i’ve been holding back on a post about this topic for a while because it’s just a magnet for nonsense on the internet. but ya know, it’s time. the topic has come up enough elsewhere that it’s time for an explanation. i’m into facts.

click on below the fold and let’s get started…

Pot, aka marijuana, comes from the dried flowers of the Cannabis sativa plant. Cannabis has got that familiar leaf shape we’ve likely all seen before… except that this part of the plant doesn’t contain a whole lot of psychotropic compound. The part that does contain the psychoactive stuff is the flower bud in female plants. So this is the part that is burned and inhaled, and gives you a “high.”

Figure 1. Marijuana. (from the DEA, via about.com)

What you’re effectively doing when you smoke this stuff is inhaling a vapor of all the chemicals contained in the plant. Cannabis, as you might imagine, produces a lot of molecules that have been named cannabinoids. Not all of the cannabinoids are particularly psychoactive. But among those cannabinoids is the psychoactive molecule delta-9 tetrahydrocannabinol, or THC.

Figure 2. Molecular structure of THC. (via wikimedia)

THC is a very, VERY lipid-soluble compound, which means it slips right through the membranes in your lungs after you inhale it and takes the bloodstream highway up to your blood-brain barrier. From there it easily crosses the highly lipophilic blood-brain barrier and starts acting on the brain.

It really takes very little time for the drug effects to kick in when you smoke marijuana. Eating it is another story. If you’d like to catch up on your pharmacokinetics to understand why this is, check out an older post.

But now that we’ve covered some of the basic background stuff, what specifically is going on here?

THC targets two major receptors that we currently know of, and as you might guess, they are called cannabinoid receptors. They are G protein coupled receptors quite creatively named CB1 and CB2, and they have quite different functions. I’m going to go backward and just briefly mention CB2, because we will be spending most of the discussion on CB1. CB2 is primarily involved in immune regulation- activation of this receptor results in suppression of immune system events like immune cell activation and proliferation, as well as production of some inflammatory mediators. It is not responsible for the psychoactive effects of THC.

CB1 is the receptor target of THC that does cause psychotropic effects.

CB1 receptors are expressed very widely in the brain. The actions of these receptors, in the various parts of the brain where they are expressed, are responsible for the many and varied effects of THC upon central nervous system function. Before I can tell you why these effects are what they are, we need to discuss how the cannabinoid signaling mechanism normally works. Let’s zoom way in from the level of “brain” to the synapse, where two neurons interact.

Figure 3. The model inhibitory synapse.

Here we have an inhibitory synapse. In this case, the presynaptic neuron provides an inhibitory input, decreasing the likelihood that the postynaptic neuron will fire. I have marked the presynaptic and postsynaptic neurons, and the direction of neuronal firing. The neurotransmitter dots in the presynaptic vesicles and in the synapse are marked red because they are inhibitory. The postsynaptic receptors are red because they are receptors for this inhibitory neurotransmitter.

Now like in all synapses, information flows from the presynaptic neuron to the postsynaptic neuron via release of neurotransmitter and activation of postsynaptic receptors. This leads to changes in the activity of the postsynaptic neuron. But the cannabinoid signaling mechanisms cause a pretty uncommon event in the world of neuronal information transmission: they allow the postsynaptic neuron to modify the activity of the presynaptic neuron. Now we have two-way communication across the synapse, rather than the presynaptic neuron being the one-way communicator.

Take a look at the green part of the figure. This is the “backward” or retrograde communication that goes on from postsynaptic cell to presynaptic cell. The green dots represent the endogenous ligands of the CB1 receptor, the endocannabinoids. These are produced by the postsynaptic cell and are able to activate CB1 receptors located on presynaptic terminals. They are produced and released on demand, not stored in vesicles like many other neurotransmitters, so there are very specific triggers for endocannabinoid production.

Alright, so what do CB1 receptors do when they are activated?

Figure 4.  Presynaptic CB1 receptor effects.

CB1 receptors affect the function of the presynaptic terminal. When CB1 receptors are activated, they signal through G proteins to close calcium channels, preventing entry of calcium into the terminal. Calcium is needed for vesicles to fuse with the membrane and release inhibitory neurotransmitters into the synapse. So CB1 signaling stops inhibitory neurotransmitters from being released to the postsynaptic neuron. CB1 receptor activation also results in opening of potassium channels. In a resting neuron, these channels are closed. Outflow of positively charged potassium ions leads to increases in the net negative charge across the membrane. This is called hyperpolarization, the opposite of depolarization. As you might imagine, since depolarization causes neurons to fire, hyperpolarization keeps a neuron from firing. This further decreases the chances that neurotransmitter will be released from the presynaptic terminal. There are some other effects too, which I won’t detail here.

The net result is that the postsynaptic neuron signals back to stop neurotransmitter release from the presynaptic neuron. This kind of two-way communication is not a common thing in neurons, and the presence of this system indicates a need for very fine regulation of neuronal firing in response to a variety of inputs.

Are we all on board with the zoomed-in details? Let’s zoom back out to the level of a simplified circuit, now that we know how regulation of synaptic communication can be disrupted.

Figure 5. A simple representation of the hunger circuit in the hypothalamus. Excitatory drive leads to hunger, but neurons that inhibit the main excitatory pathways stop that hunger trigger.

Recall I showed you how endocannabinoid stimulation of CB1 receptors on presynaptic neurons can suppress neurotransmitter release from those neurons. So if we suppress inhibitory transmission from this circuit, we have more excitation and therefore more hunger. Throwing THC into this circuit, as someone might do when they’ve smoked pot, can lead to the same effect even if endocannabinoids aren’t being released by the presynaptic neuron. This is, in the most simple way I can explain it, why pot smokers get the munchies. They are losing suppression of hunger pathways.

Now think of all the other circuits in your brain. Reward, memory, and motivation, for example. These are all circuits where CB1 receptors can be found, that can be affected by THC and lead to alterations in behavior. THC messes up the regulation of neuronal firing timing in the hippocampus, and you suddenly aren’t so great at encoding memory. It relieves suppression upon dopaminergic neurons, leading to dopamine release that makes you feel good.

I hope that this helps to make the effects of marijuana make more sense. For the record, I am not interested in discussing policy or the legal status of the drug. I am just here writing about how it works.