The Year in Drugs

Top Posts at Addiction Inbox.

By the look of it, readers had marijuana on their minds in 2012. Of the posts at Addiction Inbox with the highest number of page views, an overwhelming majority are concerned with marijuana, and specifically, with marijuana addiction, withdrawal, and brain chemistry. Of the 9 most heavily trafficked posts of the year, only one involved alcohol. Readers were also interested in the safety of e-cigarettes, and the mysteries of neurotransmitters like serotonin and dopamine. Happily, all the top posts were patently science-oriented articles.

See you in the New Year.

•  Marijuana Withdrawal

For Some Users, Cannabis Can Be Fiercely Addictive.

For a minority of marijuana users, commonly estimated at 10 per cent, the use of pot can become uncontrollable, as with any other addictive drug. Addiction to marijuana is frequently submerged in the welter of polyaddictions common to active addicts. The withdrawal rigors of, say, alcohol or heroin tend to drown out the subtler, more psychological manifestations of cannabis withdrawal.

•  Serotonin and Dopamine: A Primer

The Molecules of Reward

Serotonin and dopamine are part of a group of compounds called biogenic amines. In addition to serotonin and dopamine, the amines include noradrenaline, acetylcholine, and histamine. This class of chemical messengers is produced, in turn, from basic amino acids like tyrosine, tryptophan, and choline.

•  Marijuana Fact and Fiction

Why cannabis research is a good idea.

There is little doubt among responsible researchers that marijuana--although it is addictive for some people--is sometimes a clinically useful drug. However, there is little incentive for commercial pharmaceutical houses to pursue research on the cannabis plant itself, since they cannot patent it.

• Anandamide: The Brain’s Own Marijuana

Anxiety and the THC receptor.

Several years ago, molecular biologists identified the elusive brain receptor where THC, the active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which sticks to the same receptors, in pulverized pig brains.

•  The Mysteries of the Blunt

Why do so many smokers combine tobacco with marijuana?

People who smoke a combination of tobacco and marijuana, a common practice overseas for years, and increasingly popular here in the form of “blunts,” may be reacting to ResearchBlogging.orgsome unidentified mechanism that links the two drugs. Researchers believe such smokers would be well advised to consider giving up both drugs at once, rather than one at a time, according to an upcoming study in the journal Addiction.

•  Are E-Cigarettes a Good Idea or a Bad Idea?

A group of nicotine researchers argue for an alternative.

Electronic cigarettes are here to stay. If you're not familiar with them, e-cigarettes are designed to look exactly like conventional cigarettes, but they use batteries to convert liquid nicotine into a fine, heated mist that is absorbed by the lungs. Last summer, even though the FDA insisted on referring to e-cigarettes as “untested drug delivery systems,” Dr. Neal Benowitz of the University of California in San Francisco--a prominent nicotine researcher for many years--called e-cigarettes “an advancement that the field has been waiting for.”

•  Cannabis Receptors and the “Runner’s High”

Maybe it isn't endorphins after all.

A perennial favorite, the runner’s high post shows what 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….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. 

• Topamax for Alcoholism: A Closer Look

Epilepsy drug gains ground, draws fire as newest anti-craving pill.

A drug for seizure disorders and migraines continues to show promise as an anti-craving drug for alcoholism, the third leading cause of death in America, the Journal of the American Medical Association (JAMA) reported in its current issue.

•  Is Marijuana Addictive?

The argument continues.

Marijuana may not be a life-threatening drug, but is it an addictive one?
There is little evidence in animal models for tolerance and withdrawal, the classic determinants of addiction. For at least four decades, million of Americans have used marijuana without clear evidence of a withdrawal syndrome. Most recreational marijuana users find that too much pot in one day makes them lethargic and uncomfortable. Self-proclaimed marijuana addicts, on the other hand, report that pot energizes them, calms them down when they are nervous, or otherwise allows them to function normally.


Graphics Credit:  http://1.bp.blogspot.com (Creative Commons)

A Six-Pack of Prior Posts

Don’t fear the chemistry. 

This isn’t a top 10 list, just a compilation of five previous posts here at Addiction Inbox that have continued to draw reader interest since they were first published. If there is a theme running through this set, it is neurochemistry at its most basic level. Take a look, if any of the subjects interests you. (My most popular post of all, on Marijuana Withdrawal, has turned into a self-help message board. I note it here, but leave it off the list, as it has become a blog of its own for all practical purposes.)
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1) Don’t let anyone tell you that the basic notions involved in neurotransmitter action in the brain are over everyone’s head. This post about serotonin and dopamine basics has always been popular, partly because serotonin and dopamine have gone from obscure abstractions to pop buzzwords. But I think it also shows a growing awareness of brain science and its real-world applications among interested readers.

“…. Addictive drugs have molecules that are the right shape for the amine receptors. Drugs like LSD and Ecstasy target serotonin systems. Serotonin systems control feeding and sleeping behaviors in living creatures from slugs to chimps. Serotonin, also known as 5-HT, occurs in nuts, fruit, and snake venom. It is found in the intestinal walls, large blood vessels, and the central nervous system of most vertebrates. The body normally synthesizes 5-hydroxytryptamine, as serotonin is formally known, from tryptophan in the diet….”

Serotonin and Dopamine: A primer on the molecules of reward
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2) Continuing on the chemistry theme, this post on anandamide, the brain’s own form of internal marijuana, has garnered steady attention since 2008. It may be coincidental, but the post also makes mention of serotonin and dopamine.

“…Several years ago, molecular biologists identified the elusive brain receptor where THC, the active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which sticks to the same receptors, in pulverized pig brains. They christened the internally manufactured substance “anandamide,” after the Sanskrit ananda, or bliss…”

Anandamide, the Brain’s Own Marijuana: Anxiety and the THC receptor.
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3) Interest in the anti-craving drug Topamax, an anti-seizure medication used to treat alcoholism, remains strong with blog readers, although the drug has not become the universal blockbuster many advocates had hoped.

“…Dr. Bankole Johnson, chairman of Psychiatry and Neurobehavioral Sciences at the University of Virginia, told Bloomberg News that Topamax does everything researchers want to see in a pharmaceutical treatment for alcoholism: “First, it reduces your craving for alcohol; second, it reduces the amount of withdrawal symptoms you get when you start reducing alcohol; and third, it reduces the potential for you to relapse after you go down to a low level of drinking or zero drinking…"

Topamax for Alcoholism: A Closer Look. Epilepsy drug gains ground, draws fire as newest anti-craving pill
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4) One of the most popular posts to date was this examination of neurological questions surrounding marijuana and memory loss. Inquiring minds, uh, forget the question. Oh yeah: Does the strain of dope you smoke determine how forgetful you’ll become?

“…As far as memory goes, THC content didn't seem to matter. It was the percentage of cannabidiol (CBD) that controlled the degree of memory impairment, the authors concluded. "The antagonistic effects of cannabidiol at the CB1 receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol..." 


Marijuana and Memory: Do certain strains make you more forgetful?
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5) Finally, a popular post focusing on the biochemistry of nicotine in e-cigarettes, the new, smokeless nicotine delivery system. Are they safe? The latest in harm reduction strategies, or starter kits for youngsters?

“…You may never have heard of it—but it’s the newest drug in town. It’s called an electronic cigarette, or “e-cigarette.” Electronic cigarettes use batteries to convert liquid nicotine into a fine, heated mist that is absorbed by the lungs. No smoke, but plenty of what makes cigarettes go, if you don’t account for taste—or ashtrays and smoke rings….”

E-Cigarettes and Health: Smokeless nicotine comes under scrutiny.

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

Anandamide Hits the “Hedonic Hot Spot.”

Marijuana and the munchies.

It’s no secret that marijuana very reliably increases appetite. Recently, research published in Nature has teased out an apparent mechanism by which internal cannabinoids are involved with gut microbiota. This affects inflammation, the metabolism of adipose tissue, and other factors implicated in obesity.

In addition, research published in the Proceedings of the National Academy of Sciences, and blogged about by Neuroskeptic, showed that CB1 cannabinoid receptors on the tongue selectively boost our pleasurable responses to sweet-tasting food. Conversely, drugs that block cannabinoid receptors have been actively pursued as appetite suppressants. One such drug, trade name rimonabant, was disallowed by the FDA on the grounds that it worked so well in the guise of anandamide’s opposite number that it frequently caused debilitating depression in users. But it did appear to reduce appetites.

Neuroskeptic suggests that a CB1 antagonist that only affects specific sites, like taste buds, might be able to lessen the sweet-tooth effect with fewer complications. “Who knows,” he writes, “in a few years you might even be able to buy CB1 antagonist chewing gum to help you stick to your diet.”

We know that cannabinoids make rats and humans eat more. But how, exactly, does that happen? One reasonable hypothesis is that anandamide, other endocannabinoids, and cannabinoid drugs—anything that tickles the CB1 receptors--must increase sensations of palatability, if eaters are to eat more. A group of University of Michigan researchers chose to investigate the theory that “endogenous cannabinoid neurotransmission in limbic structures such as nucleus accumbens mediates the hedonic impact of natural rewards like sweetness.” They went looking for the precise brain location—the “hedonic hotspot for sensory pleasure”—where endocannabinoids do their work. 

 Writing in Neuropsychopharmacology in 2007, the investigators sought to discover “if anandamide microinjection into medial nucleus accumbens shell enhances these affective reactions to sweet and bitter tastes in rats.” And it did. Anandamide “doubled the number of positive ‘liking’ reactions elicited by intraoral sucrose, without altering negative ‘disliking’ reactions to bitter quinine.” Anandamide reliably increased the number of “positive hedonic reactions” the rats showed to sucrose, and never caused any aversive reactions, or increases in water drinking or other behaviors. In addition, the process worked in reverse: “Food-related manipulations, such as deprivation and satiety, or access to a palatable diet produce changes in CB1 receptor density,” leading to higher levels of endogenous anandamide. 

One location in particular, when dosed with endocannabinoids, increased “liking” responses in the rats threefold. A tiny spot, 1.6 millimeters cubed, but the hottest spot of all: the dorsal half of the medial shell of the nucleus accumbens. At that site, cannabinoid receptors and opioid receptors appear to coexist and interact. If this form of colocalization occurs regularly in rats and humans, it would constitute strong support for the idea that “endocannabinoid and opioid neurochemical signals in the nucleus accumbens might interact to enhance ‘liking’ reactions to the sensory pleasure of sucrose.”

As the authors sum it up, “magnifying the pleasurable impact of food reward” appears to be the baseline effect of endocannabinoids on “appetite or incentive motivation.” Because all of this takes place along the brain’s primary reward pathways in the limbic system, the authors conclude that it would be of interest to know “whether other types of sensory pleasure besides sweetness can be enhanced by the endocannabinoid hedonic hotspot described here.”

Mahler, S., Smith, K., & Berridge, K. (2007). Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward Neuropsychopharmacology, 32 (11), 2267-2278 DOI: 10.1038/sj.npp.1301376

Graphics Credit: NIDA

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

Anandamide: The Brain’s Own Marijuana

Anxiety and the THC receptor.

Several years ago, molecular biologists identified the elusive brain receptor where THC, the active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which sticks to the same receptors, in pulverized pig brains. They christened the internally manufactured substance “anandamide,” after the Sanskrit ananda, or bliss.

Anandamide has a streamlined three-dimensional structure that THC mimics, and both molecules slipped easily across the blood-brain barrier. Anandamide is a short-lived, fragile molecule, and does not produce a dramatic natural high, unlike a surge of endorphins, or dopamine—or the THC in a joint. In 2001, researchers at the Keck Center for Integrative Neuroscience at the University of California-San Francisco found evidence that THC may perform a signaling function in neurons containing GABA and glutamate. It appears that marijuana increases dopamine and serotonin levels through the intermediary activation of opiate and GABA receptors.

However, anandamide has a number of other effects, particularly on movement and cognition. Because of this, the “bliss molecule” moniker is a bit misleading. THC and its organic cousin make an impressive triple play in the brain: They effect movement through receptors in the basal ganglia, they alter sensory perception through receptors in the cerebral cortex, and they impact memory by means of receptors in the hippocampus.

It was left for animal physiologist Gary Weesner of the U.S. Department of Agriculture (USDA) to answer the burning question: “How do pigs use their anandamide?” While studying the possibility of using anandamide as a sedative for animals, Dr. Weesner discovered that pigs treated with anandamide tended to have lower body temperature, slower respiration, and less movement—all of which are signs of a calmer porcine state of mind.

So much for pigs. What does anandamide do in the human brain? For starters, we can look toward those controversial indications for which marijuana is already being prescribed: anxiety relief, appetite enhancement (compounds similar to anandamide have been discovered in dark chocolate) suppression of nausea, relief from the symptoms of glaucoma, and amelioration of certain kinds of pain. U.S. pharmaceutical houses, Pfizer in particular, worked with THC for years, seeking profitable patents. But Pfizer never succeeded in separating out the various pharmacological effects of marijuana, and in the end, their efforts were limited to the manufacture of synthetic THC.

Ten years ago, scientists at the National Institute of Mental Health (NIMH) uncovered preliminary evidence that cannabis may afford a measure of protection from brain cell damage due to stroke. An Israeli pharmaceutical company announced plans to test a synthetic marijuana derivative for the treatment of strokes and brain injury. There are few effective treatments for stroke, the third leading killer in the United States.

The question of short-term memory loss under the influence of pot appears to have been answered by related research. Findings from the Neurosciences Institute in San Diego show that cannabinoids are capable of blocking new memory formation in animal brain tissue. If anandamide receptors trigger a form of forgetfulness, this may be part of the brain’s system of filtering out unimportant or unpleasant memories—a vital function, without which we would all be overwhelmed by irrelevant and unprovoked memories at every turn.

For example, the brain’s own cannabis may help women “forget” the pain and stress of childbearing, allowing them to concentrate on the immediate needs of the newborn. Other animal research suggests that the uterus grows anandamide receptors in heavy concentrations before embryo implantation. Still other studies show that newborn kittens and monkeys have more marijuana receptors in the cortex than adults do, so it is possible that anandamide may play some role in setting up the development of cortical function in infants.

For more, see earlier posts:
Marijuana Withdrawal
Is Marijuana Addictive?

Photo Credit: National Institute of Drug Abuse

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