Synthetic cannabinoids (sCBs) are a class of designer drugs meant to interact with the endocannabinoid system. Going by names like spice and K2, they are used largely as a result of prohibition — many sCBs are technically legal and difficult to detect, so people will not be punished for use as they would be for smoking cannabis. Many synthetic cannabinoids are also used as research tools, allowing scientists to probe the role of the endocannabinoid system in disease when they cannot get legal access to THC or cannabis. People may be misled by the safety of cannabis, expecting sCBs to be equally safe. But unlike cannabis, the risks of these chemicals can be serious. There have been numerous instances of heart attacks, strokes, seizures, and psychotic episodes that end in death after smoking synthetic cannabinoids. British researchers recently published a report on the types of sCBs found among those who have died in the UK since 2014 (the cannabinoids were not necessarily the cause of death). Over a four-year period, their group found 113 bodies with detectable levels of 12 different synthetic cannabinoids. sCBs were found almost exclusively in men. Most of the sCBs were used for a 1-2 year period before being replaced by a new analog. This makes it very hard to prevent use or diagnose problems when people overdose and arrive in the emergency room. The common recent sCBs were 5F-ADB and AB-FUBINACA, according to this study which ended in early 2018. The current set of synthetic cannabinoids used in England is now likely different.
CBD and Liver Damage
One of the only established harmful effects of CBD is the modulation of liver enzymes. High doses of CBD — a few hundred or thousand milligrams taken orally — can inhibit drug-metabolizing enzymes. Additionally, the elevation of aminotransferases (ALT and AST) is sometimes observed in patients taking CBD and valproate, an anti-epileptic drug. When these enzymes increase, it is usually indicative of ongoing stress on the liver and potential liver damage. Although these changes appear to reverse with cessation of CBD treatment, it is important to be cognizant of the possible reaction. But these problems are seen when 20-50 mg/kg of CBD are given along with other drugs. These concerns are part of the reason that the maximum recommended dose of Epidiolex is 20 mg/kg/day in humans with healthy livers. A recent study took this well out of proportion. University of Arkansas researchers found liver harms when forcing feeding mice up to 2460 mg/kg CBD in one go (123 times the maximal recommended dose; nearly 0.25% of their body weight in pure CBD), or 615 mg/kg over 10 days. The authors propose this as evidence that CBD — at normal human doses — is hepatotoxic, and that this «raises serious concerns about … the safety of CBD.» The work that physicians have done with Epidiolex has provided important insights into legitimate worries about using isolate CBD in certain patients. But warning about the dangers of drinking over 10 bottles of Epidiolex at once adds nothing useful to the discussion.
CB1 and Hormone Therapy
Hormone replacement therapy is used to reduce some of the symptoms of menopause. Although it can reduce problems like osteoporosis, hot flashes and depression, hormonal treatments come with risks including an increased likelihood of stroke and heart attack. Among those who use hormone therapy, scientists tend to believe there is a “critical window” where hormone replacement can reduce depression and the worsening memory associated with menopause. A new study from researchers in Xi’an, China, indicates that activating CB1 may prolong this window. They examined hormone levels, biochemical regulators of CB1, and mice’s ability to adaptively learn after inducing a mouse model of menopause. Estradiol treatment improved learning, but not when given three months after the onset of the menopause model. However, when CB1 receptor levels were artificially increased, the hormone treatment became more effective. The experimental methods cannot be directly translated to humans, but the interplay between sex hormones and the endocannabinoid system is increasingly recognized as relevant to health and medicine.
Cannabis in Hospice Care
The elderly are the fastest growing population of cannabis users. But how do hospice workers feel about their patients using cannabis? A recent survey by pharmacists at the University of Maryland asked palliative care practitioners about their opinions on cannabis use among hospice patients. Over 90% of workers support the use of cannabis, but most physicians did not recommend cannabis to their patients. This may be due to a lack of knowledge about safe use of cannabis — over 80% of respondents wanted standardized protocols on the use of cannabis in palliative care. As well, many hospices receive federal funding, so workers were worried about breaking federal law, even while complying with state laws. Fewer than one in five hospices had a formal policy about medical cannabis. Workers reported that cannabis was useful in reducing pain, anxiety and nausea. But physicians would rarely bring up cannabis to their patients.
Doctor My Eyes
Robert Randall was the first U.S. citizen to legally access cannabis based on medical necessity since the start of prohibition. He and his wife, Alice O’Leary Randall, sued the government because THC-rich cannabis was the only effective medicine for his glaucoma. More recently, the American Academy of Ophthamology has taken a stance against cannabis for glaucoma, citing the high dose of THC needed and the efficacy of new medications. But whether or not cannabis is used for glaucoma, doctors should be taking note of the endocannabinoid system in many parts of the eye. Scientists led by Alex Straiker at the University of Indiana — a powerhouse of cannabinoid research — have recently described the role of cannabinoids in healing wounds on the cornea, the protective film on the eye’s surface. They looked at one of the less established cannabinoid receptors, called GPR18, which mediates some of cannabinoids’ effect on blood pressure and cardiovascular health. GPR18 is an orphan receptor, meaning its natural activator is not known. The lead candidate is a compound called NAGly (N-arachidonoylglycine). NAGly is thought to be synthesized from the breakdown products of anandamide. Using a mouse model, the researchers show that activating GPR18 with NAGly speeds up the rate at which cells proliferate to close a wound like a scratch on the cornea. Blocking this receptor has the opposite effect; it slows eye’s ability to repair.
Preventing Pain with Orphan Receptors
Phytocannabinoids consistently confuse scientists because of the multiplicity of their actions. CBD, for example, binds to a handful of neurotransmitter receptors, as well as hormone receptors, ion channels, and a variety of enzymes. Receptors without a known endogenous ligand are called “orphan” receptors. GPR18 is involved in ocular-pressure (and hence glaucoma treatment) as well as cardiovascular function. The receptor named GPR55 is relevant in cancer pathology, and works with the CB2 receptor to regulate immune migration. In a review published in Frontiers in Pharmacology, Mexican and Texan scientists describe the modern approach to pain treatment and propose a future role of cannabinoids, GPR18, and GPR55 in preventing pain.
Natural High: CBD Augments Anandamide
It has been known for some time that CBD acutely increases anandamide levels. The enhancement of cannabinoid tone is presumably responsible for some of CBD“s medical properties, from anti-psychotic actions to anti-inflammatory effects. Initial reports suggested that CBD inhibits FAAH, the enzyme tasked with breaking down anandamide. But subsequent studies didn’t back this up. In 2009, scientists at Stony Brook identified fatty-acid binding proteins (FABPs) that shuttle endocannabinoids around the cell. The Stony Brook group subsequently discovered that CBD and THC can act as endocannabinoid reuptake inhibitors by displacing anandamide from FABP transport molecules, which prolongs the activity of endocannabinoids at the surface of neurons and other cells. Now, a paper from Emma Leishman, Heather Bradwshaw, and other researchers at Indiana University has proposed yet another mechanism by which CBD elevates anandamide: promoting anandamide synthesis. At the risk of sounding overly technical, here’s how it works: Enzymes going by the name phospholipase cut fats out of the cell membrane. Then phospholipase C (PLC) teams up with DAG lipase to produce 2-AG, while a similar enzyme called NAPE-PLD synthesizes anandamide. In cell cultures or the brains of mice, applying CBD increased anandamide levels (along with many closely related fatty acids). But in mice genetically engineered to lack the anandamide synthesizing enzyme NAPE-PLD, CBD had nearly no effect. (Very strangely, anandamide levels were the same in mice without NAPE-PLD, indicating that anandamide can be synthesized in other ways.) THC, meanwhile, tended to decrease the levels of anandamide and related lipids, although there were differences across the various experimental methods used. The authors also found that a mixture of THC and CBD changed the lipid profile of cells differently than either molecule alone. The 1:1 combination created «a mosaic of the individual drug results,» that was different from THC, CBD, or what would be expected from simply adding the two. This indicates a more complex interaction between the cannabinoids, which should not be surprising for anyone familiar with the entourage effect. The effects of CBD are clearly manifold — the modulation of lipids was not quite the same across the researchers“ different models, perhaps because of the other molecular targets of CBD. The mechanism by which CBD would affect NAPE-PLD is still unclear. Yet these results affirm a number of consistent trends. CBD alters the balance between inflammatory and anti-inflammatory lipids, as does THC, and the two phytocannabinoids combine in non-obvious ways. There is a tendency for phytocannabinoids to reduce inflammation and elevate endocannabinoid levels, but this depends on the specific cell, animal, or experiment in question.
CB1 and learning
If THC makes people forgetful while they’re high, one might reasonably expect that blocking the CB1 receptor that mediates the high will promote focus and the ability to learn. But is this true? There are several issues to consider when systemically blocking the CB1 receptor, such as the increased rates of suicidal thoughts. This is, without a doubt, an unacceptable side effect. However, it’s still useful for scientists to tease apart the roles of cannabinoids in learning. Researchers at Wake Forest University, working with Allyn Howlett (the head of the team who discovered the CB1 receptor in 1988) recently published one such study. They used a rat model of learning and compared the effect of a CB1 inhibitor (Rimonabant) given acutely to chronic administration or no drug at all. The blockade of CB1 increased the expression of genes that modulate synaptic plasticity. It would appear that this makes the brain more adaptable and able to learn. But not only did the drug-treated rats not learn better, tests showed they were worse after a week. This is not surprising when considering how “learning” was measured. The researchers’ test of learning required the rats to forget, and it is well established that blocking CB1 prevents animals from letting go of irrelevant memories. In particular, the trained rats that got Rimonabant tended to worsen over time (relative to controls). This could mean that they were simply learning at a slower rate, or that chronic inhibition of CB1 led to other changes in the brain. These maladaptive changes may have been the genetic markers of brain plasticity that the scientists had found; An adaptive brain doesn’t grow indefinitely, rather it finely tunes neural connections, sometimes cutting back what is not needed and forming more useful synapses with the newly freed bandwidth. Totally preventing CB1 activation with Rimonabant may have promoted the growth side of plasticity, but other studies shows that it also shuts down the brain’s ability to prune unhelpful connections. Cannabinoids tie significantly into human learning and memory, but harnessing this with blunt chemical tools seems unlikely.
Exercise for Depression
It’s increasingly recognized that the runner’s high, which used to be attributed to endorphins, is conferred partly by endocannabinoids in the brain. In response to the stress of exercise, the brain produces anandamide, “the bliss chemical” which provides that feeling of elation along with pain reduction and health benefits. A collaboration between researchers in Wisconsin and at Iowa State University has sought to understand this phenomenon in women suffering from depression. Exercise is known to have antidepressant properties and depression is associated with changes in our endocannabinoid system; could a blissful runner’s high help pull someone up from a depressive low? Women diagnosed with major depressive disorder were assigned to a moderate exercise routine involving only 30 minutes of cycling. This routine increased anandamide levels and decreased depressive feelings. Endocannabinoid levels are often diminished in people with depression, and restoring cannabinoid tone with exercise seems promising. Of course, exercise is an important contribution to health independent of its interaction with the endocannabinoid system. Oddly, the same elevation in endocannabinoid levels was not seen when the participants exercised for 30 minutes at whatever intensity they desired. OEA (an anandamide-like molecule involved in feeling satiated with food or alcohol) levels in the blood also increased with moderate exercise, but not with the preferred-intensity group. The blood-concentration of 2-AG actually decreased with exercise, but this may have been a spurious result, as previous studies have shown an increase of 2-AG levels after working out, and the statistical methodology in this article is prone to false results.
CBD and Organ Transplant
With CBD becoming more mainstream, doctors are on the lookout for how this powerful chemical affects human health. But a typical adult in the U.S. takes at least one pharmaceutical, and CBD’s interaction with other medications can be significant, especially given how easily one can overdose on common drugs. A new potential interaction has been highlighted by scientists at the University of Cincinnati, in Ohio. They report a woman using an extremely high dose of pure CBD for epilepsy — between 2-3 grams per day. She was also taking tacrolimus, a common immunosuppresive drug, to treat a kidney disorder. When combining these two treatments, tacrolimus levels in the blood rose by three-fold — a dangerous result. Because the addition of CBD helped control the seizures, her doctors helped her adjust the dose of these two drugs. This is commonly what happens with drug-drug interactions — there is an important need to monitor drug levels, but the interaction can be managed without ill effect for many patients.
Tacrolimus is a mainstay medication for organ transplant, so this possible interaction could be important for patients who need an organ transplant. Moreover, there has been some research on the potential to use CBD in transplant patients. Both THC and CBD tend to tone down immune activity and they have recently been suggested for treating graft-versus host disease, a potentially deadly reaction to organ transplants. How relevant is a cannabinoid-drug interaction like this to the average person? It depends greatly on the dose of CBD. In this case, there are probably two proteins that CBD interferes with to increase drug exposure — it inhibits CYP3A4, an enzyme that breaks down more than half of all pharmaceuticals, and it can inhibit P-gp, a protein which pumps chemicals out of certain cells. But this woman was using multiple grams of CBD per day. If she got this from good quality cannabis flower (say, a flower that’s 20% CBD by weight), she would have to eat half an ounce each day. That’s not the normal dose that people take, even those using cannabis for epilepsy. When unpurified cannabis extracts are used, the common doses are 10-100 times lower. THC and other plant compounds appear responsible for this greater potency, and the consequent lesser risk of drug-drug interactions. In other words, THC seems to make CBD a safer more effective medicine.