A 19-year-old is rushed to the emergency room, having passed out at home. The kid can’t breathe. He’s clearly in respiratory failure. Doctors notice blood around his mouth, but there’s no discernible cause – no infection, no trauma, no other damaged organs. Except the lungs. The patient undergoes mechanical ventilation for roughly 60 hours as the medics try to diagnose and treat the stricken teenager.

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Part 1: Under the Radar

Luckily the injured youth survived, thanks to the doctor’s quick response.

“[A] chest CT scan revealed patchy scattered ground glass opacities,” according to the physician who wrote up the case. The medics determined it was a case of diffuse alveolar hemorrhage – blood vessels had ruptured, filling parts of the lungs with blood and preventing oxygen exchange.

This patient’s brush with death due to respiratory failure was described in a 2011 report on the adverse consequences of inhaling synthetic cannabinoids (sCBs), a group of hard-to-detect research chemicals that powerfully influence the endocannabinoid system.¹ This would prove to be the first in a series of case reports, extending to the present, which highlight that sCBs can cause respiratory failure.

During the Summer of 2019, the same symptoms that can indicate sCB toxicity — ground glass opacities, ruptured blood vessels, oxygen deprivation as lungs fill with fluid — would surface repeatedly in what the Centers of Disease Control (CDC) has deemed an “outbreak of lung injury associated with vaping.” Such incidents became more frequent in July. As of November 8th, more than 2000 people had been hospitalized and 39 had died from vaping-related pulmonary failure, according to the CDC, which issues weekly updates on the vaping crisis with the latest alarming statistics.²

The CDC has yet to identify a single common factor in all cases beyond the use of vaporizers or electronic cigarettes. Thus far, reported cases have involved people vaping THC (tetrahydrocannabinol) oil and/or CBD (cannabidiol) oil, as well as users of nicotine e-cigarettes. Black market THC vape cartridges are particularly suspect, but legal cannabis oil vapes and nicotine-only products have also been implicated.

Curiously, the CDC makes no mention of synthetic cannabinoids in their weekly updates, even though the symptoms of sCB-induced toxicity match symptoms that figure prominently in the current, headline-generating vaping crisis. Since the start of the outbreak, health officials have been eyeing several possible culprits — chemical flavorings, vitamin E, polymer thinning agents, metals leached from vaporizer heating coils, and so on. But vape oil contamination by synthetic cannabinoids is one possibility that has flown under the radar.^3-5

Project CBD maintains that synthetic cannabinoids deserve serious attention.

CDC Criteria for Vaping-Related Lung Injury

Let’s step back for a moment and assess the situation. A “case” is considered part of the current lung injury outbreak, according to the CDC, if an individual presents in dire respiratory distress and:

1. was vaping or dabbing sometime within 90 days of symptoms;
2. has pulmonary infiltrates in a chest scan, which, on CT scans, typically appear as ground-glass opacities; and
3. is absent of infection or another plausible cause of respiratory distress.

If the third condition is not satisfied, a patient can still be classified as a “probable” rather than a “confirmed” case.⁶

Since the CDC’s classification of a case is broadly inclusive, there are likely a multitude of factors that could contribute to vaping-related lung injuries. Many types of lung pathologies have been reported during the current outbreak. Lung problems that are implicated include lipoid pneumonia, acute eosinophilic pneumonia, alveolar damage, and diffuse alveolar hemorrhage.

Synthetic cannabinoids have not been shown to cause lipoid pneumonia. But in cases with alveolar hemorrhage, sCBs need be considered. Synthetic cannabinoids may also be relevant in patients with acute eosinophilic pneumonia and anyone with concurrent neurological or cognitive impairment.

A Potpourri of Poison

Inhaling vitamin E acetate, a thickening additive, can cause lipoid pneumonia, and this may be germane to some of the recently reported cases.⁷ But other patients were found not to have lipid buildup in the lungs,⁸ so it is not the sole cause of problems. It should be noted that vitamin E is legal in most vaping products, despite a lack of demonstrable safety when heated and inhaled. Vitamin E is Generally Recognized as Safe as a food additive by the FDA, giving rise to the unfounded sense that it is also safe to inhale.

Thinning agents, like propylene glycol and polyethylene glycol, can be carcinogenic when heated to high temperatures.^9,10 But there are no reports of acute respiratory distress from thinning agents, despite their use in nicotine e-cigarettes since roughly 2007. The potentially harmful long-term effects of thinning agents are overshadowed by nicotine, which has an established toxic profile of its own.¹¹

Flavoring agents are problematic, in part because they make products even more addictive for consumers and more appealing to children. Some flavoring additives have been linked to pulmonary problems like popcorn lung.¹² They are also legal in most vaping products, despite a lack of safety data for heating and inhaling these ingredients.

Little evidence demonstrates that thinning agents or flavoring agents are causing the recent crisis. Although we view these dodgy additives as unlikely culprits in the current lung injury outbreak, this is not to say they should be regarded as safe, or that the current regulations are sufficient for consumer protection.

Which brings us to synthetic cannabinoids.

Numerous case reports have demonstrated that sCBs can land someone in the emergency room for respiratory distress. According to various accounts, sCB adulterants have been found in some unregulated online CBD products, as well as in black market THC vapes.^13-17 Despite these findings, reports about the current outbreak generally do not discuss synthetic cannabinoids.¹⁸ And no legal market in the United States requires testing to ensure the absence of sCBs in cannabis or CBD products.

In order to assess the role that sCBs may be playing in the outbreak of vaping injuries, it’s important to understand the complex pharmacology of synthetic cannabinoids and how they are fundamentally different from THC and other naturally occurring plant cannabinoids.

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Part 2: What are Synthetic Cannabinoids?

Synthetic cannabinoids are a class of hundreds of research compounds designed to interact with the endocannabinoid system. JWH-018 was the first sCB to emerge as an abused substance in the mid-2000s along with other “designer drugs” like synthetic cathinones (sometimes called bath salts)¹⁹

Synthetic cannabinoids can be directly sprayed on cannabis or other herbs, and then are sold as products with names such as bonsai, K2, spice, herbal incense, Armageddon, and Agent Orange, among others. Products contain anywhere from one to a handful of active compounds. Some sCB products are sold as powders or concentrated oil extracts suspended in propylene glycol.

It’s nearly impossible to detect hundreds of potential sCBs in a single test, and dozens of new sCBs are designed every year. The variety of compounds also makes dosing risky for consumers, since each sCB has a different potency. If someone can’t gauge a ‘normal’ dose, they are much more likely to overdose.

There is no consistent set of symptoms during a sCB overdose, so nurses and doctors who encounter such patients in the emergency room rarely have guidance or experience to direct their actions. Between 2016-2018, a large fraction of reports pertained to two of these chemicals, called AMB-FUBINACA and 5F-ADB, either because they are particularly common or particularly lethal.

Synthetic Cannabinoids & the Lungs

Synthetic cannabinoids have been reported to cause a variety of health problems and are potentially deadly. Diffuse alveolar hemorrhage and acute respiratory failure, heart attack, stroke, seizures, and kidney damage are all possible consequences of sCB use.

The 2016 episode reported as the “New York City zombie outbreak” has been attributed primarily to the synthetic cannabinoid AMB-FUBINACA^20,21 So has a spate of roughly 50 deaths in New Zealand in 2017 and 2018.²² Because relatively few people use sCBs, the total number of deaths is small. But sCBs are highly dangerous drugs.

A handful of case reports have associated sCBs with lung toxicity. It is not the biggest risk of sCBs, considering their other potential harms, but there is a fairly consistent set of symptoms that aligns with the CDC’s diagnostic for a “confirmed cases” in the recent vaping outbreak.

While analyzing ICU visits of patients overdosing on sCBs, doctors at MedStar in Washington, DC, noted that “Pulmonary edema²³ and tachycardia were the most common findings” of sCB use and organ failure was “primarily driven by altered neurologic status and respiratory failure.”²⁴ They went on to implicate “synthetic cannabinoids as a potential cause of acute lung injury and acute respiratory distress syndrome.”

The various cases of sCB-induced respiratory depression have generally presented as follows:

• Individual was using synthetic cannabinoids for 1-3 months.
• Lung condition worsened either suddenly (within an hour of use) or over the course of a few days.
• Patient was hospitalized in significant distress with low blood-oxygen.
• Patient, if still alive, was intubated for up to a week.
• Patient was diagnosed with pulmonary edema and a CT scan showed ground-glass infiltrates in the lungs.
• Patient responded to short-term corticosteroid treatment.
• Pulmonary edema resolved and lung inflammation typically subsided.

Synthetic Cannabinoids Can Cause Respiratory Failure

There are numerous case reports of respiratory failure after intentional sCB use. These reports often align with the CDC’s current classification of a confirmed case of vaping-related illness.

The first case appears to have been reported in 2011 and was followed by several others:

1. Loschner et al (2011): A 19-year-old entered the ER after smoking a sCB called “the Greenhouse Effect.” He had been using sCBs for the prior two months. Radiography showed ground-glass opacities and alveolar infiltrates. The doctors ruled out infection as a cause and confirmed the patient had diffuse alveolar hemorrhage. He required mechanical ventilation for 60 hours and received methylprednisolone.²⁵
2. Alhadi et al (2013): A 21-year-old male who had recently used sCBs was hospitalized with “a chronic inflammatory infiltrate in both the airways and alveolar spaces.” The authors highlight that synthetic cannabinoids may have produced “distinct and rapidly resolving pulmonary lesions,” which responded to corticosteroid treatment.²⁶
3. Berkowitz et al (2015): The authors described “pneumonia in response to smoking synthetic [cannabinoids]” in four young men. All four patients had negative biological screens, ruling out infection. Three of four patients received steroids. All had ground-glass opacities in CT scans.²⁷
4. Öcal et al (2016): A case of acute eosinophilic pneumonia was diagnosed in a 21-year-old man. CT scan showed “irregular areas of ground glass opacities … evidently in the central part of the lower lobes.” Infectious diseases were ruled out as possible causes. The man admitted to using sCBs the previous month and had increased his use during the preceding week. The CT abnormalities had mostly resolved after three days of treatment with prednisolone.²⁸
5. Chinnadurai (2016): A 29-year-old man was brought to the ER after smoking K2. He had the same radiographic symptoms described by Berkowitz but they resolved spontaneously within 24 hours. He was brought to the ER because of agitation, sedated with lorazepam and haloperidol, and was kept because of a fever, not because of any residual lung symptoms.²⁹
6. Yamanoglu et al (2018): A 19-year-old smoked twice his normal dose of sCBs. He was comatose an hour later when the ER received him. Radiography suggested pulmonary edema and showed the typical “patchy ground glass density unexplained by a separate condition.”³⁰
7. Imtiaz et al (2019): Reporting on a similar case of respiratory failure within an hour of smoking K2, the authors stated, “We believe that the diagnosis of synthetic cannabinoid-induced respiratory failure can be established by the acute onset of hemoptysis³¹ and respiratory failure that is delayed 24-48 hours after inhalation of the drug, provided that alternative conditions … have been excluded.”³²

All these reports match the CDC’s classification for a probable or confirmed case in the current outbreak. In most instances, respiratory depression was linked to diffuse alveolar hemorrhage, but the exact mechanism varies between different cases (perhaps because of different sCBs).

Fake Weed, Real Dangers

There are many other published reports of respiratory depression related to sCBs that don’t precisely fit the CDC’s classification.

For example, Ivanov presented the death of an 18-year-old boy who had been using sCBs for some months.³³ The night before his death, he smoked three “fake weed” joints containing AMB-FUBINACA and 5F-ADB. Postmortem analysis indicated acute respiratory distress syndrome, pulmonary edema, and lung inflammation. However, pulmonary infiltrates are not mentioned in this report, making it unclear if this matches the CDC’s criteria for vaping-related pulmonary injury.

A report from 2016 mentions that AB-CHMINACA is sometimes added to “propylene glycol… for use in electronic cigarettes”³⁴ In this paper, Gieron and Adamowicz describe the death of an individual within hours of using AB-CHMINACA. They report that “the cause of death was acute cardiorespiratory failure of indeterminable cause,” however no details of the individual’s lung condition are given. This particular sCB, which appears to have emerged in 2014, has been implicated in several other cases.

At a 2015 meeting of Society of Forensic Toxicologists, Shanks et al described three cases of respiratory failure related to AB-CHMINACA.³⁵ In one individual, “autopsy included severe pulmonary edema and congestion,” along with other signs of organ damage. In another case, a woman involved in a car crash was found to have AB-CHMINACA in her bloodstream and “bilateral pulmonary edema and congestion along with general visceral congestion.”

In 2019, Adamowicz reported on pulmonary edema and “left-side pleural adhesions” after sCB use.³⁶ But histological analysis didn’t show ground-glass infiltrates or inflammatory changes. Two years earlier, Maeda and colleagues reported on a death in Japan with “[s]evere alveolar effusions with evidence of air bubbles and hemorrhage,” however they suggest that sCBs caused seizures which precipitated respiratory depression.³⁷ And a 2012 report identified a teen who was in respiratory distress and required ventilation after a seizure from sCB use.³⁸

When intentionally using sCBs, people tend to smoke rather than vape. But inadvertently vaping oil contaminated with sCBs is likely to result in the same toxicity as intentionally smoking sCB-laced herbs, so all these cases are potentially relevant to the current vaping scourge.

Challenges Detecting Synthetic Cannabinoids

Given the consistency of published reports on respiratory failure associated with intentional sCB use, their association with quasi-legal cannabis products, and documented examples of sCB-contaminated cannabis oils, synthetic cannabinoids should be considered a prime suspect in the outbreak of vaping-related lung injuries.

But there are a number of challenges that make it hard to detect sCBs. For starters, there are hundreds of compounds in this class of drugs, and it is unlikely that those reporting cases to the CDC have ruled out every possible chemical. Additionally, many synthetic cannabinoids are orders of magnitude more potent than THC. A chemical 100 times more powerful than THC has to be detected at very low concentrations, and most labs do not specialize in sCB detection.

Another issue: case reports have demonstrated that sCBs can be cleared from the blood within hours of administration,³⁹ so a negative blood test does not mean there was no sCB use. It would be better to test the product, if it is available.

Efforts have been made to classify sCBs.⁴⁰ A handful of common chemical scaffolds make up the bulk of sCBs that authorities encounter. In cases where officials have access to the product that injured consumers had used, detection should be possible. The CDC and other official bodies should work with toxicology labs to iron out a consistent testing methodology.

Why Are Synthetic Cannabinoids Added to Vape Oil?

If synthetic cannabinoids are indeed contributing to the outbreak of vaping-associated respiratory failure, the obvious question is why? Why would products be adulterated with sCBs? Why are they particularly common in illicit products? Is bad public policy partially to blame?

Synthetic cannabinoids are cheap to produce and not easily detected in standard drug tests. In theory, producers can heavily dilute the base oil to extend their profits, then bump the “potency” back up by adding synthetic cannabinoids. This would additionally create an association with thinning agents — a combination that is consistent with the range of products linked to vaping-related illnesses.

Nicotine products have been implicated as well as black market and legally sold THC vapes. Since legal markets do not require testing for sCBs, they could make their way into both licit and illicit products, although the bad actors adulterating products are more likely to be in the black market, evading taxes and quality controls. Currently around 80 percent of reported vaping-related lung injury cases involve THC products (mostly illegal) and about 60 percent involve nicotine. Most people are using both.

While synthetic cannabinoids have not been officially confirmed as a contributor to the vaping outbreak, they are plausible culprits. From what we know thus far, it seems certain that multiple causes are involved in the outbreak, and synthetic cannabinoids may be playing a significant yet underappreciated role.

Consuming sCBs is dangerous for many reasons. They can trigger seizures, for example, as well as heart attack and acute kidney injury. But if synthetic cannabinoids are contributing to respiratory ailments, then why haven’t we also seen a spike in these other health problems?

In fact, vaping Juul, the dominant e-cigarette, has been associated with seizures.⁴¹ After announcing an investigation in April 2019, the FDA compiled 127 reports of seizures and neurological problems associated with vaping nicotine e-cigs in the past 10 years.⁴² This information was released in August of 2019, in the middle of the outbreak of vaping-related respiratory failure. It appears that these neurological symptoms are a side effect of high doses of nicotine, not a synthetic cannabinoid issue. Seizures sometimes occur when people accidentally swallow vaping liquid, according to the FDA.⁴³

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Part 3: Escaping the Laboratory

How did a few obscure research chemicals end up spawning what is now the largest group of designer drugs?

Synthetic cannabinoids are, in many ways, a byproduct of cannabis prohibition. The proliferation of these compounds has been fostered by marijuana’s Schedule 1 status, which continues to undermine research efforts to understand the endocannabinoid system.

Scientists who want to study how plant cannabinoids impact the brain and body are barred by federal policy from accessing the most obvious research tools – cannabis extracts. Synthetic compounds that target the endocannabinoid system are okay for research purposes, according to Uncle Sam. But scientists, with few exceptions, aren’t allowed to work with oil from the plant.

So pioneers in the field had to create their own cannabinoids for research purposes. These human-designed compounds are called synthetic cannabinoids, even though their molecular structures and effects differ significantly from THC and other phytocannabinoids.⁴⁴

Groundbreaking chemists – the likes of Alexandros Makriyannis, Raphael Mechoulam, and John W. Huffman – have driven cannabinoid science forward with their unique chemical contributions. They spent much of the 1990s searching for ever more powerful tools in the form of super-potent synthetic cannabinoids. Maybe they’d hit the jackpot by creating a safe and novel (read: patent-able) chemical with therapeutic potential. More likely, drug design would follow an iterative process. New chemicals would be designed with slightly different features, and their potency or lack thereof might shine a light onto hidden facets of the cannabinoid receptors.

For drug designers, there are conflicting drives towards potency and safety. With potency being a key priority, the first synthetic cannabinoids were developed as sophisticated research tools. Human safety was not the foremost goal because these chemicals weren’t meant to make it out of the lab. They were not designed for human consumption.

Several hundred sCBs, some much stronger than THC, have been utilized extensively in preclinical research. Their formulas were published in scientific journals and underground chemists were able to reproduce and market some these compounds as synthetic substitutes for cannabis. One such concoction, a potent cannabinoid (CB₁) receptor stimulant called JWH-018,⁴⁵ inadvertently escaped from the Clemson University lab where it originated and resurfaced later as an illicit street drug.

In 2008, JWH-018 was identified as an ingredient in Spice sold in Germany.⁴⁶ Then came “CP-47,” another powerful synthetic cannabinoid. The German government banned JWH-018 and CP-47, but within weeks new analogues were sold in their place, sometimes with merely a single atom altered.⁴⁷ Facilitated initially by this legal loophole, synthetic cannabinoids took on a life of their own. But modifying these chemicals also changes their risks, such that all bets are off when it comes to consuming sCBs.

Fast forward to 2019: Over 1000 sCBs have been identified in various products around the world.⁴⁸

Cannabis vs. Synthetic Cannabinoids

Why are synthetic cannabinoids so dangerous when cannabis itself has never caused an overdose death?

Synthetic cannabinoids are worrisome, in part, because there is no historical track record indicating that they are safe. But their ultra-high potency is not necessarily what makes them risky. “Potency” is simply a number that corresponds the dose required to get an average effect from a drug. But it says nothing about what the drug actually does.

If potency was the only problem, then the deadly effects of sCBs would be replicated by a large enough dose of THC. And this has never happened. Although synthetic cannabinoids’ mechanisms of toxicity are poorly understood, it is well established that cannabis – even a high potency THC extract – bears no lethal toxicity.

The physical and psychic effects of drugs are complex, so it helps to borrow from the language of pharmacology, a field dedicated to understanding the human consequences of drug use. In pharmacological research, there are other important measures (besides potency), such as efficacy, off-target effects, and functional selectivity. These four pharmacological concepts help to clarify the differences between phytocannabinoids, endocannabinoids, and synthetic cannabinoids.

• Potency refers to the dose of a drug needed for an effect. Synthetic cannabinoids are generally much more potent than THC. Someone who knowingly or unknowingly smokes a cannabis joint sprayed with AMB-FUBINACA might think that they can smoke the whole thing, not realizing that AMB-FUBINACA is about 50-80 times more potent than pure THC.
• Efficacy describes the maximal effect a drug can have. THC has a lower efficacy than most endocannabinoids (the endogenous compounds that THC mimics). This means that at large doses, THC will hit a ceiling. Taking more THC won’t increase CB₁ receptor activity (which mediates psychoactivity) beyond a certain point. With synthetic cannabinoids, the ceiling is much higher than with plant or endogenous endocannabinoids, so overdosing can be quite disruptive to health.
• Off-target activity varies significantly with respect to THC and synthetic cannabinoids. Both confer euphoria (or dysphoria) through the activation of the CB₁ cannabinoid receptor. But THC and sCBs each have numerous off-target actions that affect other receptors and various organs in the body, and these off-target activities can produce additional side effects or harms. There is no reason to assume that the off-target effects of THC and sCBs are similar.⁴⁹ This is not well studied, partly because each individual sCB may have a different profile.
• Functional selectivity means that two different chemicals, even when activating the same receptor, can produce widely different effects in the cell. This phenomenon is known as “biased agonism.”

A drug’s potency and efficacy at a receptor can be measured with relative ease in cellular assays. But determining off-target effects and the relevance of a drug’s functional selectivity is no easy feat, especially given how quickly old sCBs are eclipsed as newer, unrecognized sCBs emerge each year.

AMB-FUBINACA’s Pharmacology

Let’s dive into the pharmacological subtleties of one particular synthetic cannabinoid to understand why, unlike THC, the sCBs can be so toxic.

“AMB-FUBINACA” has been implicated in tens, if not hundreds, of deaths in New Zealand over the past few years. As a result, scientists from New Zealand have studied this sCB in meticulous detail. This effort has been spearheaded by Michelle Glass, head of the Chemistry department at the University of Otago.

AMB-FUBINACA was first identified in the product sold as “Train Wreck 2” in Louisiana in 2014, five years after the compound had been patented by Pfizer.⁵⁰ In 2017, it showed up in New Zealand and quickly became one of the most common sCBs in that country.⁹

The intracellular effects of AMB-FUBINACA were characterized in a 2019 publication written by post-doctoral researcher David Finlay along with Dr. Glass and other scientists at the University of Otago.⁵¹ In an article in Chemical Neuroscience these researchers explored the functional selectivity of AMB-FUBINACA at the CB₁ receptor, comparing the unique toxicity of this synthetic cannabinoid to the more benign effects of THC.

Pharmacologists probe these mechanisms in precise technical detail, which we’ll describe at the risk of getting lost in a flurry of acronyms.

AMB-FUBINACA is about 25 times more potent than THC in activating CB₁ through one “canonical” pathway (the release of Gα; determined by cAMP formation). The synthetic cannabinoid AMB-FUBINACA outpowered THC to a similar degree in another canonical pathway (ERK phosphorylation, a measure of G-protein release). These two pathways are probably involved in the euphoria of THC and synthetic cannabinoids at low doses, as well as the anxiety that larger doses of either substance can produce.

In addition to its higher potency, a single molecule of this synthetic cannabinoid mobilized twice as much activity inside the cell as a single molecule of THC. In other words, THC is half as efficacious as AMB-FUBINACA in the pERK assay.

Cutting to the chase, the higher potency of AMB-FUBINACA means that users are more apt to accidentally use too much, while its higher efficacy means that overdosing could have more severe consequences.

CB₁ Desensitization & Internalization

The way sCBs activate the CB₁ receptor is particularly toxic. Could it be the cell’s overreaction — while attempting to recuperate from these highly powerful sCBs — that’s doing the most harm?

The body always tries to preserve balance. It’s a phenomenon known as homeostasis, and this adaptability is the hallmark of life. When a receptor is activated intensely or for a long period of time, the cell tries to fine-tune things back to normal by desensitizing its response to the receptor.

Some molecules are biased towards desensitization.⁵² Such compounds trick the cell into thinking that a receptor is overactive, thereby mobilizing homeostatic mechanisms to tone down the receptor’s function.

The New Zealand scientists measured desensitization by quantifying how long CB₁ receptors would remain accessible to drugs on the cell surface. Within three minutes of applying AMB-FUBINACA, more than half of the desensitized CB₁ receptors were brought inside the cell in a process called internalization. It took nearly 20 minutes for a high dose of THC to do the same.

In line with these results, AMB-FUBINACA recruited the classic markers of desensitization – called β-arrestins – to an incomparably greater degree than THC (even whooping doses of THC barely triggered cells’ β-arrestin pathways). β-Arrestins are one of the aforementioned mediators of homeostasis. They normally bind to a receptor after its activation, promoting balance by reducing the accessibility of overactive receptors.

Beyond this, β-arrestins appear to act as an alternate signaling outlet for receptor activity.⁵³ AMB-FUBINACA was considered to be the only compound⁵⁴ with a high enough potency to signal through β-arrestin in humans. Thus, the New Zealand scientists note, the unique toxicity of this synthetic cannabinoid may be related to its functionally selectivity towards arrestin signaling.

A Natural Bias

How does cannabis compare to our body’s endocannabinoids, known as anandamide and 2-AG, the native activators (or agonists) of CB₁? And how do endocannabinoids compare to synthetic cannabinoids as receptor agonists?

Finlay, along with Xiao Zhu and other collaborators at the University of Otago, have probed this question, employing similar methods they used to study synthetic cannabinoids.⁵⁵ Initially they focused on CB₁ receptor internalization in response to overstimulation.

The results for THC appear consistent between the two experiments. Their data across both studies suggest that THC is weaker than anandamide, which, in turn, is weaker than 2-AG and AMB-FUBINACA in terms of their capacity to cause CB₁ receptors to withdraw into the cell.

Among the endocannabinoids, 2-AG is considered a more tonic endocannabinoid,⁵⁶ whereas anandamide levels fluctuate rapidly in response to stress. The cellular study aligns with this fact: 2-AG levels will set the stage by determining the baseline rate of internalization. Meanwhile, the body can quickly regulate CB₁ activity with spikes and troughs in anandamide production without causing too much desensitization.

These results have significant implications for a hot topic in drug development: inhibitors of endocannabinoid breakdown, which indirectly boost CB₁ signaling. The natural “bias” of endocannabinoids suggests why new pharmaceuticals targeting enzymes that regulate the endocannabinoids system have not made it out of clinical trials.

Whether due to THC-phobia, the incentive for a molecule that can be patented, or genuine scientific interest, pharma companies are looking for new cannabinoid modulators.⁵⁷ In particular, they’ve sought out inhibitors of enzymes named FAAH and MAGL, which break down anandamide and 2-AG, respectively. Such compounds are dubiously framed as being more selective therapeutically than a blunt tool like THC.⁵⁸

But off-target effects ruined the chances of a FAAH inhibitor, dubbed BIA 10-2474, which made it to a phase I clinical trial. Trials of BIA 10-2474 were halted when one participant died and 5 others were hospitalized due to adverse off-target actions.⁵⁹

Off-target activities aren’t the only hurdle to developing enzymatic inhibitors.⁶⁰ The natural bias of both anandamide and 2-AG promote receptor internalization more potently and with greater efficacy than THC. So, it’s fair to suspect that drugs boosting endocannabinoid levels are likely to cause tolerance and require dose-escalation. And, indeed, preliminary research has highlighted that therapeutic doses of MAGL inhibitors quickly cause tolerance.⁶¹

Interpreting Pharmacology

It’s impossible to wade into this complex pharmacology and emerge with a perfect understanding of what it all means in terms of human health. When interpreting the patchwork of data and technical terminology in this report, it helps to return to the four key measures of potency, efficacy, bias, and alternate targets.

The mechanistic insights provided by various preclinical assays seem to converge on one point — that THC is a gentle modulator of the endocannabinoid system, despite what decades of fear-mongering may have led people to believe. Pharmaceutical companies will be hard pressed to create a new drug that targets the CB₁ receptor with fewer risks than THC.

It’s not just the moderate potency of THC, relative to AMB-FUBINACA or other sCBs, that makes the plant cannabinoid so much safer. THC’s lower efficacy provides a built-in guardrail that limits the harms of over-use.

And THC also has off-target actions at the CB2 receptor,⁶² which may offset some of the potentially harmful effects of CB₁ activation. For example, the pro-fibrotic effects of CB₁ in the liver can be reduced by CB2 activity.⁶³ THC’s activation of CB2 could explain the surprising but welcome association between cannabis use and better insulin sensitivity.^64,65 By being a non-selective activator of both cannabinoid receptors, the side effects of pure CB₁ activation are reduced.

THC also inhibits a pro-carcinogenic enzyme called CYP1A, which normally amplifies the toxicity of chemicals in smoke. This beneficial off-target action may explain the lack of a link between smoking cannabis and lung cancer, despite the presence of carcinogens in cannabis smoke.⁶⁶

The functional selectivity of THC also seems to work in its favor compared to synthetic cannabinoids, which are much more addictive than THC and cause a severe withdrawal syndrome. It is plausible that THC’s natural bias — its weaker desensitization patterns and weaker mobilization of β-arrestin pathways — also makes THC less prone to habit-formation and harsh withdrawal, and hence safer.

Much more clinical research needs to be done before this kind of speculation can be validated or refuted. On the pharmacological (and preclinical) side of things, we would want to see the relative bias between a compound’s aptitude to confer medical benefits and its preference for desensitization.

Yet science can only guide us so far. It’s clear that synthetic cannabinoids are more acutely toxic than tobacco. But officially sCBs have caused only a handful of lethal outcomes in the United States,⁶⁷ while cigarettes are responsible for some 480,000 deaths annually.

The extent of these problems is largely defined by drug policy and its failures. The scare around vaping should not be used to misdirect important changes in laws and regulations pertaining to cannabis, tobacco, and e-cigarettes.

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Adrian Devitt-Lee is a research scientist and longtime Project CBD contributor. © Copyright, Project CBD. May not be reprinted without permission.

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Footnotes & References

1. See here for the definition of a “case” of vaping-associated respiratory distress. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/assets/2019-Lung-Injury-Surveillance-Case-Definition-508.pdf
2. In one table in a CDC report they state that four people had confirmed use of synthetic cannabinoids while 289 had not.¹⁴ The CDC additionally suggests that clinicians ask patients if they had intentionally used sCBs. Synthetic cannabinoids have not been
3. Loschner, Anthony, et al. “Diffuse Alveolar Hemorrhage: Add ‘Greenhouse Effect’ to the Growing List.” Chest, vol. 140, no. 4, Oct. 2011, doi:10.1378/chest.1119854.
4. “Outbreak of Lung Injury Associated with the Use of E-Cigarette, or Vaping, Products.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 5 Nov. 2019, www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html#latest-outbreak-information.
5. Owermohle, Sarah. “Vitamin E Named as Primary Culprit in Vaping Illness, but Feds Urge Caution.” POLITICO, 5 Sept. 2019, www.politico.com/story/2019/09/05/vitamin-e-vaping-disease-cdc-1709200.
6. Hotz, Robert Lee. “Researchers Say Vitamin E Likely Isn’t the Culprit in Vaping-Related Ailments.” The Wall Street Journal, Dow Jones & Company, 2 Oct. 2019, www.wsj.com/articles/researchers-say-vitamin-e-unlikely-culprit-in-vaping-related-ailments-11570050000.
7. Dickson, EJ. “What’s Causing Vaping’s Mystery Illnesses? New Study Might Offer Some Answers.” Rolling Stone, 13 Sept. 2019, www.rollingstone.com/culture/culture-news/vape-illness-cause-vitamin-e-lung-illness-study-883548/.
8. Dicpinigaitis, P.V., Trachuk, P., Fakier, F. et al. Lung (2019). https://doi.org/10.1007/s00408-019-00277-6
9. Larsen BT et al. “Pathology of Vaping-Associated Lung Injury,” N Engl J Med (2019) http://doi.org/10.1056/NEJMc1913069
10. Marcu, Jahan. “How Safe Is Your Vape Pen?” Project CBD: Medical Marijuana & Cannabinoid Science, 14 July 2015, www.projectcbd.org/industry/how-safe-your-vape-pen.
11. Devitt-Lee, Adrian. “Toxic Vape Oil Additives Endanger Patients.” Update, 4 Apr. 2017, https://projectcbd.org/industry/toxic-vape-oil-additives-endanger-patients
12. Benowitz, Neal L., et al. “Cardiovascular toxicity of nicotine: Implications for electronic cigarette use.” Trends in Cardiovascular Medicine, 2016, doi:10.1016/j.tcm.2016.03.001
13. Park, H., O’Sullivan, M., Vallarino, J. et al. Transcriptomic response of primary human airway epithelial cells to flavoring chemicals in electronic cigarettes. Sci Rep 9, 1400 (2019) doi:10.1038/s41598-018-37913-9
14. “Characteristics of a Multistate Outbreak of Lung Injury Associated with E-Cigarette Use, or Vaping – United States, 2019.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 3 Oct. 2019, www.cdc.gov/mmwr/volumes/68/wr/mm6839e1.htm.
15. Kuehn B. Synthetic Cannabidiol Poisoning. JAMA. 2018;319(22):2264. doi:10.1001/jama.2018.7219
16. Justin L. Poklis, Haley A. Mulder, Michelle R. Peace, The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids, Forensic Science International, Volume 294, 2019, Pages e25-e27, ISSN 0379-0738, https://doi.org/10.1016/j.forsciint.2018.10.019.
17. Tony Rianprakaisang, Roy Gerona & Robert G Hendrickson (2019) Commercial cannabidiol oil contaminated with the synthetic cannabinoid AB-FUBINACA given to a pediatric patient, Clinical Toxicology, DOI: 10.1080/15563650.2019.1619758
18. Roberts, Chris. “With Dangerous Vapes and Killer Pills, Why Is the Surgeon General Worried About Weed?” Observer, Observer, 10 Sept. 2019, https://observer.com/2019/09/with-dangerous-vapes-and-killer-pills-why-is-the-surgeon-general-worried-about-weed/.
19. “Health Warning Issued over Fake ‘THC Vape’ That in Fact Contains ‘Spice.’” NHS Choices, NHS, 16 July 2019, www.christie.nhs.uk/about-us/news/latest-news-stories/health-warning-issued-over-fake-thc-vape-that-in-fact-contains-spice/.
20. These chemicals are often all lumped together as New Psychoactive Substances (NPS). This can obfuscate the differences between novel research chemicals. Synthetic cathinones like mephedrone and MDPV gained notoriety around 2008-2011 as major NPS. Synthetic cannabinoids are now considered to make up the majority of NPS use. Fentanyl analogues and other new opioids are a growing problem as well ^47, 48
21. Rosenberg, Eli, and Nate Schweber. “33 Suspected of Overdosing on Synthetic Marijuana in Brooklyn.” The New York Times, The New York Times, 13 July 2016, www.nytimes.com/2016/07/13/nyregion/k2-synthetic-marijuana-overdose-in-brooklyn.html.
22. Adams, Axel J., et al. “‘Zombie’ Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York.” New England Journal of Medicine, vol. 376, no. 3, 2017, pp. 235–242., doi:10.1056/nejmoa1610300.
23. Penman, Carla. “New Kind of Deadly Synthetic Drug Surfaces in Auckland.” NZ Herald, NZ Herald, 29 May 2018, www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=12060187.
24. Pulmonary edema is when fluid accumulates in the lungs and hinders breathing.
25. Tatusov, Michael, et al. “Clinical Effects of Reported Synthetic Cannabinoid Exposure in Patients Admitted to the Intensive Care Unit.” The American Journal of Emergency Medicine, vol. 37, no. 6, 2019, pp. 1060–1064., doi:10.1016/j.ajem.2018.08.048.
26. Loschner, Anthony, et al. “Diffuse Alveolar Hemorrhage: Add ‘Greenhouse Effect’ to the Growing List.” Chest, vol. 140, no. 4, Oct. 2011, doi:10.1378/chest.1119854.
27. Alhadi, S., Tiwari, A., Vohra, R. et al. J. Med. Toxicol. (2013) 9: 199. https://doi.org/10.1007/s13181-013-0288-9
28. Berkowitz, Eugene A., et al. “Pulmonary Effects of Synthetic Marijuana: Chest Radiography and CT Findings.” American Journal of Roentgenology, vol. 204, no. 4, 2015, pp. 750–757., doi:10.2214/ajr.14.13138.
29. Ocal, Nesrin, et al. “Acute Eosinophilic Pneumonia with Respiratory Failure Induced by Synthetic Cannabinoid Inhalation.” Balkan Medical Journal, vol. 33, no. 6, 2016, pp. 688–690., doi:10.5152/balkanmedj.2016.151145.
30. Chinnadurai, Thiru, et al. “A Curious Case of Inhalation Fever Caused by Synthetic Cannabinoid.” American Journal of Case Reports, vol. 17, 2016, pp. 379–383., doi:10.12659/ajcr.898500.
31. Yamanoglu, Adnan, et al. “A New Side Effect of Synthetic Cannabinoid Use by the Bucket (Waterpipe) Method: Acute Respiratory Distress Syndrome (ARDS).” Turkish Journal of Emergency Medicine, vol. 18, no. 1, 2018, pp. 42–44., doi:10.1016/j.tjem.2017.06.001.
32. Coughing up blood.
33. Imtiaz, Muhammad, et al. “A Case of Acute Life-Threatening Pulmonary Hemorrhage from Synthetic Cannabinoid Abuse.” Case Reports in Pulmonology, vol. 2019, 2019, pp. 1–3., doi:10.1155/2019/8137648.
34. Ivanov, Ivo D., et al. “A Case of 5F-ADB / FUB-AMB Abuse: Drug-Induced or Drug-Related Death?” Forensic Science International, vol. 297, 2019, pp. 372–377., doi:10.1016/j.forsciint.2019.02.005.
35. Gieroń, Joanna & Adamowicz, Piotr. (2017). Fatal poisoning with the synthetic cannabinoid AB-CHMINACA and ethyl alcohol – A case study and literature review. Z Zagadnien Nauk Sadowych. 106. 482-495.
36. Shanks, Kevin G. “Three Fatalities Associated with the Synthetic Cannabinoid AB-CHMINACA” SOFT 2015, 2015. http://soft-tox.org/files/meeting_abstracts/SOFT_2015_meeting_abstracts.pdf
37. Piotr Adamowicz, Ewa Meissner & Marta Maślanka (2019) Fatal intoxication with new synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA, Clinical Toxicology, 57:11, 1103-1108, DOI: 10.1080/15563650.2019.1580371
38. Hideyuki Maeda, Ruri Kikura-Hanajiri, Maiko Kawamura, Erika Nagashima & Ken-Ichi Yoshida (2018) AB-CHMINACA-induced sudden death from non-cardiogenic pulmonary edema, Clinical Toxicology, 56:2, 143-145, DOI: 10.1080/15563650.2017.1340648
39. Jinwala, Felecia N., and Mayank Gupta. “Synthetic Cannabis and Respiratory Depression.” Journal of Child and Adolescent Psychopharmacology, vol. 22, no. 6, 2012, pp. 459–462., doi:10.1089/cap.2011.0122.
40. Piotr Adamowicz, Ewa Meissner & Marta Maślanka (2019) Fatal intoxication with new synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA, Clinical Toxicology, 57:11, 1103-1108, DOI: 10.1080/15563650.2019.1580371
41. Potts, AJ., et al. “Synthetic cannabinoid receptor agonists: classification and nomenclature” Clinical Toxicology, 2019. doi:10.1080/15563650.2019.1661425
42. Edney, Anna, and William Turton. “Juul Devices Cited in Seizure Reports That Started FDA Probe.” Bloomberg.com, Bloomberg, 29 Aug. 2019, www.bloomberg.com/news/articles/2019-08-29/juul-devices-cited-in-seizure-reports-that-triggered-fda-probe.
43. Commissioner, Office of the. “FDA Seeks Reports Related to Seizures Following e-Cigarette Use.” U.S. Food and Drug Administration, FDA, 7 Aug. 2019, www.fda.gov/news-events/fda-brief/fda-brief-fda-encourages-continued-submission-reports-related-seizures-following-e-cigarette-use.
44. “Some E-cigarette Users Are Having Seizures, Most Reports Involving Youth and Young Adults.” U.S. Food and Drug Administration, FDA, 10 Apr. 2019, https://www.fda.gov/tobacco-products/ctp-newsroom/some-e-cigarette-users-are-having-seizures-most-reports-involving-youth-and-young-adults
45. “Spice-Like Products.” Erowid Spice Product Vault (Spice, K2, Black Magic, Smoke, JWH-018, JWH-073, Etc), www.erowid.org/chemicals/spice_product/spice_product.shtml.
46. “Experimental & Research Chemicals.” Erowid Psychoactive Vaults : Research Chemicals (Synthetic Drugs, Novel Psychoactive Substances, New Psychoactive Substances, NPS, Replacement Psychoactives), www.erowid.org/psychoactives/research_chems/research_chems.shtml.
47. In the context of this article, Marinol, a lab-manufactured form of THC, is not a synthetic cannabinoid. Crystalline CBD made in a lab is not an SC. “Synthetic” refers to the fact that they are designed by humans – primarily for research, often without human safety in mind – and found nowhere in nature. Sometimes science and media reports call synthetic cannabinoids “synthetic marijuana.” This is an unfortunate misnomer.
48. JWH stands for John William Huffman.
49. It is difficult to track exactly the emergence of synthetic cannabinoids. Spice may have been sold as early as 2002. The Research Triangle Institute, in an article written with John Huffman, states that synthetic cannabinoids were first found in Europe in 2006.⁷⁹
50. Lindigkeit, Rainer, et al. “Spice: A Never Ending Story?” Forensic Science International, vol. 191, no. 1-3, 2009, pp. 58–63., doi:10.1016/j.forsciint.2009.06.008
51. Schifano, Fabrizio, et al. “The clinical challenges of synthetic cathinones” British Journal of Pharmacology, 2019, doi:10.1111/bcp.14132
52. One clinical trial on a FAAH inhibitor was halted because of deadly off-target actions.
53. Buchler IP, Hayes MJ, Hegde SG, Hockerman SL, Jones DE, Kortum SW, et al. Indazole derivatives. Patent WO 2009/106980-A2. New York, NY, 2009.
54. See https://www.health.govt.nz/system/files/documents/pages/ab-fubinaca_and_amb_fubinaca_eacd_report.docx on the website https://www.health.govt.nz/new-zealand-health-system/key-health-sector-organisations-and-people/ministerial-health-committees/national-drug-policy-committees
55. Finlay, David B., et al. “Do Toxic Synthetic Cannabinoid Receptor Agonists Have Signature in Vitro Activity Profiles? A Case Study of AMB-FUBINACA.” ACS Chemical Neuroscience, vol. 10, no. 10, 2019, pp. 4350–4360., doi:10.1021/acschemneuro.9b00429.
56. Devitt-Lee, Adrian. “CB1 Kinetics.” Project CBD, 9 Apr. 2019, www.projectcbd.org/news/quick-hits/cb1-kinetics.
57. For example, it is thought that respiratory failure during opioid overdose is related to β-arrestin signaling, whereas the painkilling effect is mediated by G-proteins. However, these preclinical notions haven’t yet translated into a non-lethal opiate. No biased opioid agonists have made it through clinical trials as of now.
58. Compared with THC and two research chemicals, CP55,940 and WIN55,212-2, which have not reportedly been used as recreational drugs.
59. Zhu, Xiao, et al. “Model‐Free and Kinetic Modelling Approaches for Characterising Non‐Equilibrium Pharmacological Pathway Activity: Internalisation of Cannabinoid CB 1 Receptors.” British Journal of Pharmacology, vol. 176, no. 14, 2019, pp. 2593–2607., doi:10.1111/bph.14684.
60. Endocannabinoids are typically thought to be produced and released upon demand, when the body is stressed. 2-AG is present in much greater concentrations than anandamide, so the body may be more sensitive to slight changes in anandamide levels.
61. Lee, Martin A. “Better Than Cannabis?” Project CBD, 13 Dec. 2017, www.projectcbd.org/medicine/better-cannabis.
62. The argument is that if a drug prevents the breakdown of endocannabinoids, then activity is only amplified where the body is already releasing cannabinoid. There are a number of holes in this argument – one particular issue is that these enzymes are not selective for endocannabinoids. FAAH metabolizes a handful of biologically significant molecules, including PEA and OEA, in addition to anandamide (also called AEA).
63. “Activity-based protein profiling reveals off-target proteins of the fatty acid amide hydrolase inhibitor BIA 10-2474”. Presented at ICRS 2017. See P8 in http://www.icrs.co/SYMPOSIUM.2017/ICRS2017.FINAL.PROGRAMME.pdf
64. The difference between species has also posed a major challenge to developing FAAH inhibitors. Rats have only one kind of FAAH enzyme, while humans and mice each have two. Beyond this, rodent and human FAAH are genetically different, so chemicals developed to effectively treat a rat’s disease are unlikely to translate to the human counterpart.
65. Ghosh, Sudeshna, et al. “The Monoacylglycerol Lipase Inhibitor JZL184 Suppresses Inflammatory Pain in the Mouse Carrageenan Model.” Life Sciences, vol. 92, no. 8-9, 2013, pp. 498–505., doi:10.1016/j.lfs.2012.06.020.
66. Schlosburg, Joel E, et al. “Chronic Monoacylglycerol Lipase Blockade Causes Functional Antagonism of the Endocannabinoid System.” Nature Neuroscience, vol. 13, no. 9, 2010, pp. 1113–1119., doi:10.1038/nn.2616.
67. Off-target, in some sense, depends on the point of reference. THC has a high affinity for both CB1 and CB2, and its activation of CB2 could be seen as one of its primary effects.
68. Siegmund, Sören V., and Robert F. Schwabe. “Endocannabinoids and Liver Disease. II. Endocannabinoids in the Pathogenesis and Treatment of Liver Fibrosis.” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 294, no. 2, 2008, doi:10.1152/ajpgi.00456.2007.
69. Lee, Martin A. “Get High and Lose Weight?” Project CBD, 23 Nov. 2015, https://projectcbd.org/medicine/get-high-lose-weight.
70. Devitt-Lee, Adrian. “Cannabis & Weight Loss.” Project CBD, 3 Apr. 2019, https://projectcbd.org/news/quick-hits/cannabis-weight-loss-0.
71. Melamede, Robert. “Cannabis and Tobacco Smoke Are Not Equally Carcinogenic.” Harm Reduction Journal, vol. 2, no. 1, 2005, p. 21., doi:10.1186/1477-7517-2-21.
72. “Dataset Deaths Related to Drug Poisoning by Selected Substances.” Office for National Statistics, 2018, www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsrelatedtodrugpoisoningbyselectedsubstances.
73. Wiley, J., Marusich, J., Huffman, J. W., Balster, R. L., & Thomas, B. (2011). Hijacking of basic research: The case of synthetic cannabinoids. Research Triangle Park, NC: RTI Press. RTI Press Publication No. OP-0007-1111 https://doi.org/10.3768/rtipress.2011.op.0007.1111
74. The death rate is small enough that it is not tabulated by epidemiological centers like the National Institute on Drug Abuse ²⁷ or the CDC. In the UK, SCs reportedly caused 60 deaths in 2018.²⁹
75. National Institute on Drug Abuse. “Overdose Death Rates.” NIDA, 29 Jan. 2019, www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates.

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