Cannabis Receptors and the Runner’s High

[First published August 4 2010]

Maybe it isn't endorphins after all.

What do long-distance running and marijuana smoking have in common? Quite possibly, more than you’d think. A growing body of research suggests that the runner’s high and the cannabis high are more similar than previously imagined.

The nature of the runner’s high is inconsistent and ephemeral, involving several key neurotransmitters and hormones, and therefore difficult to measure. Much of the evidence comes in the form of animal models. Endocannabinoids—the body’s internal cannabis—“seem to contribute to the motivational aspects of voluntary running in rodents.” Knockout mice lacking the cannabinioid CB1 receptor, it turns out, spend less time wheel running than normal mice. 

A Canadian neuroscientist who blogs as NeuroKuz suggests that “a reduction in CB1 levels could lead to less binding of endocannabinoids to receptors in brain circuits that drive motivation to exercise.” NeuroKuz speculates on why this might be the case. Physical activity and obtaining rewards are clearly linked. The fittest and fleetest obtain the most food. “A possible explanation for the runner’s high, or ‘second wind,’ a feeling of intense euphoria associated with going on a long run, is that our brains are stuck thinking that lots of exercise should be accompanied by a reward.”

In 2004, the British Journal of Sports Medicine ran a research review, “Endocannabinoids and exercise,” which seriously disputed the “endorphin hypothesis” assumed to be behind the runner’s high. To begin with, other studies have shown that exercise activates the endocannabinoid system.

“In recent years,” according to the authors, “several prominent endorphin researchers—for example, Dr Huda Akil and Dr. Solomon Snyder—have publicly criticised the hypothesis as being ‘overly simplistic,’ being ‘poorly supported by scientific evidence’, and a ‘myth perpetrated by pop culture.’” The primary problem is that the opioid system is responsible for respiratory depression, pinpoint pupils, and other effects distinctly unhelpful to runners.

The investigators wired up college students and put them to work in the gym, and found that “exercise of moderate intensity dramatically increased concentrations of anandamide in blood plasma.” The researchers break the runner’s high into four major components. Exercise, they say, “suppresses pain, induces sedation, reduces stress, and elevates mood.” Some of the parallels with the cannabis high are not hard to tease out: “Analgesia, sedation (post-exercise calm or glow), a reduction in anxiety, euphoria, and difficulties in estimating the passage of time.”

There are cannabinoid receptors in muscles, skin and the lungs. Intriguingly, the authors suggest that unlike “other rhythmic endurance activities such as swimming, running is a weight bearing sport in which the feet must absorb the ‘pounding of the pavement.’” Swimming, the authors speculate, “may not stimulate endocannabinoid release to as great an extent as running.” Moreover, “cannabinoids produce neither the respiratory depression, meiosis, or strong inhibition of gastrointestinal motility associated with opiates and opioids. This is because there are few CB1 receptors in the brainstem and, apparently, the large intestine.”

A big question remains: What about running and the “motor inhibition” characteristic of high-dose cannabis? (An inhibition that may make cannabis useful in the treatment of movement disorders like tremors or tics.) Running a marathon is not the first thing on the minds of most people after getting high on marijuana.  The paper maintains, however, that at low doses, “cannabinoids tend to produce hyperactivity,” at least in animal models. The CB1 knockout mice were abnormally inactive, due to the effect of cannabinoids on the basal ganglia. Practiced, automatic motor skills like running are controlled in part by the basal ganglia. The authors predict that “low level skills such as running, which are controlled to a higher degree by the basal ganglia than high level skills, such as basketball, hockey, or tennis, may more readily activate the endocannabinoid system.”

The authors offer other intriguing bits of evidence. Anandamide, one of the brain’s own cannabinoids, “acts as a vasodilator and products hypotension, and may thus facilitate blood flow during exercise.” In addition, “endocannabinoids and exogenous cannabinoids act as bronchodilators” and could conceivably facilitate breathing during steady exercise. The authors conclude: “Compared with the opioid analgesics, the analgesia produced by the endocannabinoid system is more consistent with exercise induced analgesia.”

Photo Credit: http://www.madetorun.com/

What Do Long Distance Running and Marijuana Have in Common?

Maybe it isn't endorphins after all.

[From time to time, I reprint earlier posts that have remained perennial favorites at Addiction Inbox. This one originally ran on August 4, 2010.]

What do long-distance running and marijuana smoking have in common? Quite possibly, more than you’d think. A growing body of research suggests that the runner’s high and the cannabis high are more similar than previously imagined.

The nature of the runner’s high is inconsistent and ephemeral, involving several key neurotransmitters and hormones, and therefore difficult to measure. Much of the evidence comes in the form of animal models. Endocannabinoids—the body’s internal cannabis—“seem to contribute to the motivational aspects of voluntary running in rodents.” Knockout mice lacking the cannabinioid CB1 receptor, it turns out, spend less time wheel running than normal mice. 

A Canadian neuroscientist who blogs as NeuroKuz suggests that “a reduction in CB1 levels could lead to less binding of endocannabinoids to receptors in brain circuits that drive motivation to exercise.” NeuroKuz speculates on why this might be the case. Physical activity and obtaining rewards are clearly linked. The fittest and fleetest obtain the most food. “A possible explanation for the runner’s high, or ‘second wind,’ a feeling of intense euphoria associated with going on a long run, is that our brains are stuck thinking that lots of exercise should be accompanied by a reward.”

In 2004, the British Journal of Sports Medicine ran a research review, “Endocannabinoids and exercise,” which seriously disputed the “endorphin hypothesis” assumed to be behind the runner’s high. To begin with, other studies have shown that exercise activates the endocannabinoid system.

“In recent years,” according to the authors, “several prominent endorphin researchers—for example, Dr Huda Akil and Dr. Solomon Snyder—have publicly criticised the hypothesis as being ‘overly simplistic,’ being ‘poorly supported by scientific evidence’, and a ‘myth perpetrated by pop culture.’” The primary problem is that the opioid system is responsible for respiratory depression, pinpoint pupils, and other effects distinctly unhelpful to runners.

The investigators wired up college students and put them to work in the gym, and found that “exercise of moderate intensity dramatically increased concentrations of anandamide in blood plasma.” The researchers break the runner’s high into four major components. Exercise, they say, “suppresses pain, induces sedation, reduces stress, and elevates mood.” Some of the parallels with the cannabis high are not hard to tease out: “Analgesia, sedation (post-exercise calm or glow), a reduction in anxiety, euphoria, and difficulties in estimating the passage of time.”

There are cannabinoid receptors in muscles, skin and the lungs. Intriguingly, the authors suggest that unlike “other rhythmic endurance activities such as swimming, running is a weight bearing sport in which the feet must absorb the ‘pounding of the pavement.’” Swimming, the authors speculate, “may not stimulate endocannabinoid release to as great an extent as running.” Moreover, “cannabinoids produce neither the respiratory depression, meiosis, or strong inhibition of gastrointestinal motility associated with opiates and opioids. This is because there are few CB1 receptors in the brainstem and, apparently, the large intestine.”

A big question remains: What about running and the “motor inhibition” characteristic of high-dose cannabis? (An inhibition that may make cannabis useful in the treatment of movement disorders like tremors or tics.) Running a marathon is not the first thing on the minds of most people after getting high on marijuana.  The paper maintains, however, that at low doses, “cannabinoids tend to produce hyperactivity,” at least in animal models. The CB1 knockout mice were abnormally inactive, due to the effect of cannabinoids on the basal ganglia. Practiced, automatic motor skills like running are controlled in part by the basal ganglia. The authors predict that “low level skills such as running, which are controlled to a higher degree by the basal ganglia than high level skills, such as basketball, hockey, or tennis, may more readily activate the endocannabinoid system.”

The authors offer other intriguing bits of evidence. Anandamide, one of the brain’s own cannabinoids, “acts as a vasodilator and products hypotension, and may thus facilitate blood flow during exercise.” In addition, “endocannabinoids and exogenous cannabinoids act as bronchodilators” and could conceivably facilitate breathing during steady exercise. The authors conclude: “Compared with the opioid analgesics, the analgesia produced by the endocannabinoid system is more consistent with exercise induced analgesia.”

Photo Credit: http://www.madetorun.com/

The New Cannabinoids

Army fears influx of synthetic marijuana

It’s a common rumor: Spice, as the new synthetic cannabis-like products are usually called, will get you high--but will allow you to pass a drug urinalysis. And for this reason, rumor has it, Spice is becoming very popular in exactly the places it might be least welcomed: Police stations, fire departments—and army bases.

What the hell is this stuff?

Little is known about spice and other synthetic twists on basic cannabinoid molecules. We do know that the near-cannabis compounds are hard to detect, and even harder to legislate against without closing down avenues of legitimate research. It appears evident that a number of cannabinoid compounds are in circulation, and the precise nature of any given dose is difficult to determine. Much like trying the brown acid, or the joint laced with PCP, the effects vary widely. There are numerous anecdotal reports that spice and its cousins are extremely dose dependent.

The best coverage of Spice, K2, and similar “legal highs” has been generated by science bloggers—especially David Kroll at Terra Sigillata, DrugMonkey at DrugMonkey blog,  and Dr. Leigh at Neurodynamics.  Readers are advised to consult these links for the most comprehensive coverage of this emerging drug issue.

David Kroll  aptly summarized what we know about the "fake weed."

"Synthetic marijuana, marketed as K2 or spice, is an herbal substance sold as an incense or smoking material that remains legal in much of the United States but is being increasingly banned at the state and local levels. The products contain one or more synthetic compounds that behave similarly to the primary psychoactive constituent of marijuana, delta nine tetrahydrocannabinol or THC.”

Kroll writes that JWH–018 is "one of over 100 indoles, pyrroles, and indenes synthesized by the Huffman laboratory to develop cannabimimetics, drugs that mimic the effect of cannabinoids such as THC.”

Furthermore: “The compound most commonly found in these products is a chemical first synthesized by the well-known Clemson University organic chemist, Prof. John W Huffman: the eponymous JW H–018. Another compound, found in spice products sold in Germany, is an analog of CP-47, 497, a cannabinoid developed by Pfizer over 20 years ago."

The cannabimimetics are back.

Unfortunately, the chemical compositions vary, as do the effects, all of which is unpleasantly reminiscent of PCP problems in the past. To gain a better perspective on the matter, I spoke with Joe Gould, a staff writer for the Army Times  who has been covering the issue of Spice use in the Armed Forces. Gould has written extensively on the case of Spc. Bryan Roudebush, who attacked his girlfriend in Hawaii while under the influence of Spice. Roudebush had been home from an Iraq deployment for a year when the incident occurred. Two earlier experiences with spice had produced marijuana-like effects. But for Roudebush, the third time was not the charm: He beat his girlfriend and tried to throw her out a window while experiencing what he described as a trance-like state.

“What we were told by the folks at the Army Criminal Investigation Lab is that it started showing up on bases,” said Gould, “and the investigators on the bases were baffled, and the crime lab wasn’t sure what it was at first.”

What investigators discovered was “all that really defines a synthetic cannabinoid is that it activates cannabinoid receptors. We know what THC does. But the chemical composition is not THC. There are all these different strains. Some of the state laws we’ve been seeing, they’re targeting specific varieties of this stuff, but there are other varieties that the law doesn’t know about yet. So I think what the Army has done, intentionally or not, it has sort of skirted this whole question by just calling it all Spice.”

As for the Roudebush case, Gould said: “The first two times he tried it, it was very much like pot. And then the third time, by his and his girlfriend’s description, he goes into a violent trance. They think it was just a different variety. It’s kind of a mystery. What was in that batch? Why did it affect him the way it did? It just goes to how little is known about the drug. You don’t know from one batch to another.”

The U.S. Army currently has no specific testing program in place for Spice. Can you pass a drug test on Spice? “That’s what we heard,” Gould told me. “A researcher from NIH told us exactly that—they believe that the reason it’s popular, the reason they’ve seen officials using it, is because it can’t be tested for.” Despite this, Gould said he knew of “at least nine Commands that have individually passed regulations to target Spice.”

Gould downplayed any talk of an epidemic of usage, and made clear that his research shows that Spice usage is not rampant. “It’s not entirely clear how many soldiers are using Spice. The Army’s not really tracking the use of Spice. Each of these commands passed these regulations either because they saw a problem, or because they were trying to get out in front of what could potentially be a problem.”

Too far out in front for Phillip Cave, a Virginia attorney who has represented military personnel in cases involving Spice. Gould quotes Cave calling the whole thing a “witch hunt,” noting that alcohol is freely available on base, and that researchers do not yet knew whether Spice and its analogs are unsafe or addictive—and they are illegal in only a handful of states at present. Cave also objects to the fact that most cases have been resolved by an Article 15 discharge from service.

“The European Union study says there is the potential for abuse,” said Gould. “How bad it gets, we won’t know until we see more studies.”

Hand-in-hand with restrictions on Spice have come crackdowns on the use of Salvia, a plant responsible for brief but intense bouts of hallucinogenic effects. “The state laws have tended to tackle the two at once,” according to Gould.  “Like the state legislatures, the Army has a patchwork of bans they’re putting out there, and there also hitting Salvia. But what I was told by the folks at the lab was that they’re not seeing it in the same kinds of numbers. It’s been sporadic at best.”

Cannabis Receptors and the “Runner’s High”

Maybe it isn't endorphins after all.

What do long-distance running and marijuana smoking have in common? Quite possibly, more than you’d think. A growing body of research suggests that the runner’s high and the cannabis high are more similar than previously imagined.

The nature of the runner’s high is inconsistent and ephemeral, involving several key neurotransmitters and hormones, and therefore difficult to measure. Much of the evidence comes in the form of animal models. Endocannabinoids—the body’s internal cannabis—“seem to contribute to the motivational aspects of voluntary running in rodents.” Knockout mice lacking the cannabinioid CB1 receptor, it turns out, spend less time wheel running than normal mice. 

A Canadian neuroscientist who blogs as NeuroKuz suggests that “a reduction in CB1 levels could lead to less binding of endocannabinoids to receptors in brain circuits that drive motivation to exercise.” NeuroKuz speculates on why this might be the case. Physical activity and obtaining rewards are clearly linked. The fittest and fleetest obtain the most food. “A possible explanation for the runner’s high, or ‘second wind,’ a feeling of intense euphoria associated with going on a long run, is that our brains are stuck thinking that lots of exercise should be accompanied by a reward.”

In 2004, the British Journal of Sports Medicine ran a research review, “Endocannabinoids and exercise,” which seriously disputed the “endorphin hypothesis” assumed to be behind the runner’s high. To begin with, other studies have shown that exercise activates the endocannabinoid system.

“In recent years,” according to the authors, “several prominent endorphin researchers—for example, Dr Huda Akil and Dr. Solomon Snyder—have publicly criticised the hypothesis as being ‘overly simplistic,’ being ‘poorly supported by scientific evidence’, and a ‘myth perpetrated by pop culture.’” The primary problem is that the opioid system is responsible for respiratory depression, pinpoint pupils, and other effects distinctly unhelpful to runners.

The investigators wired up college students and put them to work in the gym, and found that “exercise of moderate intensity dramatically increased concentrations of anandamide in blood plasma.” The researchers break the runner’s high into four major components. Exercise, they say, “suppresses pain, induces sedation, reduces stress, and elevates mood.” Some of the parallels with the cannabis high are not hard to tease out: “Analgesia, sedation (post-exercise calm or glow), a reduction in anxiety, euphoria, and difficulties in estimating the passage of time.”

There are cannabinoid receptors in muscles, skin and the lungs. Intriguingly, the authors suggest that unlike “other rhythmic endurance activities such as swimming, running is a weight bearing sport in which the feet must absorb the ‘pounding of the pavement.’” Swimming, the authors speculate, “may not stimulate endocannabinoid release to as great an extent as running.” Moreover, “cannabinoids produce neither the respiratory depression, meiosis, or strong inhibition of gastrointestinal motility associated with opiates and opioids. This is because there are few CB1 receptors in the brainstem and, apparently, the large intestine.”

A big question remains: What about running and the “motor inhibition” characteristic of high-dose cannabis? (An inhibition that may make cannabis useful in the treatment of movement disorders like tremors or tics.) Running a marathon is not the first thing on the minds of most people after getting high on marijuana.  The paper maintains, however, that at low doses, “cannabinoids tend to produce hyperactivity,” at least in animal models. The CB1 knockout mice were abnormally inactive, due to the effect of cannabinoids on the basal ganglia. Practiced, automatic motor skills like running are controlled in part by the basal ganglia. The authors predict that “low level skills such as running, which are controlled to a higher degree by the basal ganglia than high level skills, such as basketball, hockey, or tennis, may more readily activate the endocannabinoid system.”

The authors offer other intriguing bits of evidence. Anandamide, one of the brain’s own cannabinoids, “acts as a vasodilator and products hypotension, and may thus facilitate blood flow during exercise.” In addition, “endocannabinoids and exogenous cannabinoids act as bronchodilators” and could conceivably facilitate breathing during steady exercise. The authors conclude: “Compared with the opioid analgesics, the analgesia produced by the endocannabinoid system is more consistent with exercise induced analgesia.”

Photo Credit: http://www.madetorun.com/

Consider the CB(2) Receptor

A different destination for cannabinoids.

THC and its organic cousin, anandamide, do what they do by locking into both the CB1 receptor, discovered in 1988, and the CB2 receptor (as it is commonly written in shorthand), discovered 5 years later. THC and anandamide are CB receptor agonists, meaning they activate the receptors in question. (An antagonist blocks the receptor’s action.)

CB1 is a very common receptor in the central nervous system, and, when stimulated by an agonist, is responsible for the well-known roster of alleged medical effects, such as pain relief and nausea from chemotherapy--along with the typical marijuana high. (For more on this, see the excellent 2007 post by Dr. Joan Bushwell.) Conversely, blocking CB1 activity with an antagonist like rimonabant is one controversial avenue being explored in the search for new weight loss drugs. (CB1 antagonists can also produce anxiety and depression.)

However, CB2 was long considered a “peripheral” cannabinoid receptor, meaning that scientists hadn’t managed to find CB2 receptors in the central nervous system. They were, however, plentiful in the immune system, and seemed to be involved in inflammation as well as pain responses. CB2 receptors were in fact eventually discovered in the central nervous system, and are active in the brain during certain kinds of inflammatory responses.

There is a straightforward commercial incentive for tracking the extent of CB2 expression in brain neurons. As the authors of a cannabinoid receptor study wrote in the June issue of the British Journal of Pharmacology:

“As CB(2) is an attractive therapeutic target for pain management and immune system modulation without overt psychoactivity, defining the extent of its presence in neurons will have a significant impact on drug discovery.”

Translated, this means that there are a number of new molecules that are selective for CB2 receptors. Since people don’t get a strong traditional marijuana-style buzz from CB2 receptor activation, and given the active involvement of CB2 receptors in things like immune responses and inflammatory reactions, the possibility exists of finding lucrative spinoffs like pain pills or anti-inflammatory medications.  So drug researchers would like to know exactly where those receptors are, and what they do, in the event that they end up attempting to make a medicine that stimulates or blocks  them artificially. (Credit to Vaughan Bell of Mind Hacks for highlighting this study.) 

The psychologists at Indiana University who produced the paper did their best to shed light on where the CB(2) receptor is hiding, and what, exactly, it does.  But there is still not enough known about how various substances react with this somewhat elusive receptor for cannabinoids. In 2008, scientists at the University of Madrid published research in the Journal of Biological Chemistry indicating that activation of the CB2 receptor reduced nerve cell loss in animals suffering from a disease similar to multiple sclerosis. Researchers point to the possibility that a safe drug for M.S. patients could be one of the results of CB2 research.

Atwood, B., & Mackie, K. (2010). CB2: a cannabinoid receptor with an identity crisis British Journal of Pharmacology, 160 (3), 467-479 DOI: 10.1111/j.1476-5381.2010.00729.x

Graphics Credit: www.cnsforum.com

Banning legal drugs

Fool’s errand or necessary evil?

In the cat-and-mouse game that is the designer drug industry, spinning new variations on old themes is the name of the game. When law enforcement and the courts decree a substance illegal for human use due to abuse potential—like the “date rape” drug GHB, banned several years ago in the U.S. and Britain—underground drug designers go to work on spinning molecular variations on the theme. When they hit on an acceptable “near-beer” equivalent, they can flood the market and reap another tidy illegal round of profits on, for example, GBL, which the body converts to GHB when consumed. That is, until law enforcement catches up with that one, and bans it, and then the cycle repeats itself.

The Analogue Drug Act of 1986 was designed to combat this dilemma in the United States by outlawing drugs “substantially similar” to any drug that is already illegal. However, “chemical experts disagree on whether a chemical is “substantially similar” in structure to another chemical—so much so that Federal Analogue Act litigation often degenerates into a “battle of experts,” which is founded more on opinion than on actual scientific evidence,” writes Gregory Kau in an article for the University of Pennsylvania Law Review. “One survey of Federal Analog Act jurisprudence discovered that courts sometimes considered a chemical’s two-dimensional structure rather than the three-dimensional structure as a factor; that courts sometimes ignored the difference in the number of atoms as a meaningful factor; and that courts even ignored quantitative “similarity analysis” results that pharmaceutical companies use to determine whether a chemical is structurally similar to another.”

Recently, Britain added itself to the list of nations that have banned several so-called “herbal highs,” mostly industrial chemicals or synthetic cannabinoids. In addition to GBL, or gamma-butyrolactone, the ban includes BZP, or benzylpiperazine, sold as a stimulant club drug similar to amphetamine. Both are already illegal in the U.S.

In addition, the British Home Office banned a substance known variously as Spice, Spice Gold, or Spice Diamond, which is sold as a legal herbal alternative to cannabis. The product was banned in Germany and France earlier this year. Over the past two years, tests at a German pharmaceutical company, and assays of Spice products seized by U.S. customs agents have confirmed the presence of several synthetic versions of natural chemicals found in marijuana. These cannabinoids include JWH-018, CP-47,497, and HU-210 in liquid form, which is then sprayed on herbal products. The chemicals in question currently find use only in medical research, and the extent to which they provide a high in the absence of THC is based on anecdotal reports, and varies widely.

GBL, a chemical solvent used as a paint stripper, is sometimes sold as “liquid ecstasy.” The amphetamine alternative BZP is used as a fertilizer and as a veterinary medicine. Both are now classified as Class C drugs like tranquilizers, possession of which can bring a two-year jail sentence.

Spice, or at least the synthetic cannabinoids the products contain, are now listed as Class B drugs, the same as marijuana, bringing with it the possibility of a five-year jail sentence.

In an attempt to gain a leap on underground drug designers, the British government has banned all drugs in the so-called piperazine family that includes BZP. This will likely motivate underground chemists to find a molecular family with similar effects to BZP.

Graphics Credit: www.images.tilllate.com


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