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How does cannabis get you high?

How do marijuana’s psychoactive properties work?

Have you ever looked at your hands? I mean really looked at your hands?

You might think you have, but as the above classic Doonesbury cartoon implies, people who are high on cannabis may perceive mundane objects to be far more fascinating than usual.

How is it that a plant that first emerged on what’s now the Tibetan Plateau can change humans’ perception of reality? The secret lies in a class of compounds called cannabinoids. While cannabis plants are known to produce at least 140 types of cannabinoids, there’s one that’s largely responsible for many of the effects of feeling high. It’s called tetrahydrocannabinol, or THC.

When a person smokes or inhales cannabis, THC “goes into your lungs and gets absorbed … into the blood,” according to Daniele Piomelli, a professor of anatomy & neurobiology, biological chemistry, and pharmacology at the University of California, Irvine School of Medicine. Edibles take slightly longer trip through the liver, where enzymes transform THC into a different compound that takes a bit longer to have an effect on people’s perception of reality.

THC that’s inhaled “reaches pretty high levels fairly quickly,” Piomelli told Live Science. Within 20 minutes, the circulatory system is carrying molecules of THC to every tissue in the body, including the brain, where it can alter neural chemistry.

“From the lungs, it’s a pretty straight shot to the brain,” according to Kelly Drew, a professor of chemistry and biochemistry at the University of Alaska Fairbanks.

The THC molecules that pass the blood-brain barrier will find that they fit snugly into receptors that ordinarily receive compounds called endocannabinoids, which the body produces itself. These receptors are part of the endocannabinoid system, which is involved in several functions, including stress, food intake, metabolism and pain, according to Piomelli, who also directs the Center for the Study of Cannabis at UC Irvine.

“The endocannabinoid system is the most pervasive, diffused and important modulatory system in the brain because it controls the release of pretty much every neurotransmitter,” Piomelli said. Neurotransmitters are molecules that brain cells, or neurons, use to communicate with each other. One neuron sends a message to the next by releasing neurotransmitters, such as dopamine or serotonin, into an infinitesimal gap that separates one neuron from the next. The gap is called the synapse.

The neuron on the receiving end of the synapse is called the postsynaptic neuron, and it “decides whether to fire based on the input it receives,” Drew told Live Science. These neural signals cascade through intricate circuits of neural connections that function on a tremendous scale; there are about 85 billion neurons in the brain and as many as 100 trillion connections among them.

The presynaptic neuron sends neurotransmitters across the synapse to the postsynaptic neuron, Piomelli said. But the presynaptic neuron can also receive information. When a postsynaptic neuron has fired, it can send a message across the synapse that says, “the neuron I come from has been activated,” stop sending neurotransmitters, Piomelli said. It sends this “stop” message in the form of endocannabinoids that bind to a receptor called cannabinoid 1 (CB1).

“Like a sledgehammer”

When THC enters the brain, the molecules diffuse into the synapses where they “activate CB1 receptors,” Drew said. THC doesn’t cause the most extreme possible response like some synthetic cannabinoids such as K2 or spice, but it does “turn up the volume” and increase the likelihood that the presynaptic neuron it affects will temporarily stop sending neurotransmitters, she said.

“The high is a very simple phenomenon, Piomelli said. “THC comes in like a sledgehammer,” flooding the endocannabinoid system with signals the postsynaptic neurons didn’t send. When presynaptic neurons across the brain get the memo to stop sending neurotransmitters, this alters the normal flow of information among neurons and results in a high.

Scientists have yet to decipher exactly what happens during this euphoria, however.

That’s because, in part, U.S. legal restrictions make it difficult to study cannabis. But from what researchers have gathered so far, THC appears to temporarily “unplug” the default mode network. This is the brain network that allows us to daydream and think about the past and future. When our brains are focused on a specific task, we quiet this network to let our executive function take control.

There’s evidence that THC has a significant effect on the network, but researchers aren’t quite sure how it happens. There are cannabinoid receptors all over the brain, including in “areas that constitute the key nodes of the [default mode network],” Piomelli said. It could be “that THC deactivates the [default mode network] by combining with those receptors,” but it’s also possible that THC quiets the network through an “indirect effect that involves cannabinoid receptors in other brain regions.”

Scientists are still working to find the mechanisms that result in a person feeling high, but there’s some reason to think this effect on the default mode network is a significant piece of the puzzle.

Unplugging the default mode network “takes us into a mental place where the function of the things we experience is less important than the things themselves: our hands are no longer just something we use for touching or grabbing, but something with inner existence and intrinsic value,” Piomelli said. Psychedelics, such as LSD or dried psilocybin-containing mushrooms, do the same thing.

However, people can experience highs differently. “The feeling of becoming fascinated by and ‘connected’ with ordinary things, things we see and use every day, is not universal but does happen, especially when high doses of THC-containing cannabis are used,” Piomelli said.

THC doesn’t just affect the default mode network. It may also, in the short-term, flood the brain with dopamine, the brain’s reward signal, according to a 2017 study in the journal Nature. (Long-term, it may blunt dopamine’s effects, the study found.) That, in part, may explain some of the euphoria associated with a high, and places cannabis in the company of other drugs that people use to feel pleasure.

“Every drug that has rewarding properties affects that system,” Drew said.

Aftereffects

The effects of a high from cannabis that’s smoked or inhaled typically last for a few hours, though it can take edibles almost that long to start affecting users. And while cannabis isn’t the dangerous substance it was made out to be in the 20th century, using it comes with some risk. For one, while cannabis is legal for recreational and medical use in some states, it’s still illegal in many parts of the country.

It’s also important to bear in mind that cannabis is a potent pharmacological substance. Cannabis can cross the placenta, so pregnant people should avoid it. And “heavy use in the teenage years can be problematic,” Piomelli said. For instance, cannabis — and especially synthetic cannabinoids like spice — can exacerbate psychosis. “People who are at risk for that should not smoke it,” Drew said.

Finally, cannabis does affect the ability to drive, particularly in occasional users. Drew cautioned that people should not drive for three hours after smoking.

Eventually, the THC will leave the brain; the profusion of blood that brought THC into the brain will carry it to the liver, where it will be destroyed and expelled in urine.

And you’re not gonna believe this, but your hands — they were the same the whole time.

Originally published on Live Science.

IMHO, drugs which do not easily cause overdose deaths (like THC, LSD etc) should/must be legally treated same as alcohol (which is really just another kind of drug (which do not easily cause overdose deaths))!

IMHO, just like prohibition of alcohol had caused so much crime in the past (& that is why it had been forced to be repealed later), prohibition of other similar drugs causing so much easily preventable crime today!
We need to take lesson from our past.

It gives people relief without vice.

This is precisely why it has been vilified for so long. You cannot have such things. Fun, pleasure and relief without vice?

That is blasphemy of the highest order for the “divinely” inspired. In their distorted concept of “dealing with life”, you have to tough it out. Anything which circumvents such rigors in life is sinful.

It reminds one of the famous counter-culture response: “Reality is for people who cannot deal with drugs.”

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Here’s how cannabis jumbles up typical brain processing.

Why THC gets you high and CBD doesn’t

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Contents

  1. Other cannabinoids play different roles in the ECS
  2. Cannabinoids interact with many systems in the body
  3. Terpenes play a key part in the entourage effect

The main intoxicating ingredient in cannabis is delta-9-tetrahydrocannabinol (THC). The psychoactive properties of THC were first described in the 1940s, however, our understanding of the cannabinoid dramatically improved once the Israeli scientist Rafael Mechoulam synthesized this molecule in 1965. While federal laws in the United States classify marijuana as a Schedule I substance, stifling research into possible benefits, adult-use and medical marijuana legalization has helped unearth more information on this complex plant.

The CB1 receptor is the critical target in the brain that produces intoxication.

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THC is an agonist, or activator, of the cannabinoid 1 (CB1) receptor. When cannabis is given to people who have had their CB1 receptors blocked (by a different drug, called an antagonist), cannabis cannot get them high. So, we know that the CB1 receptor must be the critical target in the brain that produces intoxication.

Brain imaging studies have shown increased blood flow to the prefrontal cortex region of the brain during THC intoxication. This region of the brain is responsible for decision-making, attention, and other executive functions, like motor skills. In short, THC intoxication can affect any of these functions to varying degrees depending on the person.

Another important factor in cannabis intoxication involves the brain’s reward circuitry, which feeds emotional and memory processes. Ultimately, the activity in these regions produces pleasurable sensations and emotions that encourage us to revisit that burger place for a calorie-dense meal or ask a potential mate out on another date.

An important factor in cannabis intoxication involves the brain’s reward circuitry, which feeds emotional and memory processes.

Cannabis activates the brain’s reward pathway, which makes us feel good, and increases our likelihood of partaking again in the future. THC binding to CB1 receptors in the brain’s reward system is a major factor in cannabis’ ability to produce feelings of euphoria.

But THC is far from the only ingredient in cannabis that has a direct impact on brain function. The most notable comparison is with cannabidiol (CBD), which is the second most abundant cannabinoid found in the plant. CBD is often touted as non-psychoactive, however this statement is somewhat misleading. Any substance that has a direct effect on the function of the brain is considered to be psychoactive. CBD most certainly creates psychoactive effects when it interacts with the brain and central nervous system, as it has very powerful anti-seizure and anti-anxiety properties.

Other cannabinoids play different roles in the ECS

CBD is indeed psychoactive; it’s just not intoxicating. In other words, the answer to the question ‘does CBD get you high?’ is no. The reason for this is that unlike THC, CBD is exceedingly bad at activating the CB1 receptor. In fact, evidence suggests that it actually interferes with the activity of the CB1 receptor, especially in the presence of THC. When THC and CBD work together to affect CB1 receptor activity, users tend to feel a more mellow, nuanced high and have a much lower chance of experiencing paranoia compared to the effects felt when CBD is absent. That’s because THC activates the CB1 receptor, while CBD inhibits it. A February 2010 study found that THC and CBD can have opposite effects on regional brain function, which could help explain why CBD tends to temper the effects of THC. Taking a closer look at the CBD vs THC dichotomy and the effects of each on the body’s cannabinoid receptors, however, reveals a more complex picture of how the two interact. Despite the noted differences between CBD and THC, the presence of both cannabinoids appear to balance the effects.

CBD may protect against cognitive impairment associated with overexposure to THC. Photo by: Gina Coleman/Weedmaps

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For instance, CBD may protect against cognitive impairment associated with overexposure to THC. In a series of studies on the cognitive effects of heavy or daily cannabis use, participants who had smoked cannabis with higher levels of CBD exhibited better memory recall than those who had lower doses of CBD. A 2013 study administered THC to participants and found that those who had been given CBD prior to THC administration showed less episodic memory impairment than patients who had been given a placebo — further indicating that CBD may curb THC-induced cognitive deficits.

CBD may also protect against THC-induced psychosis. Two separate population-based studies conducted by the same team found that people who used THC alone were more prone to psychosis (or schizophrenia-like symptoms) than those who used THC and CBD. A more recent study, published in March 2018, found that, when used alongside antipsychotic medication, CBD helped reduce symptoms in patients with schizophrenia. More clinical data is needed to explore CBD’s anti-psychosis effects more completely, but its potential for reducing the risk of THC-induced psychosis symptoms is already apparent.

Cannabinoids interact with many systems in the body

Beyond CB1 receptors, THC and CBD bind to several other targets. CBD, for example, has at least 12 sites of action in the brain. And where CBD may balance the effects of THC through inhibiting CB1 receptors, it may have other effects on THC metabolism at different sites of action.

Where CBD may have other effects on THC metabolism at different sites of action. Photo by: Gina Coleman/Weedmaps

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As a result, CBD may not always inhibit or balance THC’s effects. It may also directly enhance THC’s positive effects. CBD does, for example, have the potential to synergize, and even enhance THC-induced pain relief. THC is both an anti-inflammatory and neuroprotective antioxidant, largely due to its activation of CB1 receptors in the pain-control area of the brain. A study from 2012 revealed that CBD targets alpha-3 (α3) glycine receptors, a crucial target for pain processing in the spine, to suppress chronic pain and inflammation. It’s an example of what’s called the “entourage effect,” in which the combined effect of different cannabis compounds work together as a whole to produce a greater effect than if working separately. But even this interaction is not entirely clear. In a February 2019 study, researchers found that low doses of CBD actually enhanced the intoxicating effects of THC, while high doses of CBD reduced the intoxicating effects of THC.

Terpenes play a key part in the entourage effect

The entourage effect can be evoked by consuming cannabis products that contain both THC and CBD, and marijuana strains can offer specified levels of each of the two cannabinoids. High CBD marijuana strains, for instance, will have different, less intoxifying effects than strains with higher THC levels. Even some hemp-derived CBD oil contains small trace amounts of THC, but not at levels that would cause any intoxicating effects.

The entourage effect can be evoked by consuming cannabis products that contain both THC and CBD. Photo by: Gina Coleman/Weedmaps

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Things get particularly interesting when other cannabinoid and terpene molecules are consumed alongside THC and CBD. Although we are just beginning to understand the isolated effects of cannabinoids such as CBN, CBC, and CBG, their ability to bind to targets in the brain means they could potentially enhance, reduce, prolong, or in some other way modulate the effects of THC. It’s entirely possible that some of cannabis’ most well-known side effects (such as couch lock) may have very little to do with THC itself, but rather, the relative contributions of these lesser-known molecules. Terpenes, which are the largest group of known phytochemicals in cannabis, have also proven to be a critical piece to this puzzling entourage effect. Not only do terpenes give cannabis a distinct flavor and aroma, but they also appear to support other cannabis molecules in producing physiological and cerebral effects.

Cannabis is a complex plant with relatively little available research into its effects and interactions with the human body — and we’re just beginning to learn the many ways cannabis compounds work together and interact with our cannabinoid receptors to change the way we feel.

Why THC gets you high and CBD doesn’t Copy article link to clipboard. Link copied to clipboard. Contents Other cannabinoids play different roles in the ECS Cannabinoids