by Timmen Cermak, MD

One research scientist began his paper by saying that “Attempts to understand the mechanisms responsible for the psychoactive properties of tetrahydrocannabinol (THC) in marijuana led to the discovery of cannabinoid receptors and their endogenous ligands, the endocannabinoids.”1 Exactly what does this pithy summary mean in plain language?

Scientists were curious about how marijuana makes people “high.” They had long been able to isolate a single compound – THC – that produces most of the high that is characteristic of smoking the part of the marijuana plant that contains an oily resin. But it was not until 1964 that Rafael Mechoulam was able to determine the actual structure of the THC molecule. Because THC is the primary (but not the only) active ingredient in the cannabis plant, the class of chemicals similar in structure came to be known as cannabinoids – delta-9-tetrahydrocannabinol gave rise to the word “cannabinoids.”

The THC in marijuana alters the brain’s activity; and experience of this altered brain functioning is what people call being “high.”

But scientists were still curious and they wanted to know more about how THC is able to interact with the brain and what parts of the brain are altered. First, researchers labeled cannabinoid molecules with a marker that enabled them to visualize where THC goes in the brain. They found that, at first, THC spreads evenly throughout the brain wherever the blood flows. Then it washes away from many areas while it lodges in other portions of the brain.

The brain structures that seem to capture THC are clearly related to many of the mental functions that are altered when people are high. A particularly clear example would be the hippocampus, the brain structure that boosts short-term memory (also called “scratchpad” memory) into long-term memory. Every study of the acute effect of marijuana on memory has demonstrated disruptions in short-term memory. And everyone who has ever smoked marijuana has experienced transient memory glitches as part of the “high.” The fact that THC sticks to something in the hippocampus, the seat of short-term memory, makes some kind of sense.

I say “some kind of sense” because research scientists soon began working very hard to figure out exactly what THC sticks to. And here is where the whole story twisted and got truly fascinating. Here is where the focus of research stopped being primarily about marijuana and started being mostly about the brain. Here is where the scientific discoveries, beginning in 1988, started being absolutely awesome.

First, researchers found that the THC molecules were attaching to receptor sites, which are complex protein molecules sitting in the outer membranes of neurons. Named CB1 (i.e., “cannabinoid-1”) receptors, these sites are like locks that only permit molecules shaped similar to THC to slip into and activate. Why would our DNA contain the instructions for building receptor sites for THC? Why would we be hardwired to let marijuana get us high?

Next, in 1992, Raphael Mechoulam (the researcher who first determined the structure of THC) discovered the existence in our brain of a natural occurring cannabinoid, which he called anandamide. Our brain’s CB1 receptor was not developed for the purpose of responding to THC. It is one component of the brain’s own endogenous (meaning, internal) cannabinoid system. We now know that our DNA contains information to build not only cannabinoid receptors but also to build an array of cannabinoid molecules. Together, CB1 receptors and anandamide constitute a previously unknown neurotransmitter system – the endocannabinoid system. THC affects the brain by mimicking our natural cannabinoid transmitters!

We can now begin to put the endocannabinoid system into perspective. It appears that every animal species except insects is endowed with the DNA necessary to create the elements of an endocannabinoid system. The most primitive nervous systems known employ CB1 receptors and anandamide, which shows that the endocannabinoid system has been an integral part of nervous systems, and brains, throughout evolution.*

Unknown to scientists before two decades ago, the human brain’s endocannabinoid system is now recognized to be its largest neurotransmitter system. It actively modulates virtually every physiologic function in the body. By analogy, scientists trying to understand the “high” produced by marijuana were like Columbus when he was trying to find a way to India – both ended up discovering whole new “continents.” As a result, the science of marijuana has evolved into the neuroscience of our brain’s endocannabinoid neurotransmitter system.

An interesting question remains. Why did the cannabis plant develop cannabinoid chemistry? No other plant appears to produce a similar resin. It is not for the purpose of attracting insects for pollination, since insects do not have CB1 receptors to respond to the cannabis plant’s chemistry. While the high concentrations in today’s strains of marijuana have clearly been created by humans’ controlled cross-pollination of high yield strains, this still does not explain why this particular plant developed cannabinoid chemistry in the first place.

A parallel interesting question about the brain also remains. What is the function of our brains’ endocannabinoid system? What does it do for us?

Pursuing answers to this question is one of the hottest research areas in all of neuroscience today. This much is known:

• Our endocannabinoid system is always active. Like our heart beating, it is always working, although sometimes its activity slows in parts of the brain, and other times it quickens. We call this kind of brain activity “tonic,” meaning that there is an ongoing cannabinoid “tone” that is always present, like the motor of a car that is idling.
• Our endocannabinoid system works to modulate the sensitivity of our brain to many of the other neurotransmitters that are present, such as dopamine and serotonin.
• In order to function optimally, the brain’s endocannabinoid system needs to be finely balanced.

Beyond the three generalizations above, describing the functions of our endocannabinoid system becomes more complex. Raising or lowering endocannabinoid activity (tone) modulates the following:

• Our appetite for food (increased activity produces the “munchies” – a craving for and enjoyment of comfort food)
• Our suckling response as infants (decreased activity can eliminate suckling)
• Our level of spontaneous motor activity (increased activity produces stillness; too much produces “couch potatoes”)
• Our short-term memory (decreased activity improves memory)
• Our forgetting painful experience (increased activity facilitates extinction of aversive memories)
• Our experience of pain, especially from inflammation (the endocannabinoid system interacts with our endorphin system to reduce pain)
• Our response to stress (the entire stress response, from brain (hypothalamus) to endocrine glands (adrenal cortisol secretion) is regulated by the endocannabinoid system)
• Our anxiety and fear (A complicated relationship here: moderately increased levels of activity lowers anxiety, but higher levels of stimulation can increase anxiety, even creating panic and paranoia)
• Our sense of time (increased activity “slows” our perception of time)
• Our sense of novelty (increased activity makes even the mundane seem fresh)
• Our attention (increased activity widens our focus)
• Our sense of awe (increased activity often stimulates a sense of wonder)
• Reproductive physiology (every element of reproduction, from sperm and egg development, fertilization, embryonic development, implantation in the uterus, to maintenance of pregnancy requires proper endocannabinoid tone)

In fact, one of the founders of cannabinoid neuroscience, Raphael Mechoulam, summarized the functions of our brain’s endocannabinoid system by saying, “There is barely a physiological system in which endocannabinoids are not involved. Hence its importance is far beyond that of THC and marihuana….”2 This newly discovered chemical system is absolutely pervasive throughout the brain, modulating, regulating, and balancing other chemical systems. It is part of the intricate, and often delicate, tapestry of the brain. It is, therefore, part of the tapestry of the mind that emerges from our brain’s activity.

From the list of functions that are modulated by our endocannabinoid system, it is immediately apparent that the development of cannabinoid-based medications is inevitable, and will be welcome. Disease conditions that cause suffering from pain, inflammation, loss of appetite, nausea, anxiety and decreased memory, to name but a few, may well benefit from either increasing or decreasing activity in our endocannabinoid system. Research is currently under way to develop medications that are targeted and less likely to produce unwanted side effects.

So, we have learned that THC “works” by mimicking the action of our naturally occurring cannabinoid chemistry (e.g., anandamide). Many people enjoy the experiences and sensations that arise when they increase the activity of their endocannabinoid system by flooding their CB1 receptors with THC from smoked marijuana. This alters the natural balance within the endocannabinoid system, and within other chemical systems that are modulated by endocannabinoids. Our experience of this is an “altered” state of mind – pleasant for the majority of people.

How often, or how long, can people alter their brain/mind with marijuana before responses in the brain countering this disturbance to the normal balance begin to occur? This process is call homeostasis – the tendency of living organisms to push against disturbances in order to regain their previous balance.

Imagine for a moment that a large bank wants to keep the number of ATM uses below a certain figure. If people start using their ATMs too often, the bank could remove some of its ATMs. The effect would be to make it more inconvenient for its customers to use the ATMs as much as they want to. It would be a crazy strategy for making money, but it could safeguard a computer system that is in danger of being overwhelmed by too many ATM transactions to process.

In the event of massive stimulation coming from the outside in the form of THC, nerve cells with CB1 receptors attempt to recover their previous balance by using exactly the same strategy as our imaginary bank. The CB1 receptors are first pulled inside the cell, where they can no longer be stimulated by the THC (or by the brain’s own endocannabinoids). This is called receptor site down-regulation. If THC continues its excessive stimulation, the down-regulated receptors are literally dismantled within the cell so that their amino acids can be used elsewhere.

How soon does down-regulation begin? And how extensive is the down-regulation? Some areas of the brain begin down regulation immediately – following any exposure to THC. Most brain regions exhibit a progressive decrease in cannabinoid receptor binding with continued exposure.3 However, the pattern of down-regulation has significant regional differences in terms of onset of the decrease and the magnitude reached.4 Ultimately, some areas experience no down-regulation; other areas down-regulate up to 70% of their CB1 receptors.5 As a result, when the influx of THC stops – when marijuana smoking ends – parts of the brain are temporarily rendered less sensitive – tolerant – to the normal amount of stimulation provided by the brain’s natural endocannabinoids alone. Areas of the brain that do not down-regulate CB1 receptors are out of balance with areas that now have a deficiency.

Can the brain rebuild, or up-regulate, its CB1 receptors? Fortunately, the answer is yes. Since receptor sites are actually little complexes of protein, it can take some time to complete the up-regulation process, from 2-6 weeks, with a lot of individual variation based on how heavily an individual has smoked, how long, and the individual’s underlying health.

Is there ever any permanent brain damage from chronic marijuana use? If there is permanent damage, it is not very apparent or very profound. Enough people have smoked marijuana long enough to give us some evidence of the brain’s resilience. Nadia Solowij, one of the premier researchers in cannabis and cognition summarizes by saying, “The weight of the available evidence suggests that long-term heavy use of cannabis does not produce any severe or grossly debilitating impairment of cognitive function.”6

However, there are nagging doubts raised by some studies. Long-term human marijuana users have been shown to have reduced volumes in two areas of the brain – the hippocampus (memory and learning) and amygdala (emotion and novelty).7 Other studies demonstrate up to a 44% persistent decrease in nerve connections in the rat hippocampus dosed with THC for 90 days.8 As with all science, there is always so much more to learn.

California voters are preparing to go to the polls on November 2 to vote on whether to legalize marijuana via Proposition 19. The California Society of Addiction Medicine is deeply committed to providing voters the best information on marijuana science has to offer. We invite you to review the web pages we have prepared on “Evidence-Based Information on Cannabis/Marijuana” and then to send us your comments,

Two pages are devoted to CSAM’s formal statements on “Medical Aspects of Marijuana Legalization” and “Medical Marijuana.” We have found that splitting the two issues and discussing each independently facilitates debate on each of these topics.

Next is a section on “Marijuana’s Addictive Potential”. We have provided a shorter version for the General Public and a much longer, fully referenced version for Healthcare Professionals. Every assertion of fact in the shorter version is provided a source reference in the longer version. Each referenced article is provided with the full abstract, when available.

“The Adverse Effects of Marijuana,” particularly the ongoing or chronic use of marijuana, is similarly presented in two forms – a shorter version and a longer, referenced version.

The Rand Corporation has published the most comprehensive report estimating how marijuana legalization in California could influence marijuana consumption and public budgets. We have provided both the full 85 page original report and written a brief summary of its findings for quicker review.

Finally, we have reproduced the entire text of Prop 19, The Regulate, Control and Tax Cannabis Act of 2010.

Additional materials will be added as they become available.

Evidence-Based Marijuana Information

References

1. Schuel, H., “Tuning the oviduct to the anandamide tone” (2006)., J Clin Invest 116(8): 2087-90
2. Mechoulam, R., “New Developments in Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam” http://www.lmreview.com/articles/view/new-developments-in-cannabinoid-based-medicine-an-interview-with-dr-raphael-mechoulam/
3. Romero, J. “Time-course of the cannabinoid receptor down-regulation in the adult rat brain caused by repeated exposure to delta9-tetrahydrocannabinol” (1998), Synapse Vol 30(3); pp 298-308.
4. Romero, J. “Effects of chronic exposure to delta9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions” (1997), Brain Res Mol Brain Res Vol 46(1-2); pp 100-8.
5. Breivogel, C. S., “The effects of delta9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors” (2003), Eur J Pharmacol Vol 459(2-3); pp 139-50.
6. Nadia Solowij, Cannabis and Cognitive Functioning, Cambridge University Press, 1998
7. Yucel, M. “Regional brain abnormalities associated with long-term heavy cannabis use”, (2008), Arch Gen Psychiatry Vol 65(6); pp. 694-701.
8. Scallet, A.C., “Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC)” (1987), Brain Res Vol 436(1); pp. 193-8.