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Long-Term Marijuana Use Changes Brain at the Cellular Level, Say Scientists

Chronic use leads to chronic problems.

In March, long-term marijuana smoker Woody Harrelson surprised fans by announcing he was giving up his chronic pot habit, saying it made him “emotionally unavailable.” Likewise, in June, notorious stoner Miley Cyrus did the same, saying she “wanted to be really clear” while making her new album. Long-term pot smokers who have quit cite similar anecdotal evidence about the chronic effects of weed, but scientists have only recently begun understanding what, if anything, it actually does to the brain.

In a study on mice published Monday in the journal JNeurosci, scientists report that long-term marijuana use does indeed change the brain.

In their study, the researchers from Brigham Young University’s neuroscience department, led by Jeffrey Edwards Ph.D., focused on the brain’s ventral tegmental area (VTA), a region rich with the dopamine and serotonin receptors that comprise the brain’s reward system, looking at how its cells changed as the teen mice they studied received daily THC injections every day for a week. Researchers know that drugs of abuse, like opioids, alcohol, and marijuana, act on the VTA, and it’s thought that the active ingredients in these drugs stimulate the release of dopamine in this area, thereby triggering the flood of pleasure that drugs (as well as friendship and sex) provide — and creating cravings for more.

In particular, they looked at a type of cell in the VTA known as a GABA cell that marijuana researchers hadn’t looked at before. The cells are named for the type of neurotransmitter they pick up — GABA, short for gamma-aminobutyric acid — which is well-known for its inhibitory properties. Imagine GABA as the high-strung friend who becomes anxious when the rest of the group has too much fun. When GABA is released in the brain, it regulates the levels of happy-making dopamine, making sure revelry doesn’t go overboard.

This friend is a bit of a buzzkill but seems to be necessary to prevent the brain from having too much of a good thing. But, as it turns out, GABA neurons can be incapacitated, too.

As the researchers observed these cells in teen mice over their THC-filled week, they saw that the ability of the GABA neurons to regulate dopamine faltered as the trial went on. In contrast, mice who only received a single injection of THC — the Bill Clintons of the group — didn’t show any changes in their GABA neurons, suggesting that the effects seen in the chronic users are a consequence of long-term marijuana use. Those changes led dopamine to linger in the VTA longer than usual, which caused an abnormally drawn-out feeling of reward. And too much of those pleasurable feelings, scientists have found, is what leads to addiction.

The team behind the study hopes that their findings can eventually be used to treat people with cannabis use disorder, defined by the Diagnostic and Statistical Manual of Mental Disorders-5 as a “problematic pattern of cannabis use leading to clinically significant impairment or distress.”

The term problematic, in this case, refers to a range of criteria largely centered around the inability of people to do what they need or want to do because of their addiction to the drug. It’s not clear whether Harrelson and Cyrus had been diagnosed with cannabis use disorder, but their reasons for quitting weed seem to line up.

The ventral tegmental area (VTA) is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole cell electrophysiology in juvenile-adolescent GAD67-GFP male mice we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent long-term depression (LTD) was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice, but preserved in heterozygous littermates. Chronic injections of О”9-tetrahydrocannabinol occluded LTD compared to vehicle injections, however, a single exposure was insufficient to do so. Because О”9-tetrahydrocannabinol depresses GABA cell activity, downstream dopamine cells will be disinhibited and thus this could potentially result in increased reward. As synaptic modifications by drug of abuse are often tied to addiction, this data suggest a possible mechanism for the addictive effects of О”9-tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes.

If you liked this article, check out this video about a new study that suggests weed could be used to cure Alzheimer’s.

Chronic use leads to chronic problems.

Gaba and weed

Nearly 15% of all men and 30% of all women admit to a craving for chocolate.

Over 300 substances have been identified in chocolate. Some of these, including caffeine and theobromine (another, less powerful stimulant) could actually cause dependency effects. But the amounts of these substances in chocolate are too small to really have any effect.

The same goes for phenylethylamine, a substance related to a family of stimulants called amphetamines. For example, chocolate contains less phenylethylamine than goat cheese.

Anandamide, a neurotransmitter produced naturally by the brain, has also been isolated in chocolate. The neural receptors for anandamide are the same ones to which THC, the main active ingredient in cannabis, binds. The anandamide in chocolate might therefore contribute to the feeling of well-being reported by “chocoholics” (though you would have to eat well over 30 kilos of chocolate to experience effects comparable to one dose of cannabis!).

Be that as it may, many scientists agree that dependency on chocolate could simply be due to its taste, which causes a sensation of intense pleasure that people want to repeat.

Dopamine appeared very early in the course of evolution and is involved in many functions that are essential for survival of the organism, such as motricity, attentiveness, motivation, learning, and memorization. But most of all, dopamine is a key element in identifying natural rewards for the organism. These natural stimuli such as food and water cause individuals to engage in approach behaviours. Dopamine is also involved in unconscious memorization of signs associated with these rewards.

It has now been established that all substances that trigger dependencies in human beings increase the release of a neuromediator, dopamine, in a specific area of the brain: the nucleus accumbens.

But not all drugs increase dopamine levels in the brain in the same way.

  • Some substances imitate natural neuromediators and take their place on their receptors. Morphine, for example, binds to the receptors for endorphin (a natural “morphine” produced by the brain), while nicotine binds to the receptors for acetylcholine.
  • Other substances increase the secretion of natural neuromediators. Cocaine, for example, mainly increases the amount of dopamine in the synapses, while ecstasy mainly increases the amount of serotonin.
  • Still other substances block a natural neuromediator. Alcohol, for example, blocks the NMDA receptors.

Click on the names of each of the following drugs to read about how they work and what effects they have.

The sensations of slight euphoria, relaxation, and amplified auditory and visual perceptions produced by marijuana are due almost entirely to its effect on the cannabinoid receptors in the brain. These receptors are present almost everywhere in the brain, and an endogenous molecule that binds to them naturally has been identified: anandamide. We are thus dealing with the same kind of mechanism as in the case of opiates that bind directly to the receptors for endorphins, the body’s natural morphines.

Anandamide is involved in regulating mood, memory, appetite, pain, cognition, and emotions. When cannabis is introduced into the body, its active ingredient, Delta-9-tetrahydrocannabinol (THC), can therefore interfere with all of these functions.

THC begins this process by binding to the CB1 receptors for anandamide. These receptors then modify the activity of several intracellular enzymes, including cAMP, whose activity they reduce. Less cAMP means less protein kinase A. The reduced activity of this enzyme affects the potassium and calcium channels so as to reduce the amount of neurotransmitters released. The general excitability of the brain’s neural networks is thus reduced as well.

However, in the reward circuit, just as in the case of other drugs, more dopamine is released. As with opiates, this paradoxical increase is explained by the fact that the dopaminergic neurons in this circuit do not have CB1 receptors, but are normally inhibited by GABAergic neurons that do have them. The cannabis removes this inhibition by the GABA neurons and hence activates the dopamine neurons.

In chronic consumers of cannabis, the loss of CB1 receptors in the brain’s arteries reduces the flow of blood, and hence of glucose and oxygen, to the brain. The main results are attention deficits, memory loss, and impaired learning ability.

General links about cannabis:


For a description of the effects of cannabis and the risks of dependency associated with it, click on the following links:

Gaba and weed Nearly 15% of all men and 30% of all women admit to a craving for chocolate . Over 300 substances have been identified in chocolate. Some of these, including caffeine and