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Cannabidiol Enhances Anandamide Signaling and Alleviates Psychotic Symptoms of Schizophrenia, F. M. Leweke et. al., Nature.com, 2:3, 201-215, and Translational Psychiatry (2012) 2, e94; doi:10.1038/ tp.2012.15.
(Click image to read original article)
The rebirth of cannabinoid-based science strongly suggests that cannabinoids have numerous other applications besides reducing pain. In the paper summarized here, the scientists find that CBD (cannabidiol) provides effective relief from symptoms of schizophrenia.
In some strains of marijuana, CBD content is comparable or displaces THC. Historic research found CBD to be the predominant cannabinoid in the Indica strains. Unfortunately, growers bred Indica strains to produce the psychoactive THC instead. Research found that CBD provided a variety of desirable effects for patients, and growers have refocused on developing strains where CBD predominates.
Research on CBD’s effects on schizophrenia comes from Professor FM Leweke of the Department
of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg. Leweke found that CBD is as effective at improving psychotic symptoms as the standard antipsychotic amisulpride. Cannabidiol also generated significantly fewer side effects of motor disturbances (so-called extrapyramidal symptoms), weight gain and sexual dysfunction.
Leweke’s findings suggest a link between the antipsychotic effects of cannabidiol and CBD’s ability to inhibit anandamide degradation. CBD may enhance anandamide signaling by inhibiting the enzyme that degrades anandamide (fatty acid amide hydrolase-FAAH).
The study used dosages of 200 to 600 mg per day. A high yield CBD strain may contain 5% or 50 mg/ gram. Thus, a patient would have to consume 12 grams of CBD-yielding Indica to get the same effect
as 600 mg per day. A patient could undertake such a regimen, but it would be costly and probably unpleasant. On the other hand, CBD showed “marked tolerability and safety, when compared with current medications.”
If growers can develop Indica strains that produce CBD content as high as the THC in premium Sativa (20%), oral consumption of Indica could be a practical way to treat some forms of mental illness.
Inflammatory Bowel Disease and Cannabinoids – A Therapeutic Interaction
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is an affliction that affects approximately one million Americans, with incidence rates much higher in developing countries. IBD is characterized by illnesses such as Crohn’s disease and ulcerative colitis. Excessive inflammatory response in the gastrointestinal tract results in intestinal damage and disturbances in motility and secretion. Serious pain follows, as well as a range of other pervasive symptoms. Currently no cures are known, and treatment is measured by reduction of symptoms and suppression of flare-ups. Alleviation of IBD is currently accomplished with a number of medications that induce and retain remission. Steroidal treatment is another pathway that is currently used. These drugs possess limited efficacy however, and many contain unwanted side effects.
Cannabis and IBD
Cannabis Indica (nomenclature 2004 IU), the marijuana plant, has a long and storied history in medical application. Extracts of Cannabis were used in the USA a century ago for the treatment of abdominal pain and diarrhea. Anectodal accounts have been very prevalent regarding the effective use of Cannabis for IBD.
Self-medication under state medical cannabis laws is used by a generous subset of IBD patients for its analgesic activity in the abdomen, as well as the increase in appetite and reduction of diarrhea. However, the greatest limitation to exploring the full efficacy of cannabis on inflammation and other IBD symptoms lies with the activation of CB1 and CB2 (cannabinoid) receptors by delta-9 THC and the resulting psychoactive effect. CBD, however, does not activate CB1 or CB2, and therefore is devoid of psychoactive properties. The anti-inflammatory and antioxidant properties of CBD therefore have great potential as a candidate for medically-accepted relief from IBD symptoms and inhibition of flare-ups.
Cannabidiol and IBD
Determining the exact pathway of CBD activity in reduction of inflammatory symptoms is a necessary step to exploiting the cannabinoid as a therapeutic agent. The precise pathway must be uncovered in order to determine possible interactions with other drugs, as well as to maximize the effectiveness of a cannabis-derived therapeutic agent.
It has been proposed numerous times that CBD modulates endocannabinoid function through its ability to inhibit the enzyme fatty acid amide hydrolase (FAAH), the enzyme responsible for the hydrolysis of anandamide (the endogenous mimic of THC). FAAH inhibition results in an intestinal anti-inflammatory effect, which has led many scientists to propose the efficacy of CBD in relation to IBD symptom is linked to its role in FAAH inhibition. However, CBD also has potent antioxidant properties, as well as possible interactions with other cytokines or cell signaling molecules. Therefore a set of broad studies with all possible permutations of CBD interaction must be explored to elucidate the specifics of CBD and IBD.
The role of FAAH inhibition and CBD with relief from IBD symptoms (in other words, inhibition of motility) was explored in 2008 by Capasso et al. CBD had been shown to have a putative inhibition of FAAH. Capasso et al selectively inhibited FAAH mRNA in mice and found an increase in endocannabinoid levels (anandamide and 2-AG). This increase would result in activation of CB1 and CB2 receptors, thus leading to the anti-inflammatory action that has been observed. It is then logical that an inhibition of FAAH by CBD would result in this same effect as seen by inhibition of FAAH mRNA in mice, which is in a sense the hypothesis of Capasso et al.
However, Borrelli et al further explored this topic in 2010 in order to present a more solid hypothesis of CBD interaction. They found, surprisingly, that although CBD did have a putative inhibitory effect on FAAH expression, colonic endocannabinoid levels were in fact decreased (opposite to the expected increase). They also found that FAAH mRNA expression was unchanged with the CBD-treated mice. This cuts out the possibility of activation of CB1 or CB2 via CBD (at least through an FAAH pathway), and therefore the anti-inflammatory action of CBD must occur through a separate pathway.
Capasso et al did however find that CBD did not affect transit (present results) or defecation in the control rats, which suggests that the compound is only pharmacologically active in the presence of an intestinal inflammatory stimulus. This is important since it underlines the specificity of CBD activity on altering body conditions.
Anti-spasmodic activity of CBD was demonstrated by Capasso et al. Induced contractions via ACh was reduced by CBD. However, this effect was shown to occur in both the inflamed and the healthy intestine. Therefore the antispasmodic effect of CBD occurs separate from an inflammatory or mucosal stimulus.
An experimental model of colitis induced by a sulfonic acid (DNBS) was employed by Borrelli et al to test the effect of CBD on colonic inflammation. The introduction of CBD drastically reduced inflammation and the wet weight/colon length of the inflamed colonic tissue, which is a reliable indicator of the severity of inflammatory response. As seen with human cases of IBD, induction of colitis via DNBS led to many deleterious effects on the mice, the first of which studied was the reducing effect on body weight. Mice treated with CBD had been shown to decrease this colitis-induced reduction in weight; in other words, they lost less weight than those not treated. This CBD-related increase in weight is a correlation between reduction in inflammation via CBD and a resulting increase in appetite (in other words, this reduction in inflammation increases appetite much more than CBD’s slight appetite suppressant property). This provides an extremely valuable therapeutic insight to CBD with regards to inflammatory diseases, especially since loss of weight and appetite is a reported symptom of IBD.
Since the previously-accepted anti-inflammatory pathway of CBD via FAAH inhibition had been dethroned, Borrelli et al decided to test its effect on four cell signaling or mediating molecules (the last two are cytokines – cell signaling molecules central to, amongst other things, the development of intestinal inflammation). These encompass molecules that mediate inflammation as well as those that have a profound effect on oxidation and the resulting oxidative damage.
- inducible nitric oxide synthase (iNOS) – CBD reduced the overexpression of iNOS in response to colitis. iNOS overexpression is well correlated with disease activity with colitis, and inhibitors of iNOS lead to improvement in experimental models of IBD. iNOS results in high-output production of NO, which results in oxidative damage to the intestine via reactive oxygen species (ROS).
- cyclooxygenase-2 (COX-2) – no appreciable effect. COX-2 is heightened with IBD, but COX-2 inhibitors may both exacerbate and ameliorate the severity of experimental colitis. The fact that CBD has no effect on COX-2 is helpful in reducing the pathways that CBD may take that could present potential problems in a subset of patients.
- interleukin-1β – levels significantly increased with experimental colitis. CBD was shown to restore levels. IL-1β is shown to have potent pro-inflammatory activity and thus heightens the inflammatory response that leads to intestinal injury. IL-1β amplifies the production of inflammatory leukocytes (immune system cells), resulting in an increase of inflammation.
- interleukin-10 – levels significantly decreased with experimental colitis. CBD was shown to restore levels. IL-10 has anti-inflammatory activity by inhibiting the release of pro-inflammatory cytokines. Restoration of IL-10 activity is critical to intestinal health.
The CBD-induced reduction of iNOS expression is important largely in relation to the reduction of oxidative damage caused by experimental models of colitis. Therefore the levels of reactive oxygen species (ROS) were measured by Borrelli et al in vivo. Reactive oxygen species cause extensive tissue damage as free radicals, and have been extensively correlated with increases in iNOS expression and levels of nitric oxide (NO). CBD was found to reduce levels of ROS in the affected intestinal cells. Lipid peroxidation (a large factor in oxidative damage) was reduced, both in a dose-dependent manner. ROS production is a signification contributor to the pathogenesis of IBD as it constitutes a powerful tissue-destructive force. The reduction of iNOS and ROS by CBD, along with the reduction of lipid peroxidation, elucidates important therapeutic action of CBD in reduction of colonic inflammation by indirect reduction of oxidative damage.
The dysregulation of IL-1B and IL-10 is a well-known disruption caused by IBD. The restoration of these interleukins to normal behavior by CBD, although the specific pathway is unknown, is another important therapeutic action that CBD has on reduction of colonic inflammation. The normalization of these cytokines has a profound effect on the number of lymphocytes infiltration the affected area, thereby regulating the localization of these lymphocytes and regulating inflammation. ****
CBD and THC
Cannabis self-medication is currently the de facto method that IBD patients use in order to exploit its therapeutic benefit. Although this is not the ideal method of delivery as compared to a clinically-tested cannabinoid medication, it does present a complexity with regards to the co-administration of THC as well as CBD. The anti-inflammatory ability of THC is documented, as it activates cannabinoid receptors that are known to result in anti-inflammatory response. As discussed previously, the psychoactive component of THC is generally an unwanted side effect in medical application. Since THC is generally present with CBD in an impure preparation, it is useful to study the effect of THC alone and with CBD as a therapeutic agent towards IBD.
Jamontt et al demonstrated amelioration of IBD symptoms via the application of THC and CBD in a murine model. Colitis was induced by TNBS (a trinitrobenzene sulfonic acid that is very similar to DNBS used by Borrelli et al). The amelioration was similar to that of sulphasalazine, the standard prescription medication for treatment of IBD symptoms.
Cannabinoid normalization of IBD symptoms was argued to be a more protective, or a more effective therapeutic agent than sulphasalazine. The breadth of therapeutic effects that these cannabinoids carry is the reason for this hypothesis. As mentioned above, the cannabinoids help to mediate cytokines responsible for inflammation. In addition, Jamontt et al demonstrated the ability of the cannabinoids to increase cholinergic contractions and relaxant responses in the colitis models. In other words, the cannabinoids improved the function of both the excitatory and inhibitory nerves and therefore was much “more protective of the myenteric plexus” (a central component to the gastrointestinal nervous system).
The administration of THC and CBD was shown to be at a more effectiveness than a dose of THC without THC. The reinforcement by both cannabinoids demonstrates that although they share some of the same pathways, they do carry distinct pathways that relieve IBD symptoms (ie cholinergic motor function improvement with THC vs none with CBD). A therapeutic preparation of both cannabinoids therefore may be the most potent in reducing IBD symptoms. However, it would carry the psychoactive side effect. Therefore, a therapeutic preparation of CBD would be the most medically effective and accepted model of cannabinoid treatment.
Borrelli, Francesca, Gabriela Aviello, Barbara Romano, Pierangelo Orlando, Raffaele Capasso, Francesco Maiello, Federico Guadagno, Stefiana Petrosino, Francesco Capasso, Vincenza Di Marzo, and Angelo A. Izzo. “Cannabidiol, a Safe and Non-psychotropic Ingredient of the Marijuana Plant Cannabis Sativa, Is Protective in a Murine Model of Colitis.” J Mol Med 87 (2009): 1111-121. Print.
Capasso, R., F. Borrelli, G. Aviello, B. Romano, C. Scalisi, F. Capasso, and AA Izzo. “Cannabidiol, Extracted from Cannabis Sativa, Selectively Inhibits Inflammatory Hypermotility in Mice.” British Journal of Pharmacology 154 (2008): 1001-008. Print.
Everyone knows that cannabis delivers various medical benefits, perhaps the most important one being pain relief. Other drugs relieve pain, and doctors normally prescribe opiates or opioids to relieve severe pain. However, opioid side effects include sedation, nausea and vomiting, and addiction.
Nevertheless, the medical and cannabis communities have good cause to learn more about the combined use of cannabis and opioids. Research has shown that cannabis enhances the pain relief of opioids while reducing nausea (Narang, 2008). Patients may benefit from the cannabis-opioid combination by being able to reduce their use of the opioids and the side effects they cause. Many patients already augment their opioid pain relief regimen with cannabis, so the interaction deserves close examination.
For some patients, psychoactivity poses the most serious side effect of cannabis. Beyond that, patients can safely obtain pain relief from cannabis precisely because it has few other side effects. The inherent safety of THC is due to the scarcity of cannabinoid receptors in the parts of the brain that control metabolism and breathing.
In 2010, Dr. Donald Abrams conducted a study using 24 patients at the San Francisco General Hospital. The patients normally consumed morphine or oxycodone for significant pain due to various conditions (cancer, multiple sclerosis, migraine, etc.). The study examined the subjective effects on the patients following the addition of inhaled cannabis vapor to their opioid regimen. The patients inhaled vaporized cannabis three times a day for five days. The patients also continued their prescriptions of sustained release tablets of morphine or oxycodone.
The authors justifiably proclaim that “This is the first human study to demonstrate that inhaled cannabis safely augments the analgesic effects of opioids.” Indeed, this area deserves much more research.
The study found that cannabis reduced pain 40% on the first day, and after 5 days continued to reduce pain 27%. The patients treated with the cannabis-morphine combination experienced more consistent pain relief than the patients that received the cannabis-oxycodone combination. Cannabis and morphine pain reduction continued at about 33% throughout the 5 day trial. In contrast, cannabis and oxycodone pain reduction dropped from 44% to 21% by Day 5.
The “high” felt on the first day dropped to a tenth of the original level by Day 5 for morphine, and dropped to a third of the original level by Day 5 for oxycodone. Presumably, the patients taking oxycodone would experience still less of the high if the trial continued past five days. The fact that the high or the inebriation declines over time demonstrates the practical use of cannabis with opioids. Patients who dislike the high can merely get past the first few days to enhance their opioid with a minimum of “impairment.” In time, perhaps no feeling of inebriation would remain. If that is true, higher doses of cannabis could provide even greater relief, and a greater reduction in opioid consumption. Given the need to improve pain management and the absence of cannabis toxicity, much more work with cannabis is merited.
Cannabinoids and opioids share the effects of pain reduction, sedation, lowered body temperature and lowered blood pressure. THC slows gastrointestinal motility and thus can slow the absorption of orally administered drugs. THC also seems to help certain drugs to get into the brain, perhaps because of the vasodilation (temporary thinning of the blood vessel walls). The vasodilation effect of THC causes the reddening of the eyes as the eye capillaries enlarge.
As the reader may expect, a five-day trial can only provide a near-to-moderate time frame in which to observe effects. The study also could have been limited by only using vaporization as the means of consumption. The study made no attempt to avoid a placebo effect. In general, studies that involve vaporizing or smoking cannabis cannot employ blind or double blind methods because of the “high.”
The study only used 24 volunteers, a number below that needed to generate good statistics. Reliable statistics generally require a sample size of thirty or more. Below thirty, statistical findings cannot establish confidence levels above 90 percent. Nevertheless, small clinical studies provide the direction for larger, better funded studies.
Still another weakness related to the timing of two drug effects. Inhaling THC produces a rapid and strong blood concentration while consuming opiate orally produces a maximum effect an hour or three after ingestion. Indeed, another study (Narang, 2008) tested opioids with oral THC (synthetic Dronabinol) and this study also demonstrated significant decreases in chronic pain.
For the purposes of relieving pain alongside opioids, orally administered THC may be preferred by some patients over inhaled THC. On the other hand, oral consumption of THC suffers from decreased control over the dosing, absorption being strongly affected by the types of food consumed and by patient metabolism.
Other issues worthy of comment include the following: Some research indicates that cannabinoids increase endorphins, the neurotransmitters that opioids mimic. And yet, research has clearly distinguished the CB1 and CB2 receptors (cannabinoid receptors) as being entirely different from those affected by opioids. The interactions of CBD or other cannabinoids with opioids remains unexplored and will surely yield very exciting discoveries.
It is important to reinforce the finding that even within a week, the psychotropic effects of the THC decreased much more than the pain-relieving effects. In the near absence of toxicity, the THC dose can be safely increased to compensate for the reduction in the “high.” The few patients who dislike the THC inebriation can expect to get improved pain relief without the high after a few days.
In summary, this study provides an important benchmark in showing the value of inhaled THC to help opioids relieve pain.
Abrams, D. I., et. al. Cannabinoid-opioid interaction in chronic pain. Nature 90:6, 844-851 (Dec 2011). Narang, S., et. al. Efficacy of Dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J. Pain 9,254-264(2008).
article source: http://www.nature.com/clpt/journal/v90/n6/full/clpt2011188a.html
A new review of cannabis use during pregnancy, published in the journal Future Neurology on July 1, 2011, clearly indicates that there are risks of long term cognitive effects when exposing unborn children to cannabis.
[Developing Brain CME Chia-Shan Wu, PhD; Christopher P. Jew; Hui-Chen Lu, PhD CME Released: 07/01/2011; Valid for credit through 07/01/2012]
Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized.
Cannabis is the world’s third most popular recreational drug, after alcohol and tobacco. The hallmarks of its effects are euphoria and relaxation, perceptual alterations, time distortion, appetite inducement and the intensification of ordinary sensory experiences. Cannabis preparations are largely derived from the female plant of Cannabis sativa, and consist of approximately 60 plant-derived cannabinoid compounds (phytocannabinoids), with ∆9-tetrahydrocannabinol (THC) being the predominant psychoactive constituent. Efforts aimed at understanding how THC produces its psychoactive effects have led to the discovery of the endocannabinoid system.
The endocannabinoid system is comprised of endogenous cannabinoids (endocannabinoids [eCBs]), the metabolic enzymes responsible for the formation and degradation of eCBs, and the cannabinoid receptors and their interacting proteins.[4,5] eCB signaling is involved in a myriad of physiological processes including retrograde signaling and modulation of synaptic function in the CNS, and analgesic and metabolic effects on lipid profile and glucose homeostasis in the periphery.[6–11] Indeed, several therapeutic effects have been ascribed to compounds targeting the endocannabinoid system, including treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and related metabolic dysfunctions, cardiovascular conditions and liver diseases.[12,13] Synthetic THC (dronabinol) is approved in the USA to alleviate the emesis and nausea associated with cancer and chemotherapy, and weight loss associated with HIV infection. Clinical trials are underway to determine whether cannabis-based compounds are effective in the treatment of multiple sclerosis and neuropathic pain. Sativex, a pharmaceutical preparation containing the psychoactive THC with the nonpsychotropic cannabidiol in approximately a 1:1 weight ratio, was approved in Canada for the treatment of neuropathic pain associated with multiple sclerosis, and in England for the spasticity associated with multiple sclerosis. Furthermore, several forms of pharmacological manipulation of the endocannabinoid system, including synthetic cannabinoid receptor agonists and antagonists and inhibitors of endocannabinoid degradation are undergoing clinical development.[17–20]
The increasing popularity of cannabis consumption among young people between 15 and 30 years of age, the critical period for adolescent brain development, has raised concerns over the health consequences of cannabis use. In addition, cannabis is the most commonly abused illicit drug in pregnant women in Western societies. Given the lipophilic nature of THC, it is estimated that one-third of THC in the plasma crosses the fetoplacental barrier, and is secreted through the breast milk. Given that the THC content of confiscated cannabis samples has increased substantially over the past 20 years, fetuses of cannabis-using mothers could be exposed to significant amounts of THC during the perinatal period. Therefore, cannabis abuse is potentially deleterious to the children of cannabis-using mothers through abnormal brain development owing to exogenous cannabis exposure during the perinatal period. This article will focus on the neurobehavioral consequences of prenatal cannabis exposure in humans.
A central role for eCB signaling in brain development is now emerging.[7,24,25] Perinatal and adolescent cannabis exposure may disrupt the precise temporal and spatial control of eCB signaling at critical stages of neural development, leading to detrimental effects on later nervous system functioning. Indeed, longitudinal studies in humans with prenatal cannabis exposure demonstrated exaggerated startle response and poor habituation to novel stimuli in infants, and hyperactivity, inattention and impaired executive function in adolescents.[26–29] Many of these behavioral effects have also been modeled in animal studies. Furthermore, possible teratogenic effects of endocannabinoid system-based therapies in pregnant women and long-term exposure to eCB signaling-modifying agents such as organophosphate pesticides need to be taken into consideration.
This article aims to summarize the existing literature on the behavioral consequences of prenatal exposure to the phytocannabinoid THC, summarizing key findings from epidemiological studies in humans. Experimental studies in rodents have been reviewed extensively elsewhere and will be only briefly discussed here.[29–32] The molecular composition of the endocannabinoid system and their temporal and spatial distributions in embryonic brain in humans and rodents are also summarized. Finally, experimental evidence demonstrating how eCB signaling in this molecular framework affects specific events in developing neural circuits is discussed.
“When you get the message, hang up the phone.” – Alan Watts
If you’ve used cannabis medicinally for some time, it’s possible to develop cannabis dependency and unwanted tolerance issues. This can be of concern to members and their families. While cannabis is relatively nontoxic, too much and too often can become an issue, in part because of the plant’s low toxicity.
According to the International Association for Cannabinoid Medicines (IACM), tolerance to some effects of cannabis has been noted. Tolerance means, that the effects of cannabis decrease over time.
Development of tolerance includes developing a tolerance to cannabis’ psychoactive effects, its cognitive and coordination impairment, effects on the heart and circulation, effects on the hormonal system, internal eye pressure, and anti-vomiting effects. Some of these tolerances, such as fewer occurrences of rapid heartbeat, are usually welcomed by members, while others are not.
CRC’s approach to tolerance issues is to encourage patients to minimize their dosage. Counter intuitively, it appears that tolerance may actually be avoided, reduced or even eliminated by reducing dosage. The folk wisdom that you can avoid tolerance by switching strains of cannabis seems to be partially effective, but typically only results in increased dosage and ongoing problems with tolerance. Our rule of thumb at CRC is: Always use the least amount of cannabis required to relieve the symptoms, and then wait at least ninety minutes before dosing again.
According to the IACM, cannabis does pose potential for addiction. This is usually not a problem when using cannabis as a short-term therapy, but can be of concern when cannabis is being used to treat chronic conditions. While withdrawal symptoms of cannabis dependency are considered mild by medical experts, these symptoms are not always perceived as mild by patients trying to halt their cannabis use. Most patients can stop using cannabis without noticeable withdrawal symptoms. Other patients may notice increased anxiety, restlessness, and insomnia after discontinuing cannabis use. In some patients, physical withdrawal symptoms such as increased salivation and diarrhea may occur.
As for dependency and withdrawal issues, there is emerging research that indicates that the cannabinoid called cannabidiol or CBD might help reduce symptoms of cannabis or THC withdrawal. We definitely recommend the “cold turkey” approach for the majority of patients, since the withdrawal symptoms for most patients are unnoticeable.
For those patients for whom the withdrawal syndrome is more pronounced, you may wish to switch to a high-CBD med, such as Harlequin or H2 for a few days, before discontinuing cannabis use.
One other strategy is to first honestly assess how much cannabis you’re using over a ten-day period. Clean out your medicinal supply and replace it with a new ten day supply (or keep enough of your favorite strain(s) for five days). Make certain that half of your total supply is a high-CBD strain of at least 2:1 CBD to THC, such as Harlequin or H2 (the higher the CBD, the lower the THC… the better). Check projectcbd.org for other high-CBD strains and their expected CBD/THC ratio.
So, now you’ve got two weeks of meds, half of which are high-CBD. Get a calculator and a scale. Divide the total amount of meds by 10. So if, you’ve got ten grams, the answer would be one-gram. Your answer will be your daily allotment. You’re going to blend the high-THC strain and the high-CBD strain together, slowly increasing the ratio of high-CBD cannabis while reducing the amount of high-THC cannabis that you use over ten days.
So, day one would be .9g of high-THC blended with .1g of high-CBD. Day two is .8g of high-THC blended with .2g of high-CBD. By day five you’re using a 50/50 blend. By day ten, you’re using a 10% of a high-THC strain blended with 90% of a high CBD strain. On day 11, stop. If you’re still experiencing withdrawal symptoms, only use a high-CBD strain for a few days, and then stop. It’s unlikely that you’ll notice any withdrawal symptoms, whatsoever.
We’re blessed at CRC with having a smart and responsible membership. We want their usage of cannabis to be just as smart and responsible. Remember, do the medicine; don’t let the medicine do you.
Cannabis and its Constituents
Cannabis is a plant as ubiquitous as it is therapeutic. For centuries Cannabis has held an integral role in many societies as a medicine and as a relaxant. A century ago, Cannabis extracts were used in the United States as a normalizer for disruptions in appetite and for cases of nausea, amongst their plethora of other alleviative properties. Since the early twentieth century, reports of Cannabis use turned to an anecdotal form due to the social controversy over the psychoactivity of Cannabis and the scheduling of Cannabis on the controlled substance list. Since then, illicit use continued, with anecdotes of profound therapeutic potential. The diversity of therapeutic effects attributed to Cannabis is staggering. Reports encompass relief from gastrointestinal disruption and illness, decrease in ocular pressure, analgesia, and normalizing depression to list just a few. This wide range of purported medical benefit is unlikely to be attributed to merely one psychoactive compound, the notorious delta-9 THC. THC may be accredited to a large variety of therapeutic benefit, but the variance in psychoactivity seen between strains invites the theory that these variances are caused by different relative ratios of THC to the other cannabinoids, and perhaps even more importantly, the terpenoids.
Terpenoids are small organic molecules that are derived from 5-carbon isoprene units. These units assemble in a diverse manner and utilize different functional groups to create a vast array of terpenoids. Their relative small size (THC, for example, has 21 carbon atoms) adds to a volatile characteristic, meaning that these molecules can more easily dissipate into the air. This contributes to their aroma, and arguably the slight loss in medical efficacy with samples that have not been stored properly, and thus lost much of their volatile terpenoid content. Terpenoids, like cannabinoids, increase in production with light exposure, but interestingly decrease in production with soil fertility.
Contrary to the omnipresent terpenoids, phytocannabinoids are produced exclusively in Cannabis. Their involvement with the endocannabinoid receptor system in humans has been an intriguing mystery, with theories such as the surreptitious mimic and others that are beyond the scope of this review (for more information, refer to the National Insitute of Medicine’s publication in 2003: “Marijuana and Medicine: Assessing the Science Base). Its evolutionary role as a functional component of the plant is much clearer. Many phytocannabinoids carry antifungal activity, and the sticky nature of the glandules that carry them allows for insect defense. However, most interesting are the biochemical interactions with the human endocannabinoid system as well as other possible receptors, and the combined interaction of multiple cannabinoids. In terms of cannabinoids production, increases are seen with light exposure as well as with soil fertility.
In 2010, Ethan Russo set out to consolidate the mass of research that has been conducted on phytocannabinoids and terpenoids, and in particular their synergistic effect when combined with THC. He defined synergy into four characteristics:
1) Multi-target effects
2) Pharmacokinetic effects such as improved solubility or bioavailability
3) Agent interactions affecting bacterial resistance
4) Modulation of adverse events
Russo theorized that “phytocannabinoids [could] function analogously to the endocannabinoid system (ECS) with its combination of active and ‘inactive’ synergists…This type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are better drugs than the natural products isolated from them” (p. 1345). This is a solid explanation for anecdotal evidence that patients do not respond as well to marinol or drobadil (synthetic analogues of THC) as they do to whole-plant extracts. The presence of other phytocannabinoids and terpenoids is lost, and any therapeutic benefit arising from synergy is gone.
The most psychoactive phytocannabinoid, THC, “is produced in the plant via an allele co-dominant with CBD. THC is a partial agonist at CB1 and cannabinoid receptor 2 (CB2), analogous to AEA [anandamide], and underlying many of its activities as a psychoactive agent, analgesic, muscle relaxant and antispasmodic. Additionally it is a bronchodilator, neuroprotective antioxidant, antipruritic agent in cholestatic jaundice and has 20 times the anti-inflammatory power of aspirin and twice that of hydrocortisone” (p. 1348).
CBD is an extremely versatile cannabinoid that is best known for its analgesic properties, and its ability to mediate the psychoactivity and other adverse side effects caused by THC. It has little affinity towards the cannabinoid receptors that THC binds to; however, it does act as an antagonist in the presence of THC (in other words, modulating the uptake of THC). Through the regulation of nitric oxide, CBD is also a neuroprotective antioxidant that is more potent than tocopherol or ascorbate. In fact, there are many more therapeutic benefits to which CBD has been attributed. For years, Cannabis breeding efforts have focused on increasing THC levels, which inevitably has led to a decreased amount of CBD in samples. However, recent study and burgeoning interest into the medical efficacy of CBD has led to an increased effort to create libraries of high-CBD strains. Russo cites research that studied perceived pain response in the presence of CBD, THC, and THC/CBD. The cancer patients (who were unresponsive to opioid treatment) who were treated with THC failed to distinguish from a placebo. Those treated with CBD received moderate analgesia, and the combination of THC/CBD resulted in successful reduction of 30% or more in pain. This synergy is an important revelation, as it directly supports the anecdotal evidence that the natural plant has more analgesic efficacy than synthetic THC mimics currently licensed for prescribed use.
There are many other phytocannabinoids present in the Cannabis plant. Although THC and CBD are the most prevalent and carry the most therapeutic efficacy, there are a few other worth noting, particularly THCV (tetrahydrocannabivarin), a propyl analogue of THC. Generally found in native West African strains of Cannabis, it carries 25% of the psychoactive potency of THC. The most interesting of its properties is its ability to produce weight loss and decreased body fat; in other words, contradicting the increase in appetite associated with THC.
Terpenoids are in such high use that the Food and Drug Administration deem them to be safe. They are also extremely potent – concentrations of above 0.05% are considered to be of pharmacological interest, and animal studies have supported that the levels found in Cannabis are certainly of high enough concentration to carry a pharmacological effect.
Lemons and citrus fruits may attribute much of their ‘sour’ nature to D-limonene, the second most prevalent terpenoid in nature. It also is a precursor to many other terpenoids. It has been linked to powerful anxiolytic and antidepressant activity. It also helps to induce apoptosis in breast cancer cells. Limonene is rapidly metabolized; however, there are “indications of accumulation and retention in adipose tissues (e.g. brain)” (1350).
Another common terpenoid found in Cannabis is B-myrcene, a potent sedative amongst its many other properties. It acts as an anti-inflammatory as well as carries a small analgesic property. It has a strongly herbal aroma and is a major component of bay, thyme, and hops.
Alpha-Pinene, known for creating the strong aroma from pine needles, is the “most widely encountered terpenoid in nature” (1350). It acts as an anti-inflammatory, as well as a bronchodilator (perceived expansion in the lungs). It also has a very interesting attribute of inhibiting acetylcholinesterase; in other words, aiding memory retention. Russo argues that “this feature could counteract short-term memory deficits induced by THC intoxication” (1352).
There are many other terpenoids present in Cannabis; all of which have an impressive Rolodex of therapeutic attributes. D-linalool, most commonly found in the lavender plant, has a local anesthetic property that is equal to those of procaine and menthol. It also contains anxiolytic and anticonvulsant attributes. B-Caryophyllene, common to black pepper, is another potent anti-inflammatory. Nerolidol, present in orange and citrus peels, is a sedative. This diverse array of terpenoids and the multitude of therapeutic pathways they provide are quite astounding, yet minute in magnitude when taken into consideration co-administration with a whole complex of phytocannabinoids and the potential synergy that may arise.
Specific Examples of Synergy
Acne sufferers are one group that may benefit from Cannabis synergy. CBD had previously been shown to induce sebocyte apoptosis. This attenuation at the pathological root of acne is a promising revelation. Russo argues that a few Cannabis terpenoids may also offer complementary activity. Limonene had been shown to inhibit Propionibacterium acnes (at a potency higher than that of triclosan). Pinene also inhibits P. acne. Linalool functions to suppress inflammation in response to acne. Russo argues that an isolation of CBD prepared with terpenoids is “a novel and promising therapeutic approach that poses minimal risks in comparison to isotertinoin”(p. 1353).
MSRA, or Methicillin-resistant Staphylococcus aureus, is a particularly nasty bacterium that is responsible for a number of extremely difficult-to-treat infections. In fact, it caused more deaths last year in the USA than those attributed to human immunodeficiency virus. CBD, as well as the phytocannabinoid cannabigerol (CBG), have been proved to powerfully inhibit MSRA. Additionally, pinene was shown to be as effective against MSRA as vancomycin and other agents. Pinene also has the ability to increase skin permeability, a large barrier against uptake of phytocannabinoids. CBD/CBG-based extracts with pinene may prove to be a fruitful investigation into battling MSRA.
Terpenoid and cannabinoid application in psychiatry has been largely ignored in past years, due to governmental restrictions and methodological concerns. However, a few synergies have come to light that may prove useful in future study. Those terpenoids associated with citrus (ie limonene) have particularly effective anti-depressant capabilities; a combination of this with CBD and small amounts of THC could offer a therapeutic benefit. In fact, Russo ties in the theory of neural plasticity (burgeoning research is occurring in this field) with hypothetical connections to this phytocannabinoid synergy. He presents a hypothesis of deep, neurological treatment of depression, and not simply momentary alleviation of symptoms. Additionally, CBD has been consistently linked to providing relief from anxiety; the anxiolytic limonene or linalool may prove to be a synergistic combination with CBD. Cannabis extracts have also been linked to many other psychiatric benefits such as that of assisting sleep, and certainly this field of study will bear abundant discoveries.
There is one more psychopharmacological synergy that is worth noting with phytocannabinoids and a non-native Cannabis extract. Russo cites ancient “Ayurvedic tradition of India (Lad, 1990, p. 131):
Calamus root is the best antidote for the ill effects of marijuana … if one smokes a pinch of calamus root powder with the marijuana, this herb will completely neutralize the toxic side effects of the drug.” (p. 1355)
Specifically, the toxic side effects mentioned generally have to do with a “clearer thinking and improved memory” (p. 1355), to which Russo attributes the compound beta-asarone. An acetylcholinesterase inhibitor, beta-asarone does carry biochemical significance to improving memory. Pinene was also described to act as a memory enhancer on a biochemical level; this may add synergy.
So Cannabis has synergy – what does this all mean?
Cannabis has been described to have a rich variety of phytocannabinoids and terpenoids that have a diverse set of therapeutic and biological significance. However, there is a discontinuity when taking into regard the fact that for the past twenty years, Cannabis breeding efforts have focused almost solely on increasing THC production. Russo argues that the general breeding evolution to simply maximize THC results in an improperly balanced set of phytocannabinoids and terpenoids in the flower, and indeed a deficit of these cannabinoids and terpenoids. Therefore “selective breeding of Cannabis chemotypes rich in ameliorative phytocannabinoid and terpenoid content offer complementary pharmacological activities that may strengthen and broaden clinical applications and improve the therapeutic index of Cannabis extracts containing THC, or other base cannabinoids” (p. 1355). In essence, high-THC extracts do not prove to be of a particularly large medical significance when compared to the synergy that is displayed with the combination of natural phytocannabinoids and terpenoids. And, by selecting extracts or flowers that carry the specific terpenoids and phytocannabinoids that prove therapeutic to a patient’s particular ailment, one could dramatically increase the medical efficacy and alleviation that is provided.
All information herein was provided by Ethan Russo’s article, cited below. Please refer to the article in order to gain original citations of facts and experiments. Additionally, ideas not explicitly stated to be that of Russo’s are those of the author’s and not necessarily stated by Russo.
Russo, Ethan B. “Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects.” British Journal of Pharmacology Part I Cannabinoids in Biology and Medicine (2011): 1344-364.
Have you ever heard that women get cranky and crave chocolate during a specific time of the month? Most people know that the menstrual cycle triggers certain behavior, but until recently science has failed to acknowledge that varying levels of hormones in females altered mood, behavior, and cognitive function (ie. memory, concentration, etc.). Because diseases such as Alzheimer’s, anxiety, depression, and arthritis occur more frequently in females, understanding female specific factors in therapeutics remains important.
Estrogen is abundant in the brain and plays an important role in how the brain communicates. Though both men and women have estrogen, its levels only vary in pre-menopausal women as a function of the menstrual cycle (see graph below). Females might not be surprised to hear that they may crave chocolate during certain points in their menstrual cycle, but may not think something like cannabis potency could vary as a result of hormonal fluctuation. However, studies show that the potency of THC on pain relief in female rats increases during times of high estrogen levels.
Estrogen appears to play a two-fold effect in cannabis messaging within the brain. First, it increases the conversion of THC to active THC. This means that after THC consumption, more active THC will be produced when estrogen levels are high such as during the pre-ovulatory peak; thus less cannabis may be needed to produce the same effects. Secondly, it changes the availability and excitability of receptors. Since the therapeutic effects of cannabis occur through activation of receptors, the variability in receptors alters the ability of active THC to produce effects such as pain relief, sedation and euphoria. In modern medicine proper dosage is central to the effectiveness of the treatment. So is the case with medical marijuana. This makes understanding the variability in cannabis potency across the menstrual cycle important. This means women may need to experiment with their dosage at different menstrual cycle time points.
This graph shows the change in estrogen levels across the normal menstrual cycle in pre-menopausal women not using hormonal birth control. Hormonal birth control, pregnancy, breast-feeding, menopause, and menstrual irregularities caused by medication or other reasons will all change variability in estrogen levels. The red line is the average estrogen level for women and the area between the blue and green line represents the range of estrogen levels. Estrogen levels peak right before ovulation, with a smaller rise post ovulation. The extent of change in estrogen levels varies between women and between cycles. This means that some women experience large fluctuations in estrogen and potentially cannabis potency, while others do not.
For review of other behavioral sex differences see (Craft, 2005)
For review on sex differences in pharmacokinetics see (Rubino and Parolaro, 2011)
Craft RM (2005) Sex differences in behavioral effects of cannabinoids. Life Sci 77:2471-2478.
Rodriguez de Fonseca F, Cebeira M, Ramos JA, Martin M, Fernandez-Ruiz JJ (1994) Cannabinoid receptors in rat brain areas: sexual differences, fluctuations during estrous cycle and changes after gonadectomy and sex steroid replacement. Life Sci 54:159-170.
Rubino T, Parolaro D (2011) Sexually dimorphic effects of cannabinoid compounds on emotion and cognition. Front Behav Neurosci 5:64.
Tseng AH, Craft RM (2001) Sex differences in antinociceptive and motoric effects of cannabinoids. Eur J Pharmacol 430:41-47.
Wakley AA, Craft RM (2011) Antinociception and sedation following intracerebroventricular administration of Delta-tetrahydrocannabinol in female vs. male rats. Behav Brain Res 216:200-206.
Rob Kampia – MPP
1. Congress defunds drug czar’s ad campaign: In 1998, Congress and President Clinton enacted a law creating the “National Youth Anti-Drug Media Campaign,” which received an average of $186 million of taxpayer money annually over its first five years. MPP lobbied Congress for the last decade to eliminate this program, which was eventually funded with “only” $35 million in 2011. Finally, on December 23, Congress and President Obama entirely eliminated funding for the ads for 2012!
2. Our ideal bill is finally introduced in Congress: On June 23, Congressmen Barney Frank (D-MA) and Ron Paul (R-TX) introduced a bill that would let states determine their own marijuana policies — not just medical-marijuana policies — without federal interference. MPP had lobbied Congress for five years to initiate this legislation, which MPP helped draft. As of today, 21 House members are sponsoring this legislation.
3. Public support for legalization reaches all-time high: On October 17, the Gallup organization announced that public support for “making marijuana legal” rose to 50% for the first time ever. This means that support has been rising by 1.5% annually since 1995.
4. Delaware legalizes medical marijuana: On May 13, Gov. Jack Markell (D) signed legislation making Delaware the 16th state to legalize medical marijuana. Of all the state laws that MPP has helped pass, the Delaware law was the cheapest, costing us less than $100,000 over the course of 2010 and 2011.
5. Maryland and Vermont improve their medical marijuana laws: On May 10, Gov. Martin O’Malley (D) signed a bill that improved Maryland’s law, allowing people who are arrested for marijuana possession to escape conviction if they demonstrate in court that their marijuana use was medical in nature. And on June 2, Gov. Pete Shumlin (D) signed a bill that improved Vermont’s existing medical-marijuana law by legalizing four dispensaries to sell marijuana to patients.
6. Maine, New Jersey, New Mexico, and D.C. implement/expand their medical marijuana laws: Abiding by a ballot initiative that 59% of Maine voters approved in November 2009, Maine’s health department issued eight dispensary licenses in 2010; all but one of the dispensaries have now opened their doors. In New Jersey, Gov. Chris Christie (R) famously held a news conference on July 19, saying he didn’t believe New Jersey dispensaries would be targeted under federal law; as a result, six dispensaries will open up in his state this year. In New Mexico, the number of dispensaries was increased from 17 to 25. And the D.C. government launched an application process that will result in 10 growers and five dispensaries being licensed in our nation’s capital by April!
7. Arkansas and Connecticut lower penalties for marijuana possession: On June 30, Gov. Dan Malloy (D) signed legislation decriminalizing marijuana in Connecticut, making the possession of under a half-ounce punishable by a fine of $150. And in Arkansas, Gov. Mike Beebe (D) signed legislation relaxing the penalty for possessing up to four ounces of marijuana — previously punishable by up to a year in jail and a $1,000 fine — judges may now punish first-time offenders with a year’s probation.
8. World leaders speak out: On June 2, the “Global Commission on Drug Policy” announced its support for rolling back the drug war, as a way of rejecting President Nixon’s launch of the modern drug war precisely 40 years earlier. Specifically, luminaries like Kofi Annan, George Shultz, and Richard Branson endorsed the decriminalization of marijuana. Shortly afterwards, President Carter followed suit. All of this generated huge waves of positive media coverage in the U.S. and worldwide.
9. Ron Paul shakes up the political debate: Congressman Ron Paul (R-TX), running for the Republican presidential nomination, continued to be fearless while attacking the U.S. drug war. As public support for his campaign continued to rise over the course of 2011, his words became more and more amplified, making “Ron Paul” a household name and opposition to the drug war respectable in Republican circles. And now he’s the number-two candidate on the Republican side — and certainly better than President Obama!
10. Governors ask the feds to reschedule marijuana: On November 30, Governors Christine Gregoire (D-WA) and Lincoln Chafee (I-RI) formally petitioned the DEA to move marijuana from Schedule I to Schedule II, thereby declaring that marijuana has medical value. While both governors did this for political reasons — Gregoire to posture that she’s better on medical marijuana than she really is, and Chafee to avoid a legal conflict with the feds — the fact remains that this is the most significant challenge to the federal government’s classification of marijuana since Congress and President Nixon declared marijuana to have no medical value in 1970.