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

Marijuana and Memory

Do certain strains make you more forgetful?

Cannabis snobs have been known to argue endlessly about the quality of the highs produced by their favorite varietals: Northern Lights, Hawaiian Haze, White Widow, etc. Among dedicated potheads, debates about the effects of specific cannabis strains are often overheated, and, ultimately, kind of boring. It's a bit like listening to a discussion of whether the wine in question evinces a woody aftertaste or is, instead, redolent of elderberries. For most people, the true essence of wine drinking is pretty straightforward: a drug buzz, produced by a 12 to 15 % concentration of ethyl alcohol derived from grapes, which can be had in a spectrum of varietal flavors.

However, there is no doubting that, unlike the case of wine, different strains of marijuana can have markedly different psychoactive effects. With weed, it's not just a matter of taste.

Over the past couple of years, the cannabis debate has taken a nasty turn, after British scientists published several controversial studies suggesting that high-THC "skunk" cannabis was responsible for increased mental problems among young people--including an increased risk of developing the symptoms of schizophrenia. British drug policy makers have continued to lead the charge on this, with mixed results. See my earlier post.

Recently, a study published in the British Journal Of Psychiatry concluded that marijuana
high in THC--including so-called "skunk" cannabis--caused markedly more memory impairment than varieties of marijuana containing less THC.

In an article at Nature News, Arran Frood spelled out the details of the study:

"Curran and her colleagues traveled to the homes of 134 volunteers, where the subjects got high on their own supply before completing a battery of psychological tests designed to measure anxiety, memory recall and other factors such as verbal fluency when both sober and stoned. The researchers then took a portion of the stash back to the laboratory to test how much THC and cannabidiol it contained....  Analysis showed that participants who had smoked cannabis low in cannabidiol were significantly worse at recalling text than they were when not intoxicated. Those who smoked cannabis high in cannabidiol showed no such impairment."

The two main ingredients in cannabis are THC and cannabidiol (CBD). CBD shows less affinity for the two main types of cannabis receptors, CB1 and CB2, meaning that it attaches to receptors more weakly, and activates them less robustly, than THC.  The euphoric effects of marijuana are generally attributed to THC content, not CBD content. In fact, there appears to be an inverse ratio at work. According to a paper in Neuropsychopharmacology, "Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of delta-9-THC."

So, CBD specifically does not produce the usual marijuana high with accompanying euphoria and forgetfulness and munchies. What the researchers found was that pot smokers suffering memory impairment and those showing normal memory "did not differ in the THC content of the cannabis they smoked. Unlike the marked impairment in prose recall of individuals who smoked cannabis low in cannabidiol, participants smoking cannabis high in cannabidiol showed no memory impairment."

As far as memory goes, THC content didn't seem to matter. It was the percentage of 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."

The idea that cannabidiol may protect against THC-induced memory loss is still quite speculative.  Other research has suggested that a paucity of CB1 receptors may be protective against memory impairment. Marijuana growers select for high-THC strains, not high-CBD strains, and thus there is little data available about the CBD levels of most marijuana.

An earlier study in Behavioural Pharmacology by Aaron Ilan and others at the San Francisco Brain Research Institute did not find any connection between memory and CBD content. However, Ilan speculated in the Nature News article that the difference might have been due to methodology: In Britain, the subjects were studied using marijuana of their own choosing.  In the U.S., National Institute of Health research policy has decreed that marijuana for official research must be supplied by the National Institute on Drug Abuse (NIDA). And if there is one thing many researchers seem to agree on, it is that NIDA weed "is notorious for being low in THC and poor quality."

But CBD still does something, and that something just might be pain relief.  Lester Grinspoon, a long-time marijuana researcher at Harvard Medical School, thinks that if the study proves out, it could have an important impact on the medical use of marijuana. Also quoted in Nature News, Grinspoon said: "Cannabis with high cannabidiol levels will make a more appealing option for anti-pain, anti-anxiety and anti-spasm treatments, because they can be delivered without causing disconcerting euphoria."

Morgan, C., Schafer, G., Freeman, T., & Curran, H. (2010). Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study The British Journal of Psychiatry, 197 (4), 285-290 DOI: 10.1192/bjp.bp.110.077503

Graphics Credit: http://sites.google.com