Welcome back to part 2 of this exploration into the world of DUIs and cannabis tolerance. If you haven’t read part 1 I suggest you check that out first, as the content I’ll be covering here builds upon the research, conclusions and questions examined in that part. 

There’s an anecdotal-based narrative I carry about cannabis tolerance, based around past and present friends who are consistent cannabis smokers. Essentially, some of them smoke a lot. Like at least once every day. And most of them get behind the wheel every day, and somehow none of them have ever been involved in a serious accident. I know for sure if I smoked up with them, I wouldn’t be able to do the same thing. Why? Are they just exceptional drivers?

To answer these questions, I need to first do a quick dive back into the Ramaekers et al. (2009) article from part 1, because when it comes to that study’s methods section there’s a major stone that I left unturned and a critical point which I cannot ignore. As you might remember, the authors found that there are differences in neurocognitive processes between frequent cannabis users and infrequent ones. Ramaekers et al. (2009) found that after giving both groups a hefty dose of weed, consistent users greatly outperformed infrequent users on a mental processing task.

But what was really interesting was that frequent users performed just as well and just as fast as the placebo control groups on these tasks, suggesting that a part of their mental processing was still working and still continuous. 

However, despite this finding, there’s an important facet of their study design that must be examined. With the exception of weight, participants in both the occasional and frequent groups were given the same amount of cannabis. (They were given 500 μg/kg, which is equivalent to around 30mg. If you’re unfamiliar with the numbers, that’s a solid dosage of THC). This obviously raises an important dilemma, as the logical assumption can be made that frequent cannabis users would normally be smoking more than infrequent users. To provide a bit of context for this issue, the authors conducted a “subjective high” poll, upon which the participants rated how intoxicated they felt from 0% to 100%.

Looking again at just the 0-1 hour time range, they saw that occasional users rated themselves at a subjective high of 80% after smoking, while frequent users rated themselves only at 50%.

But why?

Why aren’t frequent cannabis users feeling the same effects of THC? Why are they also not experiencing the same cognitive impairments? Are their brains “fried,” as many anti-drug organizations have tried to claim in the past? Surely something isn’t functioning as normal, because the occasional users are still feeling high and getting impaired. So what’s actually going on when we repeatedly smoke cannabis?

To figure this out, we need to enter the world of reward pathways and our endocannabinoid system. 

The endocannabinoid system is one of the most important biological systems in our body and it’s something we’ve only known about for a little over 30 years (Matsuda et al., 1990). Back in the year 1990 (before running water), Dr. Lisa A. Matsuda and her lab were doing some molecular cloning to figure out where exactly cannabis was having psychoactive effects on the brain. Through the process, they found one of the largest regulators of chemical signals our body has, and we now know the endocannabinoid system plays a role in everything from appetite to energy metabolism to pain. Not to get into too much detail about the specifics of their study (it does a lot with copied DNA and nucleotide sequencing), but based on the immense activity of a particular cloned section of DNA, they were able to distinguish a particular receptor that is more responsive to psychoactive cannabinoids than non-psychoactive cannabinoids. From there, Matsuda et al. (1990) make this incredible almost-prediction about an endocannabinoid system:

Now I’ll back up.

You might be wondering, what the hell is a “non-psychoactive cannabinoid?” Or an “endogenous cannabinoid?”

There are two types of cannabinoids that interact with our endocannabinoid system. One type is called endogenous cannabinoids. The prefix “endo” is important to emphasize, meaning these are produced by our body naturally i.e. endogenously (the most prevalent being 2-AG and anandamide).

The other type are exogenous cannabinoids. These are cannabinoids found outside of our body like THC and CBD and these are the ones most commonly linked with psychoactive effects i.e. that euphoric, impairing, “high” feeling (if you’re curious CBD is often considered psychoactive but not intoxicating).

Both endogenous and exogenous cannabinoids interact with the endocannabinoid system through many of the same receptors (review by Lu & Mackie, 2016). It is at the synapse of a receptor where, through a process not all that unsimilar to a lock-and-key, signals can be communicated synaptically from one neuron to another. The most important of these receptors in the context of cannabis tolerance are CB1 receptors, often in the basal ganglia and the cortex (review by Lu & Mackie, 2016). I’m going to focus on this one type of cannabinoid receptor because it is through these CB1 receptors that the effects of exogenous cannabinoids like THC are spread and felt throughout the rest of the body (it’s worth noting that 2-AG can reinforce drug use at the same CB1 receptors that THC impacts, but a discussion of endogenous cannabinoids and drug addiction in conjunction with cannabis tolerance would make this a thesis rather than a blog post).

Cannabis operates as an agonist to the CB1 receptors, meaning it activates the receptor and causes it to produce a response. When our CB1 receptors are activated by THC, all hell breaks loose. Or more scientifically, a key reward pathway in our brain, called the mesolimbic pathway, gets powered into action. This mesolimbic reward pathway starts in our midbrain with a region called the Ventral Tegmental Area (VTA). THC causes a large amount of dopamine release within the VTA, (up to a 55% increase with 7.875 mg dose as found by French et al., 1997). On a synaptic level, this occurs by a process of “inhibiting the inhibitor,” as GABA neurotransmitters which are usually inhibiting dopamine release in the VTA are themselves inhibited by the release of THC, allowing lots of dopamine be released into this reward circuit (review by Ramaekers et al., 2020). This dopaminergic output then travels to a few other parts of the brain, each playing a varying role in our behavior and memory that encodes reward. 

I put reward in italics not because it’s a key term but because it’s a debated term. For a while, there has been a general belief in the field of neuroscience that anything dopamine related has to do with reward and pleasure. I think this is still the way dopamine is thought of in the pop-science world, as the “feel-good” chemical that gets released when we treat our bodies well. This is a gross oversimplification of dopamine, which is also involved in behavioral processes such as fear (Fadok et al., 2009), pain modulation (review by Wood, 2008), and REM cycles (review by Monti & Jantos, 2008). I think a large part of this misconception comes from the word “reward” itself, which in non-scientific literature carries a positive connotation, however in the context of cannabis research it is mainly referring to the mesolimbic reward pathway. It is through this pathway, from the VTA through other parts of the brain, that dopamine is acting more as an amplifier, tuning up or tuning down the signals these brain regions are sending to the rest of our body (I won’t be talking about the role of excitatory glutamate and the prefrontal cortex in the mesocortical pathway which is like the slightly less cool half-brother to the mesolimbic pathway as the only other dopaminergic reward pathway in the limbic system because it just comes up a lot less in the world of cannabis tolerance research). 

If the mesolimbic reward pathway starts by THC activating a dopaminergic response in the VTA, it “ends” with a few different outputs:

• The nucleus accumbens, the main target of dopamine release, which helps to build the motor connection by  transferring our motivation (of consuming cannabis) into action (review by Klawonn & Malenka, 2019)
• The amygdala, which helps us encode incentive salience cues, such as building emotional relevance between the environmental cues around us with the enjoyment we’re deriving from the cannabis consumption (Cunningham & Brosch, 2012)
• The hippocampus, which works in our declarative memory to establish and easily recall experiences during the specific time period we were consuming cannabis (review by Ramaekers et al., 2020)

This is where we see something interesting again between occasional and frequent users, because all of these brain regions are players in a larger game of repeated drug consumption. When occasional users start taking in THC, our body has to change to adapt to this foreign set of chemicals. We’ll have lots of CB1 receptors binding with THC → reducing the GABAergic inhibition in the VTA → releasing lots of dopamine down the mesolimbic pathway → and amplifying the signal to nucleus accumbens at the end of the pathway to start establishing learned associations with the event (review by Kalivas & Volkow, 2005). This whole process is essentially a form of adaptive behavior, which makes sense as part of an evolutionary characteristic: we need to be able to remember what behaviors make us feel good and what do not. However, if we start consistently pushing THC through our mesolimbic reward pathway, our body starts to adjust. Just like last time, I’m going to give you the figure first: 

This imaging comes from a PET scan study done by Ceccarini et al. (2015). The authors in this study were looking to dig into the endocannabinoid systems of frequent cannabis users to see why they weren’t having those same subjective high and cognitive impairment effects found in occasional users. To do this, Ceccarini et al. (2015) used [18F]MK-9470 PET scans to compare the CB1 receptor levels of 10 frequent smokers and 10 non-smoking controls (unfortunately, there is not yet to my knowledge a published CB1 receptor study between frequent and occasional users in humans). [18F]MK-9470 is a specific radiotracer that was literally made for detecting CB1 receptor activity (Burns et al., 2007), and maps well onto the heat-map style voxel analysis by using a method called Modified Standardized Uptake Value (mSUV). 

The most important part of the mSUV method is that “mSUV” simply represents a math equation. It combines factors such as the subject’s body weight, injected radiation dose from the scan, and most importantly their CB1 receptor activity to create the axis on the bottom right corner of the heat map above. Areas in the dark red have the highest quantity of CB1 receptors available, while areas on the dark blue have no CB1 receptors available. What they found was that there was an 11.7% decrease in CB1 receptor availability between the control condition and the frequent cannabis users (Ceccarini et al. 2015). This was a huge finding, and now is known as a natural process called CB1 downregulation. With frequent THC users, our CB1 receptors are essentially getting over-stimulated by the amount of THC we’re taking in, and shutting down as a result (Hirvonen et al., 2012). Often times, these receptors will literally be pulled back inside their cells so that they cannot be binded to, in a process called endocytosis (Hirvonen et al., 2012). This process of CB1 downregulation sometimes takes only a few days to begin initiating, and is reversible upon withdrawal through 4 weeks of abstinence (Hirvonen et al., 2012). 

The effect of this downregulation explains the lowered amount of subjective high in frequent users, as the less CB1 receptors, the less psychoactive effects there will be. The lack of cognitive and motor impairment, however, needs one last visual figure to connect the dots:

I mentioned before that when occasional users consume cannabis, the THC binds to the CB1 receptors leading to that “inhibit the GABA inhibitor process” that releases lots of dopamine from the VTA at the beginning of our mesolimbic reward pathway through to the nucleus accumbens. 

But what happens when CB1 receptors are downregulated, as is the case in frequent users? Now, there’s nothing to decrease the GABA inhibition into the VTA, and that inhibition is going to suppress dopamine release. The nucleus accumbens has no need for all its dopamine receptors, and will start the endocytosis process of down regulating its dopamine receptors back to a level of equilibrium. 

The visual above is looking at functional connectivity of the nucleus accumbens between occasional and frequent cannabis users (Mason et al., 2019). In this case, functional connectivity is a determination of how much the nucleus accumbens is communicating with other cortical regions in the brain to relay information about neurocognitive functioning. Looking at the right side of the panel, we see that in occasional users, functional connectivity decreases, which is what gives us that impairment. In the frequent users, functional connectivity is almost the exact same as the placebo, as the lack of dopamine firing through our mesolimbic pathway works to restore our neurocognitive functioning.

There’s a lot going on here. If there’s one thing to takeaway from this, it’s that our body always wants to achieve homeostasis, and that taking cannabis is going to push us out of that homeostasis. Whether it is good or not good to push our bodies out of equilibrium does not have a simple conclusion. In fact, I think it is a question worth asking ourselves throughout the course of our lives.

~

In part 3, Finally, I want to broaden back out into the world of DUIs and discuss potential implications for this cannabis tolerance research, including whether we need to reshape DUI laws themselves.

References

Bellocchio, L., Cervino, C., Pasquali, R., & Pagotto, U. (2008). The endocannabinoid system and energy metabolism. Journal of neuroendocrinology, 20(6), 850-857. 10.1111/j.1365-2826.2008.01728.x

Burns, H. D., Van Laere, K., Sanabria-Bohórquez, S., Hamill, T. G., Bormans, G., Eng, W. S., … & Hargreaves, R. J. (2007). [18F] MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proceedings of the National Academy of Sciences, 104(23), 9800-9805. 10.1073/pnas.0703472104

Ceccarini, J., Kuepper, R., Kemels, D., van Os, J., Henquet, C., & Van Laere, K. (2015). [18 F] MK‐9470 PET measurement of cannabinoid CB 1 receptor availability in chronic cannabis users. Addiction biology, 20(2), 357-367. 10.1111/adb.12116

Cunningham, W. A., & Brosch, T. (2012). Motivational salience: Amygdala tuning from traits, needs, values, and goals. Current Directions in Psychological Science, 21(1), 54-59. 10.1177/0963721411430832

Fadok, J. P., Dickerson, T. M., & Palmiter, R. D. (2009). Dopamine is necessary for cue-dependent fear conditioning. Journal of neuroscience, 29(36), 11089-11097. 10.1523/JNEUROSCI.1616-09.2009

French, E. D., Dillon, K., & Wu, X. (1997). Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport, 8(3), 649-652. 10.1097/00001756-199702100-00014

Jager, G., & Witkamp, R. F. (2014). The endocannabinoid system and appetite: relevance for food reward. Nutrition research reviews, 27(1), 172-185. 10.1017/S0954422414000080

Justinová, Z., Yasar, S., Redhi, G. H., & Goldberg, S. R. (2011). The endogenous cannabinoid 2-arachidonoylglycerol is intravenously self-administered by squirrel monkeys. Journal of Neuroscience, 31(19), 7043-7048. 10.1523/JNEUROSCI.6058-10.2011

Hirvonen, J., Goodwin, R. S., Li, C. T., Terry, G. E., Zoghbi, S. S., Morse, C., … & Innis, R. (2012). Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Molecular psychiatry, 17(6), 642-649. 10.1038/mp.2011.82

Kalivas, P. W., & Volkow, N. D. (2005). The neural basis of addiction: a pathology of motivation and choice. American Journal of Psychiatry, 162(8), 1403-1413. 10.1176/appi.ajp.162.8.1403

Lu, H. C., & Mackie, K. (2016). An introduction to the endogenous cannabinoid system. Biological psychiatry, 79(7), 516-525. 10.1016/j.biopsych.2015.07.028

Mason, N. L., Theunissen, E. L., Hutten, N. R., Tse, D. H., Toennes, S. W., Jansen, J. F., … & Ramaekers, J. G. (2021). Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users. Addiction biology, 26(1), e12870. 10.1111/adb.12870

Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C., & Bonner, T. I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346(6284), 561-564. 10.1038/346561a0

Pete, D. D., & Narouze, S. N. (2021). Endocannabinoids: Anandamide and 2-arachidonoylglycerol (2-AG). In Cannabinoids and Pain (pp. 63-69). Cham: Springer International Publishing. 10.1007/978-3-030-69186-8_9

Ramaekers, J. G., Kauert, G., Theunissen, E. L., Toennes, S. W., & Moeller, M. R. (2009). Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. Journal of psychopharmacology, 23(3), 266-277. 10.1177/0269881108092393

Ramaekers, J. G., Mason, N. L., & Theunissen, E. L. (2020). Blunted highs: pharmacodynamic and behavioral models of cannabis tolerance. European Neuropsychopharmacology, 36, 191-205. 10.1016/j.euroneuro.2020.01.006Woodhams, S. G., Sagar, D. R., Burston, J. J., & Chapman, V. (2015). The role of the endocannabinoid system in pain. Pain control, 119-143. 10.1007/978-3-662-46450-2_7