Smoking high-potency marijuana concentrates boosts blood levels of THC but don’t boost impairment

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Smoking high-potency marijuana concentrates boosts blood levels of THC more than twice as much as smoking conventional weed, but it doesn’t necessarily get you higher, according to a new study of regular users published today by University of Colorado Boulder researchers.

“Surprisingly, we found that potency did not track with intoxication levels,” said lead author Cinnamon Bidwell, an assistant professor in the Institute of Cognitive Science.

“While we saw striking differences in blood levels between the two groups, they were similarly impaired.”

The paper, published June 10 in JAMA Psychiatry, is the first to assess the acute impact of cannabis among real-world users of legal market products. It could inform everything from roadside sobriety tests to decisions about personal recreational or medicinal use.

But the study also raises concerns that using concentrates could unnecessarily put people at greater long-term risk of side-effects.

“It raises a lot of questions about how quickly the body builds up tolerance to cannabis and whether people might be able to achieve desired results at lower doses,” said Bidwell.

While 33 states have legalized medicinal marijuana use, and 11 have legalized recreational use, both uses remain illegal at the federal level. Researchers are also prohibited from handling or administering marijuana.

Some previous studies have used strains supplied by the government, but those strains contain far less THC than real-world products.

In order to study what people really use, Bidwell and her colleagues utilize two white Dodge Sprinter vans, also known as the “cannavans,” as mobile laboratories. They drive the vans to the residences of study subjects who use cannabis they purchase on their own inside their homes and then walk out for tests.

“We cannot bring legal market cannabis into a university lab, but we can bring the mobile lab to the people,” she said.

For the current study, the team assessed 121 regular cannabis users. Half typically used concentrates (oils and waxes that include the active ingredients without the leaves and stems). The other half typically used flower from the plant.

Flower users purchased a product containing either 16% or 24% [tetrahydrocannabinol (THC)], the main psychoactive ingredient in marijuana. Concentrate users were assigned to a product containing either 70% or 90% THC.

On test day, researchers drew the subjects’ blood, measured their mood and intoxication level and assessed their cognitive function and balance at three time points: before, directly after and one hour after they used.

Those who used concentrates had much higher THC levels at all three points, with levels spiking to 1,016 micrograms per milliliter in the few minutes after use, while flower users spiked at 455 micrograms per milliliter. (Previous studies have shown that THC levels hover around 160 to 380 micrograms per milliliter after marijuana use).

Regardless of what type or potency of cannabis participants used, their self-reports of intoxication, or “feeling high,” were remarkably similar, as were their measures of balance and cognitive impairment.

“People in the high concentration group were much less compromised than we thought they were going to be,” said coauthor Kent Hutchison, a professor of psychology and neuroscience at CU Boulder who also studies alcohol addiction. “If we gave people that high a concentration of alcohol it would have been a different story.”

The study also found that, among all users, balance was about 11% worse after using cannabis, and memory was compromised. But within about an hour, that impairment faded.

“This could be used to develop a roadside test, or even to help people make personal decisions,” said Bidwell.

The researchers aren’t sure how the concentrate group could have such high THC levels without greater intoxication, but they suspect a few things are at play: Regular users of concentrates likely develop a tolerance over time.

There may be genetic or biological differences that make some people metabolize THC more quickly. And it may be that once compounds in marijuana, called cannabinoids, fill receptors in the brain that spark intoxication, additional cannabinoids have little impact.

“Cannabinoid receptors may become saturated with THC at higher levels, beyond which there is a diminishing effect of additional THC,” they write.

The authors caution that the study examined regular users who have learned to meter their use based on the desired effect, and does not apply to inexperienced users. Those users should still be extremely cautious with concentrates, said Hutchison.

Ultimately, the researchers hope to learn what, if any, long-term health risks concentrates truly pose.

“Does long-term, concentrated exposure mess with your cannabinoid receptors in a way that could have long-term repercussions?

Does it make it harder to quit when you want to?” said Hutchison. “We just don’t know yet.”


What Are Cannabinoids?
Cannabinoids (CBs) are a group of chemical compounds which have varying affinity to cannabinoid receptors. Generally, cannabinoids can be classified into three groups namely, phytocannabinoids (isolated from natural source, C. sativa), synthetic cannabinoids, and endocannabinoids (Richter et al., 2018).

Although cannabinoids can be extracted naturally from the plants, it can also be cultivated indoors using hydroponic and artificial lighting system nowadays. It was first cultivated in Central Asia however gradually it was brought to cultivate all over the world (Singh et al., 2018).

Generally, it is collected from three strains of cannabis plant named C. sativa, Cannabis indica, and Cannabis ruderalis which differ in the content and amount of the active ingredients called Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (Booth et al., 2017) (see Figure 1) and among these strains, the highest proportion of THC is present in C. sativa.

THC was isolated as one of the first phytocannabionoids (Gaoni and Mechoulam, 1964). In the plant C. sativa, this molecule is present as tetrahydrocannabinolic acid which is then decarboxylated to THC (Richter et al., 2018).

Usually, the buds and the leaves of the cannabis plants contain the highest amount of psychoactive ingredient, THC. This THC can be taken up from dried buds and leaves by smoking as well as it can be taken in other forms for instance edibles, waxes, oils, liquid incense, or vapor for both medical and recreational uses.

For medical purpose, cannabis has been used to treat nausea and vomiting due to chemotherapy, neuropathic pain related to cancer and advanced neurological disorders (Singh et al., 2018).

However, the popularity of cannabis use lies in its recreational purposes. Therefore, in spite of being listed as a schedule 1 substance according to the Section 202 of the Controlled Substances Act of 1970 by Drug Enforcement Administration of USA, the use of cannabis has been legalized or decriminalized in different states of USA (Singh et al., 2018).

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Figure 1
Chemical structure of two of the major cannabinoids contained in Marijuana. Depicted on the left is the chemical structure of tetrahydrocannabinol (THC). THC is the principal psychoactive constituent of cannabis. THC acts as a partial agonist at the cannabinoid receptor CB1 (primarily located in the brain and spinal cord as well as CB2 receptor expressed in cells of the immune system. On the right is depicted the chemical structure of cannabidiol (CBD). By contract with THC, CBD does not have any psychotropic effects, but appears to have some have anti-anxiety and anti-psychotic properties. CBD has a lower affinity for both CB1 and CB2 receptor when compared to THC. Highlighted in red are the chemical structure differences between CBD and THC.

Besides natural sources, THC compounds can be synthesized for both medical and recreational uses. Since 1985, two synthetic THC compounds named dronabinol and nabilone have been using in USA in capsule forms for treating nausea, vomiting, and weight loss related to chemotherapy and acquired immunodeficiency syndrome.

Recently, an oral solution of dronabinol has been approved by US FDA for treating anorexia and nausea/vomiting associated with acquired immunodeficiency syndrome and chemotherapy respectively.

Besides, highly potent cannabinoids and cannabimimetics can be synthesized illegally by altering the structure of THC in numerous ways for recreational purposes which have already gained popularity among the users due to its potency, longer duration, and the failure of conventional drug screening tests to recognize the compounds (Gurney et al., 2014).

Chemical Composition of C. Sativa
More than 421 chemicals are present in C. sativa of which 61 chemicals are cannabinoids. During cannabis smoking, over 2,000 compounds including hydrocarbon, nitrogenous compounds, amino acids, fatty acid, sugar etc. are produced by pyrolysis and all of these substances are responsible for different pharmacological as well as toxicological properties of cannabis (Sharma et al., 2012).

Pharmacokinetics of Cannabinoids
Around 20%-70% of THC can be delivered through smoking (Adams and Martin, 1996). Smoking a 500 to 1,000 mg cannabis cigarette provides a THC dose of 0.2–4.4 mg where a pharmacologic effect of cannabis requires a dose of 2–22 mg. The THC level in the brain typically represents only ∼1% of the administered dose and usually corresponds to 2–44 μg.

THC is absorbed and reaches high blood concentration rapidly after inhalation through lungs (Vandevenne et al., 2000). Due to extensive lipid solubility and large volume of distribution, THC has a long biological half-life (18 h to 4 days) (Adams and Martin, 1996; Ashton, 2001) and gets distributed in adipose tissue, liver, lung, and spleen (Chiarotti and Costamagna, 2000; Sharma et al., 2012).

Hydroxylation of THC generates psychoactive compound, 11-hydroxy ▵9_tetra hydrocannabinol (11-OH-THC), and further oxidation of this compound yields inactive compound, 11-nor-9-carboxy-▵9-tetrahydrocannbinol (THCCOOH) which is important for diagnostic purposes (Musshoff and Madea, 2006). The bioavailability of ▵9 THC depends on several factors including inhalation depth, duration of puff, and breath hold.

It has been found that, the systemic bioavailability of THC is around 23–27% in heavy users whereas the value is 10–14% in case of occasional users (Sharma et al., 2012). The time to reach maximum plasma concentrations for ▵9 THC, 11-OH-THC, and THCCOOH is 8, 15, and 81 min after onset of smoking, respectively.

On the other hand, systemic absorption of THC is relatively slow after oral ingestion compared to inhalation. In case of oral ingestion, the peak plasma concentration of ▵9 THC was observed after 1–2 h of ingestion which could be further delayed by few hours in some cases (Lemberger et al., 1971; Hollister et al., 1981). The oral bioavailability of ▵9 THC may be reduced by 4–12% by extensive hepatic metabolism (Owens et al., 1981).

Regular cannabis use can be defined as taking cannabinoids 10 to 19 times monthly, whereas heavy use can be termed as using 20 times in a month. However, both regular and heavy use of cannabis are related to several chronic health problems including anxiety, depression, and neurocognitive alterations (Hall and Degenhardt, 2009).

Endocannabinoid System
Cannabinoids interact directly with our body through a complex system named endocannabinoid system which helps to maintain homeostasis of body by regulating metabolism, intercellular communication, appetite, and memory, immune, and pain responses.

This endocannabinoid system (ECS) consists of two types of receptors namely CB1 and CB2 (Zou and Kumar, 2018) (see Figure 2). CB receptors mainly belong to the G-protein coupled receptor (GPCR) family, having inhibitory function on the cyclic adenosine monophosphate (cAMP) pathway through intracellular signal transduction (Richter et al., 2018).

Although CB1 receptors are scattered all over the body, these are present predominantly in anatomical regions of the brain (Grotenhermen, 2005) related to memory, anxiety, cognition, pain sensory, motor coordination, endocrine function (Herkenham et al., 1990; Adams and Martin, 1996).

CB1 receptors have the inhibitory action on cAMP production which is facilitated by the activation of adenyl cyclase inhibitor subunit of G proteins (Gi/0 proteins). Ultimately, this leads to an inhibition of N and P/Q type calcium currents and an activation of A type, inwardly rectifying potassium currents and mitogen activated protein kinase (Sierra et al., 2015) (see Figure 3).

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Figure 2
Schematic illustration of the primary location of CB1 and CB2 receptor. Note that CB1 receptor are primarily located in the brain and spinal cord and to a much lesser extent there are also present in the gastrointestinal tract, reproductive organs as well as muscles and vascular system. CB2 receptors are primary located in spleen, skin, and bones as well as the immune cells.
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Figure 3
Subcellular localization and activity of CB1 receptors. CB1 receptors are primary located on the cell membrane where their activation lead to inhibition of adenylate cyclase and a resulting reduction of cyclic AMP. In parallel CB1 activation promotes the upregulation of mitogen-activated protein kinase (MAPK) which is involved in directing cellular responses to mitogens, heat shock, osmotic stress, and proinflammatory stimuli (e.g. cytokines). At the mitochondrial level, CB1 activation leads to inhibition of mitochondrial respiration and production of cAMP. CB1 receptors are also present at the level of lysosomes where they prompt a release of calcium from these internal storage units and increase the intracellular calcium levels. Lysosome permeability is also increased.

On the other hand, CB2 receptors are located in peripheral nervous system and immune system and the primary function of this receptor is anti-inflammatory activity through initiating an immune response to reduce inflammation as well as tissue damage (Turcotte et al., 2016). Also, it plays a pivotal role in the immune suppressive action of the cannabinoids (Sharma et al., 2012) (see also Figure 2).

The psychoactive agent of cannabis, THC binds with the cannabinoid 1 (CB1) receptor in the brain and the non-psychoactive component, CBD is the most likely to interact with cannabinoid 2 (CB2) receptor and exert their activities. Therefore, cannabis is used in medical purposes to reduce inflammation, relieve pain, and decrease seizures (Rivera-Olmos and Parra-Bernal, 2016; Perucca, 2017).

Moreover, phytocannabinoid Δ9 THC can also bind with other binding sites including the transient receptor potential cation-channel subfamily V member 1 (TRPV1) and peroxisome proliferator activator receptors (PPARs) (O’Sullivan, 2016). Also, GPR 18 receptor has been proposed as a potential cannabinoid receptor (Console-Bram et al., 2014).

Effect of Cannabis Inhalation on the Cerebrovascular System
Studies on acute neurovascular events related to cannabis use have appeared as early as 1964 (Mohan and Sood, 1964). Stroke is the fifth leading cause of death in USA (Vijayan et al., 2019) and recent preclinical studies, population based study, case reports, and reviews have portrayed the correlation of cannabis (both naturally and synthetically derived) to ischemic and hemorrhagic cerebrovascular diseases (Rose et al., 2015) which clearly suggests that cannabis plays a pivotal role in the etiology of cerebral stroke (Wolff et al., 2015a)

Population-Based Study
Due to the alarming effect of cannabinoids on public health, several population-based studies have been performed to correlate the relation between cannabinoid exposure as well as cerebrovascular diseases.

Various studies demonstrated that cannabinoids may act as a risk or prognostic factor for cerebrovascular diseases such as stroke (Westover et al., 2007; Barber et al., 2013; Hemachandra et al., 2016; Rumalla et al., 2016a; Rumalla et al., 2016b). Table 2 summarizes all the findings from population-based analysis, conducted between 2000 and 2015.

Table 2

Summary of population-based analysis related to cannabis use, conducted between 2000 and 2015.

Study typeDurationStudy designOutcomeStrengthLimitationRef
Cross-sectional2000–2003N = 3,148,165 patients’ age: 18–44Cannabis was considered as a risk factor for IS (OR 1.76, 95% CI 1.15–2.71) and for hemorrhagic stroke (OR 1.36, 95% CI 0.9–2.06)-Large sample size, other risk factors e.g. amphetamine, cocaine were considered-Unable to distinguish between primary and secondary or recurrent strokes.(Westover et al., 2007)
-Study was conducted in a database representative of hospitalized conditions in all but the smallest rural hospitals in Texas.– Possibility of misclassification of variables in a database of International classification of diseases, ninth revision, clinical modification (ICD-9-CM)–coded discharge diagnoses.
Cross-sectional2004–2007N = 200, Mean age at admission was 28.0 years (95% CI 26.7, 29.3).Four cerebrovascular accidents in patients below 40 were found related to cannabis use-Accurate detection of cannabis related hospitalization.-Study was conducted in a restricted geographical area(Jouanjus et al., 2011)
-Other AEs e.g. psychiatric disorders, acute intoxication, respiratory and cardiovascular disorders were recorded.-Small sample size.
– Difficulty in assessing precise epidemiological reference data in a context of illicit drug consumption.
Case-control2009Patients’ age: 18–5515.6% of patients had IS/TIA, cannabis use was related to increased risk of IS/TIA (OR: 2.30, 95% CI 1.08–5.08)-Evidence of an association between a lifestyle that includes cannabis and tobacco, and IS-Association between cannabis and IS/TIA independent of tobacco could not be confirmed.(Barber et al., 2013)
– Use of a control cohort– Other factors e.g. socioeconomic or employment status, alcohol and/or drug use, could not be measured.
-Urinary drug screens were conducted.-Absence of extensive comparisons between patients and controls
Case series2006–2010N = 1,979, mean age: 34.31.8% cardiovascular complications reported, three of which were cerebrovascular complications (acute cerebral angiopathy, transient cortical blindness and cerebral artery spasm.-Long study period-lack of data due to underreporting of cases.(Jouanjus et al., 2014)
-Cardiovascular disorders were focused.Some cases were not exhaustively informed.
– Toxicologic analyses were available in only 37% of cases. Lack of data on cardiac or vascular disease history, body mass index.
Cross-sectional1999–200220–24 years (N = 2,383), 40–44 years (N = 2,525), and 60–64 years (N = 2,547)153 stroke/TIA cases (2.1%). Cannabis users (n = 1,043) had 3.3 times the rate of stroke/TIA (95% CI 1.8–6.3, p < 0.001). Elevated stroke/TIA was specific to participants who used cannabis weekly or more often (IRR 4.7, 95% CI 2.1–10.7)-Large sample size based on different age range.-Lack of detailed history of participants’ cannabis use.(Hemachandra et al., 2016)
-Able to adjust for a wide variety of lifestyle and health factors that were related to stroke/TIA.-Only correlate past year cannabis use with lifetime occurrence of stroke.
-Unable to control tobacco consumption concurrently with cannabis, family history of stroke/TIA, hyperlipidemia, or other drug use (e.g. recreational stimulant use)
Cohort2004–2011N = 2,496,166
Patients’ age: 15–54
Greater incidence of IS among cannabis users compared to non-users (RR 1.13, 95% CI 1.11–1.15)-Long study period-Only primary diagnoses of AIS were included which may resulted in under-diagnosis of AIS patients.(Rumalla et al., 2016a)
-Association of other risk factors e.g. tobacco, cocaine, amphetamine was also considered.-Unable to comprise any dose-dependent mechanisms of cannabis use due to the limitations of the ICD-9-CM coding system.
– lack of data on preadmission functional status and severity in the NIS, constrains adjustment for AIS severity.
Cohort2004–2011Cannabis users: N = 2,496,165
Non-cannabis users: N = 116,163,453
Patients’ Age: 15–54
Aneurysmal SAH incidence was slightly increased in the cannabis cohort compared to non-cannabis cohort (RR 1.07, 95% CI 1.02–1.11)-Long study period– Possibility of inaccuracy of diagnoses and procedural codes used to identify SAH patients from the NIS database.(Rumalla et al., 2016b)
– Use of the NIS database.– Possibility of misclassification and under-classification of drug use using secondary ICD-9-CM codes.
-Large sample size– No data related to the time from last drug use to aSAH was available.
– Assessment of preadmission functional status and severity of aSAH at admission was not possible to determine using NIS.
Cohort2009–2014N = 725 ICHCannabinoid use in 8.6% ICH. No link was found between cannabinoid use and specific characteristics of ICH. CB+ patients had milder ICH presentation and less disability at discharge.-Use of international, multicenter, observational, collaborative database.-Lack of data on time of cannabis consumption.(Di Napoli et al., 2016)
Cohort2010–2015N = 108
Patients’ age ≥18 years
25.9% with CB+ and delayed cerebral ischemia was diagnosed in 50% of CB+. CB+ was independently associated with delayed cerebral ischemia (OR, 2.68; 95% CI, 1.03–6.99; P = 0.01) and poor outcome (35.7% versus 13.8%; P = 0.01) in SAH patients.-Long study period-Lack of patient care uniformity.(Behrouz et al., 2016)
– UDS was performed.-Limited ability to identify and include other relevant clinical features, including cardiopulmonary comorbidities, infections, recurrent aneurysmal rupture, hydrocephalus, and seizures.
-Unable to differentiate new cannabis use from residual drug excretion, considering that cannabinoids may persist in the urine for several days/weeks.
-Unable to differentiate chronic use from single-episode cannabis consumption.
-Unable to eliminate the possibility of false positive or negative UDS completely.
OR, odds ratio; CI, confidence interval; RR, relative risk; ICH, intracranial hemorrhage; SAH, subarachnoid hemorrhage; TIA, transient ischemic stroke; IS, ischemic stroke; CB+, cannabinoid user; UDS, urine drug screen.

The result from these large sample size studies provide information on the temporal relationship between cannabis use and cerebrovascular complications like intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and ischemic strokes (IS). Along with cannabinoids, other predominant risk factors were also considered in the assessments however, these studies have several limitations.

This include lack of consideration for the high lipid solubility of cannabis metabolites which helps them to persist in fatty tissues, therefore they may be detected in the urine weeks after the initial use (Mateo et al., 2005) and this may lead to erroneous result interpretation.

Probable Mechanism Associated With Cannabis-Mediated Neurovascular Diseases
It is evident from various studies that, consumption of cannabinoids through inhalation and combustion, is associated with the occurrence of cerebral infarcts (Garrett et al., 1977; Wolff and Jouanjus, 2017).

Natural cannabis and synthetic cannabinoids may act as possible trigger for reversible intracranial vasoconstriction (Wolff et al., 2015a) which along with severely reduced cerebral blood flow (CBF) could be a major prodromal factor to neuronal death by ischemia (Wolff et al., 2014; Wolff and Jouanjus, 2017).

Different types of mechanisms might be involved in the development of stroke in cannabis users including orthostatic hypotension with the secondary impairment of the CBF autoregulation, altered cerebral vasomotor function, supine hypertension, and fluctuations in blood pressure, cardioembolism with atrial fibrillation, vasculopathy and vasospasm (Singh et al., 2012; Wolff et al., 2013; Hirapara and Aggarwal, 2016), cerebral artery luminal stenosis, increased carboxyhemoglobin level, RCVS, and angiopathy (Goyal et al., 2017).

Although none of these mechanisms have been fully vetted to explain the association between use of cannabis and stroke occurrence, reversible cerebral vasoconstriction triggered by cannabis could be the most convincing theory to explain it (Wolff and Jouanjus, 2017).

It was shown in different case reports that, cannabis use was associated with reversible multifocal intracranial arterial stenosis (Noskin et al., 2006; Calabrese et al., 2007; Koopman et al., 2008; Renard and Gaillard, 2008; Wolff et al., 2011; Marder et al., 2012; Tsivgoulis et al., 2014; Nouh et al., 2014; Yau et al., 2015; Wolff et al., 2015a).

Along with this, another eye-catching mechanism to explain the relationship between cerebrovascular complications and cannabis use could be the cellular effect of cannabis on brain mitochondria.

A recent in vivo study conducted on mice has shown that THC inhibited the complexes I, II, and III of the respiration chain of mitochondria and increased the amount of hydrogen peroxide production (Wolff et al., 2015b).

This strongly suggests that ROS production and therefore, oxidative stress, could be the linking mechanism between cannabis use and stroke. This well cope with current knowledge that oxidative stress and inflammation are established prodromal factors for the onset of stroke and other neurological disorders in humans (Chen et al., 2011) (see also Figure 4).

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Figure 4
Schematic illustration of the Activation of the cellular antioxidative response system under normal and stress condition. Under normal conditions, the response to injury is adaptive, designed to restore homoeostasis and to protect the cell from further injury. In response to excessive oxidative stress stimuli, NADPH oxidase is activated, producing an excess of O2‑ which in the presence of nitric oxide (.NO; also abundant in CS and release in response to IR) results in formation of peroxinitrite (ONOO‑). Furthermore, the excess of H2O2 leads to the formation of hydroxyl radicals (OH; Fenton’s reaction). The unchecked OS leads then to mitochondrial depolarization, lipid peroxidation, DNA fragmentation and inflammation which at the cerebrovascular level can cause BBB damage and ultimately facilitate the onset of CNS diseases.

More information: JAMA Psychiatry (2020). DOI: 10.1001/jamapsychiatry.2020.0927

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