydroxylation of C 4 of the pentyl side chain produced the most common THC metabolite in the brains of these animals, similar to THC metabolites produced in the lung.

    These metabolites are pharmacologically active, but their relative activity is unknown. CBD Metabolism is similar to that of THC, with primary oxidation of C 9 to the alcohol and carboxylic acid [ 8 ][ ], as well as side-chain oxidation [ 88 ][ ]. Co-administration of CBD did not significantly affect the total clearance, volume of distribution, and terminal elimination half-lives of THC metabolites.

    Numerous acidic metabolites are found in the urine, many of which are conjugated with glucuronic acid to increase their water solubility. Another common problem with studying the pharmacokinetics of cannabinoids in humans is the need for highly sensitive procedures to measure low cannabinoid concentrations in the terminal phase of excretion, and the requirement for monitoring plasma concentrations over an extended period to adequately determine cannabinoid half-lives.

    The slow release of THC from lipid-storage compartments and significant enterohepatic circulation contribute to a long terminal half-life of THC in plasma, reported to be greater than 4. Isotopically labeled THC and sensitive analytical procedures were used to obtain this drug half-life. No significant pharmacokinetic differences between chronic and occasional users have been substantiated [ ]. An average of This represents an average of only 0.

    Prior to harvesting, cannabis plant material contains little active THC. When smoked, THC carboxylic acids spontaneously decarboxylate to produce THC, with nearly complete conversion upon heating. Pyrolysis of THC during smoking destroys additional drug. Drug availability is further reduced by loss of drug in the side-stream smoke and drug remaining in the unsmoked cigarette butt. These factors contribute to high variability in drug delivery by the smoked route.

    It is estimated that the systemic availability of smoked THC is ca. THC Bioavailability is reduced due to the combined effect of these factors; the actual available dose is much lower than the amount of THC and THC precursor present in the cigarette.

    Another factor affecting the low amount of recovered dose is measurement of a single metabolite. Following controlled oral administration of THC in dronabinol or hemp oil, urinary cannabinoid excretion was characterized in 4, urine specimens [ ][ ].

    THC Doses of 0. The two high doses 7. The availability of cannabinoid-containing foodstuffs, cannabinoid-based therapeutics, and continued abuse of oral cannabis require scientific data for the accurate interpretation of cannabinoid tests. These data demonstrate that it is possible, but unlikely, for a urine specimen to test positive at the federally mandated cannabinoid cutoffs, following manufacturer's dosing recommendations for the ingestion of hemp oils of low THC concentration.

    An average of only 2. Specimen preparation for cannabinoid testing frequently includes a hydrolysis step to free cannabinoids from their glucuronide conjugates. Alkaline hydrolysis appears to efficiently hydrolyze the ester glucuronide linkage. Mean THC concentrations in urine specimens from seven subjects, collected after each had smoked a single marijuana cigarette 3. Using a modified analytical method with E.

    We found that OH-THC may be excreted in the urine of chronic cannabis users for a much longer period of time, beyond the period of pharmacodynamic effects and performance impairment. Compared to other drugs of abuse, analysis of cannabinoids presents some difficult challenges. Complex specimen matrices, i. Care must be taken to avoid low recoveries of cannabinoids due to their high affinity to glass and plastic containers, and to alternate matrix-collection devices [ - ].

    Whole-blood cannabinoid concentrations are approximately one-half the concentrations found in plasma specimens, due to the low partition coefficient of drug into erythrocytes [ 96 ][ ][ ]. THC Detection times in plasma of 3. In the latter study, the terminal half-life of THC in plasma was determined to be ca. This inactive metabolite was detected in the plasma of all subjects by 8 min after the start of smoking.

    The half-life of the rapid-distribution phase of THC was estimated to be 55 min over this short sampling interval. The relative percentages of free and conjugated cannabinoids in plasma after different routes of drug administration are unclear.

    Even the efficacy of alkaline- and enzymatic-hydrolysis procedures to release analytes from their conjugates is not fully understood [ 24 ][ 77 ][ 93 ][ ][ ][ ][ - ]. In general, the concentrations of conjugate are believed to be lower in plasma, following intravenous or smoked administration, but may be of much greater magnitude after oral intake.

    There is no indication that the glucuronide conjugates are active, although supporting data are lacking. Peak concentrations and time-to-peak concentrations varied sometimes considerably between subjects. Most THC plasma data have been collected following acute exposure; less is known of plasma THC concentrations in frequent users. No difference in terminal half-life in frequent or infrequent users was observed.

    There continues to be controversy in the interpretation of cannabinoid results from blood analysis, some general concepts having wide support. It is well-established that plasma THC concentrations begin to decline prior to the time of peak effects, although it has been shown that THC effects appear rapidly after initiation of smoking [ 15 ]. Individual drug concentrations and ratios of cannabinoid metabolite to parent drug concentration have been suggested as potentially useful indicators of recent drug use [ 24 ][ ].

    This is in agreement with results reported by Mason and McBay [ 96 ], and those by Huestis et al. Measurement of cannabinoid analytes with short time courses of detection e.

    This correlates well with the suggested concentration of plasma THC, due to the fact that THC in hemolyzed blood is approximately one-half the concentration of plasma THC [ ]. Accurate prediction of the time of cannabis exposure would provide valuable information in establishing the role of cannabis as a contributing factor to events under investigation.

    Two mathematical models for the prediction of time of cannabis use from the analysis of a single plasma specimen for cannabinoids were developed [ ]. More recently, the validation of these predictive models was extended to include estimation of time of use after multiple doses of THC and at low THC concentrations 0.

    Some 38 cannabis users each smoked a cigarette containing 2. The predicted times of cannabis smoking, based on each model, were then compared to the actual smoking times. The most accurate approach applied a combination of models I and II. All time estimates were correct for 77 plasma specimens, with THC concentrations of 0.

    The models provide an objective, validated method for assessing the contribution of cannabis to accidents or clinical symptoms. These models also appeared to be valuable when applied to the small amount of data from published studies of oral ingestion available at the time.

    Additional studies were performed to determine if the predictive models could estimate last usage after multiple oral doses, a route of administration more popular with the advent of cannabis therapies. Each of twelve subjects in one group received a single oral dose of dronabinol 10 mg of synthetic THC. In another protocol, six subjects received four different oral daily doses, divided into thirds, and administered with meals for five consecutive days.

    There was a d washout period between each dosing regimen. The daily doses were 0. The actual times between ingestion of THC and blood collection spanned 0. These results provide further evidence of the usefulness of the predictive models in estimating the time of last oral THC ingestion following single or multiple doses. Detection of cannabinoids in urine is indicative of prior cannabis exposure, but the long excretion half-life of THC-COOH in the body, especially in chronic cannabis users, makes it difficult to predict the timing of past drug use.

    This individual had used cannabis heavily for more than ten years. However, a naive user's urine may be found negative by immunoassay after only a few hours following smoking of a single cannabis cigarette [ ]. Assay cutoff concentrations and the sensitivity and specificity of the immunoassay affect drug-detection times. A positive urine test for cannabinoids indicates only that drug exposure has occurred.

    The result does not provide information on the route of administration, the amount of drug exposure, when drug exposure occurred, or the degree of impairment. THC-COOH concentration in the first specimen after smoking is indicative of how rapidly the metabolite can appear in urine.

    Thus, THC-COOH concentrations in the first urine specimen are dependent upon the relative potency of the cigarette, the elapsed time following drug administration, smoking efficiency, and individual differences in drug metabolism and excretion. The mean times of peak urine concentration were 7. Although peak concentrations appeared to be dose-related, there was a twelvefold variation between individuals.

    Drug detection time, or the duration of time after drug administration in which the urine of an individual tests positive for cannabinoids, is an important factor in the interpretation of urine drug results. Detection time is dependent on pharmacological factors e.

    Mean detection times in urine following smoking vary considerably between subjects, even in controlled smoking studies, where cannabis dosing is standardized and smoking is computer-paced. During the terminal elimination phase, consecutive urine specimens may fluctuate between positive and negative, as THC-COOH concentrations approach the cutoff concentration.

    It may be important in drug-treatment settings or in clinical trials to differentiate between new drug use and residual excretion of previously used cannabinoids. After smoking a cigarette containing 1. This had the effect of producing much longer detection times for the last positive specimen. Normalization of cannabinoid concentration to urine creatinine concentration aids in the differentiation of new from prior cannabis use, and reduces the variability of drug measurement due to urine dilution.

    Due to the long half-life of drug in the body, especially in chronic cannabis users, toxicologists and practitioners are frequently asked to determine if a positive urine test represents a new episode of drug use or represents continued excretion of residual drug. Random urine specimens contain varying amounts of creatinine, depending on the degree of concentration of the urine. Hawks first suggested creatinine normalization of urine test results to account for variations in urine volume in the bladder [ ].

    Whereas urine volume is highly variable due to changes in liquid, salt, and protein intake, exercise, and age, creatinine excretion is much more stable. If the increase is greater than or equal to the threshold selected, then new use is predicted. This approach has received wide attention for potential use in treatment and employee-assistance programs, but there was limited evaluation of the usefulness of this ratio under controlled dosing conditions.

    Huestis and Cone conducted a controlled clinical study of the excretion profile of creatinine and cannabinoid metabolites in a group of six cannabis users, who smoked two different doses of cannabis, separated by weekly intervals [ ]. As seen in Fig. Being able to differentiate new cannabis use from residual THC-COOH excretion in urine would be highly useful for drug treatment, criminal justice, and employee assistance drug testing programs. The ratio times of the creatinine normalized later specimen divided by the creatinine normalized earlier specimen were evaluated for determining the best ratio to predict new cannabis use.

    The most accurate ratio To further substantiate the validity of the derived ROC curve, urine-cannabinoid-metabolite and creatinine data from another controlled clinical trial that specifically addressed water dilution as a means of specimen adulteration were evaluated [ ]. Sensitivity, specificity, accuracy, and false positives and negatives were These data indicate that selection of a threshold to evaluate sequential creatinine-normalized urine drug concentrations can improve the ability to distinguish residual excretion from new drug usage.

    Cannabinoids were detectable for 93 d after cessation of smoking, with a decreasing ratio of cannabinoids to creatinine over time. An excretion half-life of 32 d was determined.

    When cannabinoid concentrations had not been normalized to creatinine concentrations, a number of false positive indications of new drug use would have occurred. Within this range, cannabinoid excretion is more variable, most likely based on the slow and variable release of stored THC from fat tissue.

    The factors governing release of THC stores are not known. Additional research is being performed to attempt to determine appropriate ratio cutoffs for reliably predicting new drug use in heavy, chronic users. Oral fluid also is a suitable specimen for monitoring cannabinoid exposure, and is being evaluated for driving under the influence of drugs, drug treatment, workplace drug testing, and for clinical trials [ - ].

    The oral mucosa is exposed to high concentrations of THC during smoking, and serves as the source of THC found in oral fluid. Only minor amounts of drug and metabolites diffuse from the plasma into oral fluid [ ]. Following intravenous administration of radiolabeled THC, no radioactivity could be demonstrated in oral fluid [ ]. Oral fluid collected with the Salivette collection device was positive for THC in 14 of these 22 participants.

    Several hours after smoking, the oral mucosa serves as a depot for release of THC into the oral fluid. In addition, as detection limits continue to decrease with the development of new analytical instrumentation, it may be possible to measure low concentrations of THC-COOH in oral fluid.

    Detection times of cannabinoids in oral fluid are shorter than in urine, and more indicative of recent cannabis use [ ][ ]. Oral-fluid THC concentrations temporally correlate with plasma cannabinoid concentrations and behavioral and physiological effects, but wide intra- and inter-individual variation precludes the use of oral-fluid concentrations as indicators of drug impairment [ ][ ].

    THC may be detected at low concentrations by radioimmunoassay for up to 24 h after use. After these times, occasional positive oral-fluid results were interspersed with negative tests for up to 34 h. They suggested that the ease and non-invasiveness of sample collection made oral fluid a useful alternative matrix for detection of recent cannabis use.

    Oral-fluid samples also are being evaluated in the European Union's Roadside Testing Assessment ROSITA project to reduce the number of individuals driving under the influence of drugs and to improve road safety.

    The ease and non-invasiveness of oral-fluid collection, reduced hazards in specimen handling and testing, and shorter detection window are attractive attributes to the use of this specimen for identifying the presence of potentially performance-impairing drugs. They determined that, with a limit of quantification of 0.

    As mentioned above, oral-fluid specimens tested positive for up to 34 h. Positive oral-fluid cannabinoid tests were not obtained more than 2 h after last use, suggesting that much lower cutoff concentrations were needed to improve sensitivity. Detection of cannabinoids in oral fluid is a rapidly developing field; however, there are many scientific issues to resolve. One of the most important is the degree of absorption of the drug to oral-fluid collection devices. Recently, there has been renewed interest in oral-fluid drug testing for programs associated with drug treatment, workplace, and driving under the influence of drugs.

    Small and inconsistent specimen volume collection, poor extraction of cannabinoids from the collection device, low analyte concentrations for cannabinoids, and the potential for external contamination from environmental smoke are limitations to this monitoring method. Recently, independent evaluations of the extraction of cannabinoids from the collection device [ - ] and measurement of oral-fluid THC-COOH in concentrations as low as picograms per milliliter appear to adequately address these potential problems.

    The extraction efficiency of the buffer was reported to be between Specimens collected almost immediately after smoking cannabis, i. Some 95 specimens This limitation has curtailed the use of oral-fluid testing to monitor cannabis use. First, oral-fluid collection devices were contaminated when opened within the smoke-filled car. When the specimens were collected outside of the car, immediately following smoking, specimens from passive smokers were negative.

    Environmental cannabis smoke can contaminate collection devices, unless specimens are collected outside the area of smoke contamination. To date, there are no published data on the excretion of cannabinoids in sweat following controlled THC administration, although our laboratory at NIH is conducting such research.

    Sweat testing is being applied to monitor cannabis use in drug treatment, criminal justice, workplace drug testing, and clinical studies [ ][ ].

    In , Balabanova and Schneider used radioimmunoassay to detect cannabinoids in apocrine sweat [ ]. Generally, the patch is worn for 7 d, and then exchanged for a new patch once each week during visits to the treatment clinic or parole officer. Theoretically, this permits constant monitoring of drug use throughout the week, extending the window of drug detection and improving test sensitivity.

    As with oral-fluid testing, this is a developing analytical technique, with much to be learned about the pharmacokinetics of cannabinoid excretion in sweat, potential re-absorption of THC by the skin, possible degradation of THC on the patch, and adsorption of THC onto the patch-collection device.

    Understanding the pharmacokinetics of THC excretion also is important for the interpretation of hair cannabinoid tests, as sweat has been shown to contribute to the amount of drug found in hair see below. Several investigators have evaluated the sensitivity and specificity of different screening assays for detecting cannabinoids in sweat [ ][ ].

    The same investigators also evaluated forehead swipes with cosmetic pads for monitoring cannabinoids in sweat from individuals suspected of driving under the influence of drugs [ ].

    There are multiple mechanisms for the incorporation of cannabinoids in hair. THC and its metabolites may be incorporated into the hair bulb that is surrounded by capillaries.

    Drug may also diffuse into hair from sebum secreted onto the hair shaft, and from sweat excreted onto the skin surface. Drug may also be incorporated into hair from the environment.

    Cannabis is primarily smoked, providing an opportunity for environmental contamination of hair with THC in cannabis smoke. Basic drugs such as cocaine and methamphetamine concentrate in hair due to ionic bonding to melanin, the pigment in hair that determines hair color. The more neutral and lipophilic THC is not strongly bound to melanin, resulting in much lower concentrations of THC in hair as compared to other drugs of abuse. An advantage of measuring THC-COOH in hair is that this compound is not present in cannabis smoke, avoiding the issue of passive exposure from the environment.

    Analysis of cannabinoids in hair is challenging due to the high analytical sensitivity required. It is difficult to conduct controlled cannabinoid-administration studies on the disposition of cannabinoids in hair because of the inability to differentiate administered drug from previously self-administered cannabis.

    If isotopically labeled drug were administered, it would be possible to identify newly administered drug in hair. There are advantages to monitoring drug use with hair testing, including a wide window of drug detection, a less invasive specimen-collection procedure, and the ability to collect a second specimen at a later time. However, one of the weakest aspects of testing for cannabinoids in hair is the low sensitivity of drug detection in this alternate matrix.

    In the only controlled cannabinoid dosing study published to date, Huestis et al. Hair specimens were collected from each subject at the time of admittance to a closed research unit, following smoking of two cigarettes containing 2.

    Pre- and post-dose detection rates did not differ statistically. Therefore, all 53 specimens were considered as one group. For specimens with detectable cannabinoids, concentrations ranged from 3. All participants showed positive urine cannabinoid tests at the time of hair collection. An understanding of human cannabinoid pharmacokinetics is important for the development and monitoring of new therapeutic medications and to the interpretation of cannabinoid test results in a wide variety of biological matrices, including blood, plasma, urine, oral fluid, sweat, and hair.

    With the advent of new preparations containing THC, CBD, and other cannabinoids, and new administration routes, additional research is needed.

    Also, controlled drug-administration studies that provide the scientific database for interpreting cannabinoid concentrations in biological fluids and tissues are increasingly difficult to conduct due to safety and ethical concerns, and because of the high costs of performing human research.

    However, these data are essential for appropriate application of pharmacotherapies, and for drug testing in treatment, workplace, and forensic cases. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jun 2. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Chem Biodivers.

    See other articles in PMC that cite the published article. Introduction A multitude of roles for the endogenous cannabinoid system has been proposed by recent research efforts. Open in a separate window. Pharmacokinetics of Cannabinoids 2. Smoking Route of drug administration and drug formulation determine the rate of drug absorption. Oral There are fewer studies on the disposition of THC and its metabolites after oral administration of cannabis as compared to the smoked route.

    Oromucosal Due to the chemical complexity of cannabis plant material compared to synthetic THC, extracts of cannabis that capture the full range of cannabinoids are being explored as therapeutic medications. Rectal Several different suppository formulations were evaluated in monkeys to determine the matrix that maximizes bioavailability and reduces first-pass metabolism [ 40 ][ 41 ]; THC-hemisuccinate provided the highest bioavailability of Transcutaneous Another route of cannabinoid exposure that avoids first-pass metabolism and improves THC bioavailability is topical administration [ 43 ].

    Intravenous Although THC is not abused by the intravenous route, pharmacodynamic and pharmacokinetic cannabinoid research has employed this technique.

    Cannabidiol Absorption Cannabidiol CBD is a natural, non-psychoactive [ 49 ][ 50 ] constituent of Cannabis sativa , but possesses pharmacological activity, which is explored for therapeutic applications.

    Distribution THC Plasma concentrations decrease rapidly after the end of smoking due to rapid distribution into tissues and metabolism in the liver. Extrahepatic Metabolism Other tissues, including brain, intestine, and lung, may contribute to the metabolism of THC, although alternate hydroxylation pathways may be more prominent [ 86 ][ - ]. Metabolism of Cannabidiol CBD Metabolism is similar to that of THC, with primary oxidation of C 9 to the alcohol and carboxylic acid [ 8 ][ ], as well as side-chain oxidation [ 88 ][ ].

    Terminal Elimination Half-Lives of THC-COOH Another common problem with studying the pharmacokinetics of cannabinoids in humans is the need for highly sensitive procedures to measure low cannabinoid concentrations in the terminal phase of excretion, and the requirement for monitoring plasma concentrations over an extended period to adequately determine cannabinoid half-lives. Cannabinoid—Glucuronide Conjugates Specimen preparation for cannabinoid testing frequently includes a hydrolysis step to free cannabinoids from their glucuronide conjugates.

    Interpretation of Cannabinoid Concentrations in Biological Fluids 3. Plasma Concentrations Compared to other drugs of abuse, analysis of cannabinoids presents some difficult challenges.

    Prediction Models for Estimation of Cannabis Exposure There continues to be controversy in the interpretation of cannabinoid results from blood analysis, some general concepts having wide support. Urine Concentrations Detection of cannabinoids in urine is indicative of prior cannabis exposure, but the long excretion half-life of THC-COOH in the body, especially in chronic cannabis users, makes it difficult to predict the timing of past drug use.

    THC-COOH Detection Windows in Urine Drug detection time, or the duration of time after drug administration in which the urine of an individual tests positive for cannabinoids, is an important factor in the interpretation of urine drug results.

    Normalization of Cannabinoid Urine Concentrations to Urine Creatinine Concentrations Normalization of cannabinoid concentration to urine creatinine concentration aids in the differentiation of new from prior cannabis use, and reduces the variability of drug measurement due to urine dilution.

    Oral-Fluid Testing Oral fluid also is a suitable specimen for monitoring cannabinoid exposure, and is being evaluated for driving under the influence of drugs, drug treatment, workplace drug testing, and for clinical trials [ - ]. Cannabinoids in Sweat To date, there are no published data on the excretion of cannabinoids in sweat following controlled THC administration, although our laboratory at NIH is conducting such research.

    Cannabinoids in Hair There are multiple mechanisms for the incorporation of cannabinoids in hair. The CB2 receptor is also stimulated by plant-based cannabinoids.

    Reduced Risk of Cancer Could cannabidiol help prevent tumors and other cancers before they grow? A study showed that animals treated with CBD were significantly less likely to develop colon cancer after being induced with carcinogens in a laboratory. Continuing research is focused on the best ratio of CBD to THC and the most effective dose level in cancer prevention and treatment. Cannabinoids are neuroprotective, meaning that they help maintain and regulate brain health.

    The effects appear to be related to several actions they have on the brain, including the removal of damaged cells and the improved efficiency of mitochondria. Extra glutamate, which stimulates nerve cells in the brain to fire, causes cells to become over-stimulated, ultimately leading to cell damage or death.

    Thus, cannabinoids help protect brain cells from damage, keeping the organ healthy and functioning properly. CBD has also been shown to have an anti-inflammatory effect on the brain. As the brain ages, the creation of new neurons slows down significantly. In order to maintain brain health and prevent degenerative diseases, new cells need to be continuously created. A study showed that low doses of CBD- and THC-like cannabinoids encouraged the creation of new nerve cells in animal models, even in aging brains.

    Cannabinoids are facilitative of the process of bone metabolism—the cycle in which old bone material is replaced by new at a rate of about 10 percent per year, crucial to maintaining strong, healthy bones over time. CBD in particular has been shown to block an enzyme that destroys bone-building compounds in the body, reducing the risk of age-related bone diseases like osteoporosis and osteoarthritis. In both of those diseases, the body is no longer creating new bone and cartilage cells.

    CBD helps spur the process of new bone-cell formation, which is why it has been found to speed the healing of broken bones and, due to a stronger fracture callus, decrease the likelihood of re-fracturing the bone bones are 35—50 percent stronger than those of non-treated subjects.

    Protects and Heals the Skin The skin has the highest amount and concentration of CB2 receptors in the body. When applied topically as an infused lotion, serum, oil, or salve, the antioxidant a more powerful antioxidant than vitamins E and C [] in CBD oil has many benefits and can repair damage from free radicals like UV rays and environmental pollutants. Cannabinoid receptors can be found in the skin and seem to be connected to the regulation of oil production in the sebaceous glands.

    In fact, historical documents show that cannabis preparations have been used for wound healing in both animals and people in a range of cultures spanning the globe and going back thousands of years.

    The use of concentrated cannabis and CBD oils to benefit and treat skin cancer is gaining popularity with a number of well-documented cases of people curing both melanoma and carcinoma-type skin cancers with the topical application of CBD and THC products. Best known is the case of Rick Simpson, who cured his basal cell carcinoma with cannabis oil and now has a widely distributed line of products.

    Cannabis applied topically is not psychoactive. Cannabinoids have been proven to have an anti-inflammatory effect in numerous studies. CBD engages with the endocannabinoid system in many organs throughout the body, helping to reduce inflammation systemically. The therapeutic potential is impressively wide-ranging, as inflammation is involved in a broad spectrum of diseases. The oral use of cannabis and CBD for anxiety appears in a Vedic text dated around BCE,[] and it is one of the most common uses of the plant across various cultures.

    While THC can increase anxiety in some patients, it lowers it in others. However, CBD effects have been shown to consistently reduce anxiety when present in higher concentrations in the cannabis plant. On its own, CBD has been shown in a number of animal and human studies to lessen anxiety.

    The stress-reducing effect appears to be related to activity in both the limbic and paralimbic brain areas. A research review assessed a number of international studies and concluded that CBD has been shown to reduce anxiety , and in particular social anxiety, in multiple studies and called for more clinical trials.

    It is suggested that patients work with a health care practitioner experienced in recommending cannabidiol or medicinal cannabis so that dosage and delivery methods can be developed and fine-tuned on an individual basis. At the same time, educated and aware patients can be their own highly informed health consultants. For anxiety, CBD products with a ratio of High-CBD cannabinoids can be very effective in reducing chronic anxiety, treating temporary stress, and protecting the body from the physiological effects of both.

    Varieties high in linalool, a terpene shared with lavender, are known to be effective for relieving anxiety. Always start with the micro dose to test sensitivity and go up as needed within the dosing range, before going to the next, until symptoms subside. The micro to standard dose is usually recommended to treat stress and anxiety with CBD.

    For relief of immediate symptoms, as in a panic or anxiety attack, vaporizing or smoking work well. The medication lasts one to three hours, whereas most ingested products, including CBD oil, take thirty to sixty minutes before taking effect and last six to eight hours. Herbal vaporizers that use the whole plant are also an effective delivery method. Sublingual sprays or tinctures taken as liquid drops take effect quickly and last longer than inhaled products.

    The Cannabis Health Index CHI is an evidence-based scoring system for cannabis in general, not just CBD oil effects and its effectiveness on various health issues based on currently available research data. Using this rubric and based on eleven studies, cannabis rated in the possible-to-probable range of efficacy for treatment of anxiety. Elixinol Organic High Potency CBD Capsules Elixinol offers a highly concentrated, high-potency, organic whole-hemp plant CBD oil , which is naturally extracted with carbon dioxide and free of all synthetics and chemicals.

    Whole-hemp plant extracts contain synergistic compounds that are believed to enhance the effectiveness and benefits of CBD. Clinical depression is a serious mood disorder characterized by persistent sadness and loss of interest, sometimes leading to decreased appetite and energy and suicidal thoughts. Commonly used pharmaceuticals for depression often target serotonin, a chemical messenger that is believed to act as a mood stabilizer.

    The neural network of the endocannabinoid system works similarly to the way that serotonin, dopamine, and other systems do, and, according to some research, cannabinoids have an effect on serotonin levels. Whereas a low dose of THC increases serotonin, high doses cause a decrease that could worsen the condition. CBD products with a ratio of Specifically, products made with Valentine X or Electra 4 are more energizing, helping relieve depression.

    When low energy is an issue, sativa or other stimulating strains can be helpful for improving energy and focus when THC can be tolerated. Varieties that are high in the terpene limonene are recommended for mood elevation.

    Always start with the micro dose to test sensitivity and go up as needed within the dosing range before going to the next, until symptoms subside. The micro to standard dose is usually recommended to treat depression. Vaporized or smoked cannabis is recommended for relief of immediate symptoms, or a boost in dosage, and it can also be useful for sleep issues. The Cannabis Health Index CHI is an evidence-based scoring system for cannabis in general, not just CBD effects and its effectiveness on various health issues based on currently available research data.

    Using this rubric and based on twenty-one studies, cannabis rated in the possible-to-probable range of efficacy for treatment of depression. Research in called for clinical trials to look into the effectiveness of cannabinoids for bipolar disorder manic depression.

    It also works on the GABA-glutamate system and the hypothalamic-pituitary-adrenal axis. Its main role is restoring balance through inhibition when levels are too high and enhancement when they are too low.

    This is the most likely reason phytocannabinoids in general and CBD specifically are able to regulate depression and anxiety.

    The scientific inquiry into cannabis over the past several decades has confirmed that it is an effective and safe analgesic for many kinds of pain. Of all the reasons that people use CBD today, pain is the most common. The same can be said of cannabis in general. In the United States, over seventy million people suffer from chronic pain, which is defined as experiencing over one hundred days per year of pain.

    Physicians differentiate between neuropathic usually chronic and nociceptive pains usually time-limited , and cannabis works on most neuropathic and many nociceptive types of pain. A number of studies have demonstrated that the endocannabinoid system is both centrally and peripherally involved in the processing of pain signals.

    Cannabinoids can be used along with opioid medications, and a number of studies have demonstrated that they can reduce the amount of opioids needed, lessen the buildup of tolerance, and reduce the severity of withdrawal. It is suggested that patients work with a health care practitioner experienced in recommending CBD oil or medicinal cannabis so that dosage and delivery methods can be developed and fine-tuned on an individual basis. Oral CBD products with a ratio of Most discussions of treating pain with CBD suggest that finding the right dosage is critical.

    Always start with the micro dose to test sensitivity and go up as needed within the dosing range by body weight until symptoms subside. If CBD-dominant products alone are not enough to treat a particular case, products with a higher ratio of THC are sometimes recommended to better manage pain.

    For day use, more stimulating, sativa varieties with higher concentrations of myrcene could be added to the formula. In general, for pain, and especially for evening and nighttime, indica strains are favored for their relaxing, sedative effect.

    A person without experience with THC should use caution and titrate slowly up to higher doses. Research as well as patient feedback have indicated that, in general, a ratio of 4: THC is the most effective for both neuropathic and inflammatory pain.

    Each individual is different, however—for some, a 1:

    Human Cannabinoid Pharmacokinetics

    At sufficient dosages, CBD will temporarily deactivate cytochrome P enzymes , This means that the body's metabolism of THC can make it more potent. Jun 26, How do we get the most effectiveness out of our CBD? These are crucial questions that can all be addressed by understanding what bioavailability means . of CBD in the product in question, which leads us to a very important While this method, by definition, delivers % of CBD into the body. metabolism whereby lower doses of CBD are more therapeutic than THC. To understand the mechanism of action pursued by cannabinoids, it is imperative to explore the Endogeneous cannabinoid system (ECS) in the body that is responsible . Cannabidiol: pharmacology and potential therapeutic role in epilepsy and.

    2. Pharmacokinetics of Cannabinoids



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