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Cannabinol CBN; Figure 1 , much of which is thought to be formed from THC during the storage of harvested cannabis, was the first of the plant cannabinoids phytocannabinoids to be isolated, from a red oil extract of cannabis, at the end of the 19th century. Its structure was elucidated in the early s by R. Cahn, and its chemical synthesis first achieved in in the laboratories of R. Adams in the U. Among the first pharmacological observations to have been made with individual cannabinoids are those of Loewe , who noted that THC and synhexyl, but not CBD, induced catalepsy in mice, that CBN induced catalepsy in mice but only at high doses that were also lethal, that THC and synhexyl had a central excitant action, particularly in rabbits and mice, and that THC and synhexyl but not CBN or CBD elicited corneal areflexia in rabbits.
These were, of course, some of the first indications that cannabinoids exhibit marked structure—activity relationships. Since it is now generally accepted that the ability of cannabinoids to produce signs of catalepsy in rodents correlates well with their psychotropic activity see below , these results also provided early evidence that CBN has much lower potency than THC as a psychotropic agent, and that CBD lacks psychotropic activity altogether.
An even earlier experiment, carried out by Haagen-Smit et al. Another finding made at this time, that sleep induced in mice by an unnamed barbiturate can be prolonged by CBD, although not by higher doses of CBN or THC, is also attributable to Loewe In the mids and early s research into the pharmacology of cannabinoids increased markedly.
This was mainly in response to the widespread use of cannabis as a recreational drug in the U. In contrast, there was less interest in the therapeutic potential of cannabinoids even though tincture of cannabis was then still a licensed medicine in the U. An important prerequisite for seeking out the modes of action of any drug is the availability of quantitative bioassays.
The possibility of using rats or mice instead of dogs or monkeys was also explored and this approach led to the development of several new in vivo bioassays. Eventually, in vitro assays for cannabinoids were also developed and it was two of these in particular, a bioassay that measures adenylate cyclase activity and a radioligand binding assay, that provided conclusive evidence for the existence of the cannabinoid CB 1 receptor. In the mids, two groundbreaking findings were made in Allyn Howlett's laboratory at St Louis University that provided conclusive evidence that cannabinoid receptors do indeed exist reviewed in Howlett, The first of these findings owed much to advances that were taking place at that time in our understanding of signalling by G-protein-coupled receptors and was facilitated by the development by Pfizer of several novel potent cannabinoids.
The second major advance in Allyn Howlett's laboratory was made in collaboration with Bill Devane in reviewed in Howlett, This was made possible firstly, by the availability of a then relatively new technique that allowed the presence of the recognition sites of receptors to be detected using a radiolabelled ligand, and secondly, by labelling the Pfizer cannabinoid, CP, with tritium.
The results obtained with [ 3 H]-CP provided evidence for the presence of high-affinity binding sites for this ligand in rat brain membranes. Since the discovery of CB 1 and CB 2 receptors, a great deal has become known about how these receptors signal and about their roles reviewed in Howlett et al.
CB 1 receptors are found predominantly but not exclusively at central and peripheral nerve terminals where they mediate inhibition of transmitter release reviewed in Pertwee, ; Howlett et al. Their distribution pattern within the central nervous system accounts for several characteristic effects of CB 1 receptor agonists, including their ability to produce hypokinesia and catalepsy and to induce signs of analgesia in both animals and man reviewed in Howlett et al.
CB 2 receptors occur mainly on immune cells, likely roles of these receptors including modulation of cytokine release and of immune cell migration. Although often regarded as peripheral receptors, CB 2 receptors have been detected in the central nervous system, for example, on microglial cells reviewed in Howlett et al.
The discovery of cannabinoid receptors prompted the development of a number of in vitro bioassays that could be used to monitor the activation or blockade of these receptors reviewed in Pertwee, , b ; Howlett et al.
Others, performed with isolated nerve-smooth muscle preparations such as the mouse vas deferens and the myenteric plexus longitudinal muscle MPLM preparation of guinea-pig small intestine, exploit the ability of neuronal CB 1 receptors to mediate a concentration-related inhibition of the electrically evoked release of contractile transmitters, the measured response being the decrease in smooth muscle contractions that results from this inhibition of transmitter release.
However, the mouse isolated vas deferens was not used for this purpose until the s, initially in the U. One obvious need at this time was for strategies that could be used to establish whether or not a particular effect of a cannabinoid was cannabinoid receptor-mediated.
However, in the early s when neither selective antagonists nor transgenic mice were available, other strategies were devised reviewed in Howlett et al. For the in vivo bioassay of cannabinoids, one of these was to exploit the apparent ability of animals to discriminate between the subjective effects of psychotropic cannabinoids and those of noncannabinoids or of cannabinoids that lack psychotropic activity. Another in vivo strategy, devised in Billy Martin's laboratory at Virginia Commonwealth University, was to compare the ability of a test compound to produce four effects in a group of mice: One or other of these effects can be produced by a wide range of noncannabinoids.
Consequently, at least some degree of selectivity can be achieved by subjecting animals to all four tests. One of the first in vitro strategies used to distinguish cannabinoid receptor agonists from other ligands was to perform bioassays either with cells that had been transfected with CB 1 or CB 2 receptors or with membranes obtained from these cells. For validating a particular bioassay, it also proved helpful to establish whether a correlation existed between the potencies exhibited by a set of cannabinoids or by a pair of enantiomeric cannabinoids for displacing a radioligand from CB 1 binding sites and the pharmacological potencies shown by the same compounds in the bioassay under investigation.
Once cannabinoid receptors had been discovered, it became important to establish whether mammalian tissues also produce a cannabinoid receptor agonist or whether these receptors are targets only for plant cannabinoids and their synthetic cousins. The search for an endogenous cannabinoid had begun. One likely candidate was isolated from pig brain by Bill Devane, who was now working in Jerusalem with Raphael Mechoulam Devane et al. To establish whether this endogenous ligand would activate CB 1 receptors, a few micrograms were sent to Aberdeen where it was found that this test material did indeed share the ability of CB 1 receptor agonists to inhibit electrically evoked contractions of the mouse isolated vas deferens Devane et al.
Moreover, it produced this inhibitory effect in a naloxone-insensitive manner and with an EC 50 value that approximated to its CB 1 K i value, a finding that is in line with its subsequent classification as a CB 1 receptor partial agonist reviewed in Howlett et al. Evidence that anandamide was acting through CB 1 receptors in the vas deferens was initially obtained by demonstrating that tissues rendered tolerant to established CB 1 receptor agonists but not to noncannabinoid inhibitors of electrically evoked contractions such as clonidine or opioid receptor agonists reviewed in Pertwee, also exhibit tolerance to anandamide Pertwee et al.
It was subsequently confirmed that anandamide is active in other established bioassays for cannabinoid receptor agonists reviewed in Pertwee, ; and, once the first CB 1 -selective antagonist, SRA, had been developed see below , that anandamide is susceptible to antagonism by this ligand Rinaldi-Carmona et al. It was fortuitous that the first isolated tissue experiments with the minute amounts of anandamide that had been extracted from pig brain were not carried out with the guinea-pig MPLM preparation, then also being used in Aberdeen for the bioassay of cannabinoids, as it subsequently became apparent that anandamide is rapidly metabolized by this guinea-pig preparation but not by the mouse vas deferens Pertwee et al.
The discovery of anandamide was followed by reports that mammalian tissues contain a number of other fatty acid derivatives that behave as endogenous cannabinoids reviewed in Di Marzo et al. Apart from anandamide, the most investigated of these has been 2-arachidonoyl glycerol Figure 2. They are then metabolized intracellularly, anandamide by fatty acid amide hydrolase and 2-arachidonoyl glycerol mainly by monoacylglycerol lipase reviewed in Di Marzo et al.
Most of the endogenous cannabinoids that have so far been identified are high- or low-efficacy cannabinoid receptor agonists. All these compounds proved to be agonists for both CB 1 and CB 2 receptors that bind more or less equally well to each receptor type but that vary in their CB 1 and CB 2 affinities and relative intrinsic activities.
Agonists that activate CB 1 receptors or CB 2 receptors selectively have also been developed. One other major advance prompted by the discovery of cannabinoid receptors was the development of selective cannabinoid receptor antagonists reviewed in Howlett et al.
The availability of selective CB 1 and CB 2 receptor antagonists and agonists has greatly facilitated research into the pharmacology of cannabinoids. These antagonists seem to lack the apparent ability of ligands such as SRA to reduce the degree of any constitutive activity exhibited by CB 1 receptors reviewed in Pertwee, a. A common property of all cannabinoid receptor agonists and antagonists currently used as experimental tools is one of high lipophilicity and low or negligible water solubility.
This necessitates the use of a vehicle such as dimethyl sulphoxide, Tween or ethanol, which may itself produce pharmacological changes or influence the free concentration of a cannabinoid at its site of action.
This practical difficulty prompted an exploration of the possibility of developing a water-soluble cannabinoid receptor agonist, leading to the synthesis by Raj Razdan of O, a classical cannabinoid that is readily soluble in water and yet almost as potent as CP as a CB 1 and CB 2 receptor agonist Pertwee et al. It is now generally accepted that, in contrast to 2-arachidonoyl glycerol and established non-eicosanoid cannabinoids, anandamide can activate not only CB 1 and CB 2 receptors but also vanilloid TRPV1 receptors reviewed in Ross, In addition, evidence has recently emerged that the orphan G-protein-coupled receptor, GPR55, is a cannabinoid receptor see, e.
This should be borne in mind when selecting a cannabinoid receptor agonist for use as a pharmacological tool or potential medicine. Also, the possibility still remains that cannabinoids produce some of their effects by inducing structure-dependent perturbations of membrane lipids as proposed by Edward Gill and David Lawrence see above.
One other recent finding of note is that the CB 1 receptor has an allosteric site Price et al. However, a fuller elucidation of the mechanisms that underlie the development of this tolerance had to await the discovery of cannabinoid receptors. It then became possible to establish, at least for effects mediated by cannabinoid CB 1 receptors, that internalization of these receptors with or without their subsequent degradation, decreases in CB 1 receptor protein synthesis, and reductions in the efficiency of CB 1 receptor signalling desensitization can all contribute to the development of tolerance to agonists for these receptors.
Interestingly, the extent to which any one of these mechanisms is involved in the production of this tolerance seems to be brain area-dependent and also to be influenced by agonist efficacy. Not much is presently known about tolerance to effects mediated by cannabinoid CB 2 receptors. 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: Chemotypes high in beta-caryophyllene, myrcene, and linalool provide additional pain relief and increase the effectiveness of other cannabinoids for analgesia. For relief of immediate symptoms, as in a flare-up of pain, vaporizing or smoking work well. The medication effect is immediate and lasts one to three hours, whereas most ingested products take thirty to sixty minutes before taking effect faster on an empty stomach and last six to eight hours.
Sublingual sprays or tinctures taken as liquid drops also take effect quickly and last longer than inhaled products. When pain is localized, topical products can be applied.
Topicals affect the cells near application and through several layers of tissue but do not cross the blood-brain barrier and are, therefore, not psychoactive.
The skin has the highest amount and concentration of CB2 receptors in the body. Considering all of the studies together, which number over forty for various types of pain , CBD and cannabis are shown to have a rating of likely probable efficacy. It is one of the best-substantiated medical uses of cannabinoids. Sativex, a cannabis plant—derived oromucosal spray containing equal proportions of THC and CBD, has been approved in a number of countries for use to treat specific types of pain.
Numerous randomized clinical trials have demonstrated the safety and efficacy of Sativex for treatment of central and peripheral neuropathic pain, rheumatoid arthritis, and cancer pain. A study showed that CBD and CBC stimulated descending pain-blocking pathways in the nervous system and caused analgesia by interacting with several target proteins involved in nociceptive control.
Sleep Disorders Insomnia, Sleep Apnea Cannabis and sleep have a complex relationship that is only beginning to be understood by science. In general, for most people, indica strains are more relaxing and effective for sleep disorders, whereas sativa strains are more stimulating and tend to keep people awake.
Several studies conducted between and demonstrated the variable effect of different cannabinoids on sleep. Another study found CBD to be wake-inducing for most subjects, though some reported better sleep a few hours after taking it. However, a significant number of people find THC, even indica strains, will make the mind more active.
For these people, CBD oil can benefit them and tends to work well, providing the relaxation and calm for the mental as well as the physical body.
For these people, CBD taken at nighttime as part of a bedtime regime produces a restful sleep, not the alertness produced in the daytime. This bidirectional effect of CBD is the result of balancing the endocannabinoid system. In relation to sleep apnea, a animal study observed the ability of THC to restore respiratory stability by modulating serotonin signaling and reducing spontaneous sleep-disordered breathing. It is suggested that patients work with a health care practitioner experienced in recommending CBD or medicinal cannabis so that dosage and delivery methods can be developed and fine-tuned on an individual basis.
As mentioned previously, while CBD-dominant products help some people sleep, in others it promotes wakefulness. These tend to be high in myrcene and linalool, a terpene shared with lavender and known to be effective for relaxation.
Cannabis combinations with ratios of 1: THC can be used when patients want to reduce psychoactivity. Oral consumption is recommended as it usually lasts the whole night.
The micro to standard dose is usually recommended to treat insomnia and sleep apnea. When relaxing indica strains are used with higher THC levels, a dose of 5—10 mg is usually sufficient. Other people find they need larger doses, such as 15—40 mg. CBD taken as a tincture or edible will aid in a restful six to seven hours of sleep. This type of disorder varies widely from one patient to the next. Often, one needs to perform some experimental research and try strains of different CBD: For immediate medicinal effects, vaporizing or smoking work well.
This can be helpful for either initial sleep onset or for wakefulness in the middle of a rest period but only lasts one to three hours. The medication effect is immediate, whereas most ingested products take thirty to sixty minutes before taking effect faster on an empty stomach and last six to eight hours.
Vaporizers that use a cartridge filled with the CO2 concentrate are convenient and highly effective, and these are available in various ratios of CBD to THC. Using this rubric, the use of cannabis-based products for treating insomnia has a rating of likely probable efficacy based on the four studies available at press time 3.
Cannabinoid pharmacology: the first 66 years
Side effects and risks of medicinal cannabis are very well documented in the literature, The reality, therefore, is a massive amount of evidence on cannabis, which mankind has been using psychoactive cannabis for at least 10, years. . The anti cancer properties of THC, CBD, CBG and other cannabinoids are well. Cannabidiol (CBD) is an active ingredient in cannabis derived from the The evidence for cannabidiol health benefits We need more research but CBD may be prove to be an option for .. That said, the relationships are complex, will likely take years to The topical works great for my chronic neck pain. Medical marijuana is any part of the marijuana plant that you use to treat health problems. . Based on its research, the committee concluded that current information In fact, CBD appears to have effects opposite of THC.