Why marihuana scares me

There’s an editorial in the current Science concerning how very little we know about the effects of marihuana on the developing adolescent brain [ Science vol. 344 p. 557 ’14 ]. We know all sorts of wonderful neuropharmacology and neurophysiology about delta-9 tetrahydrocannabinol (d9-THC) — http://en.wikipedia.org/wiki/Tetrahydrocannabinol The point of the authors (the current head of the Amnerican Psychiatric Association, and the first director of the National (US) Institute of Drug Abuse), is that there are no significant studies of what happens to adolescent humans (as opposed to rodents) taking the stuff.

Marihuana would the first mind-alteraing substance NOT to have serious side effects in a subpopulation of people using the drug — or just about any drug in medical use for that matter.

Any organic chemist looking at the structure of d9-THC (see the link) has to be impressed with what a lipid it is — 21 carbons, only 1 hydroxyl group, and an ether moiety. Everything else is hydrogen. Like most neuroactive drugs produced by plants, it is quite potent. A joint has only 9 milliGrams, and smoking undoubtedly destroys some of it. Consider alcohol, another lipid soluble drug. A 12 ounce beer with 3.2% alcohol content has 12 * 28.3 *.032 10.8 grams of alcohol — molecular mass 62 grams — so the dose is 11/62 moles. To get drunk you need more than one beer. Compare that to a dose of .009/300 moles of d9-THC.

As we’ve found out — d9-THC is so potent because it binds to receptors for it. Unlike ethanol which can be a product of intermediary metabolism, there aren’t enzymes specifically devoted to breaking down d9-THC. In contrast, fatty acid amide hydrolase (FAAH) is devoted to breaking down anandamide, one of the endogenous compounds d9-THC is mimicking.

What really concerns me about this class of drugs, is how long they must hang around. Teaching neuropharmacology in the 70s and 80s was great fun. Every year a new receptor for neurotransmitters seemed to be found. In some cases mind benders bound to them (e.g. LSD and a serotonin receptor). In other cases the endogenous transmitters being mimicked by a plant substance were found (the endogenous opiates and their receptors). Years passed, but the receptor for d9-thc wasn’t found. The reason it wasn’t is exactly why I’m scared of the drug.

How were the various receptors for mind benders found? You throw a radioactively labelled drug (say morphine) at a brain homogenate, and purify what it is binding to. That’s how the opiate receptors etc. etc. were found. Why did it take so long to find the cannabinoid receptors? Because they bind strongly to all the fats in the brain being so incredibly lipid soluble. So the vast majority of stuff bound wasn’t protein at all, but fat. The brain has the highest percentage of fat of any organ in the body — 60%, unless you considered dispersed fatty tissue an organ (which it actually is from an endocrine point of view).

This has to mean that the stuff hangs around for a long time, without any specific enzymes to clear it.

It’s obvious to all that cognitive capacity changes from childhood to adult life. All sorts of studies with large numbers of people have done serial MRIs children and adolescents as the develop and age. Here are a few references to get you started [ Neuron vol. 72 pp. 873 – 884, 11, Proc. Natl. Acad. Sci. vol. 107 pp. 16988 – 16993 ’10, vol. 111 pp. 6774 -= 6779 ’14 ]. If you don’t know the answer, think about the change thickness of the cerebral cortex from age 9 to 20. Surprisingly, it get thinner, not thicker. The effect happens later in the association areas thought to be important in higher cognitive function, than the primary motor or sensory areas. Paradoxical isn’t it? Based on animal work this is thought to be due pruning of synapses.

So throw a long-lasting retrograde neurotransmitter mimic like d9-THC at the dynamically changing adolescent brain and hope for the best. That’s what the cited editorialists are concerned about. We simply don’t know and we should.

Having been in Cambridge when Leary was just getting started in the early 60’s, I must say that the idea of tune in turn on and drop out never appealed to me. Most of the heavy marihuana users I’ve known (and treated for other things) were happy, but rather vague and frankly rather dull.

Unfortunately as a neurologist, I had to evaluate physician colleagues who got in trouble with drugs (mostly with alcohol). One very intelligent polydrug user MD, put it to me this way — “The problem is that you like reality, and I don’t”.

Why drug discovery is so hard: Reason #22 — Drugs aren’t doing what we think they are

50 or so years ago, Cambridge apocrypha had it that Timothy Leary, put LSD into the punch at a party to observe its effects on social behavior (an early double blind experiment).  A student, having imbibed, decided he was God and could walk across Massachusetts avenue with impunity, losing his life in the process, his death being hushed up by Harvard.  It could have been an urban myth, but it was widely prevalent, showing that even the highly intelligent aren’t immune to this sort of thing.

So we all knew (and know) that LSD and other hallucinogens causes a degree of excitement.  We then assume that excitement is synonymous with increased brain activity, correct?  Wrong says [ Proc. Natl. Acad. Sci. vol. 109 pp. 1820 – 1821, 2138 – 2143 ’12 ] !

Hallucinogens like LSD and psilocybin bind to lots of neurotransmitter receptors (serotonin alone has at least 14, and this doesn’t count the splice variants).  Still, the best correlation of hallucinogenic activity is with agonist activity at one serotonin subtype, the serotonin 2A receptor (5HT2AR). In man, the psychedelic activity of psilocin is blocked by pretreatment with 5HT2AR antagonists.

There are now noninvasive methods to study brain activity in man.  The most prominent one is called BOLD, and is based on the fact that blood flow increases way past what is needed with increased brain activity.  This was actually noted by Wilder Penfield operating on the brain for epilepsy in the 30s.  When the patient had a seizure on the operating table (they could keep things under control by partially paralyzing the patient with curare) the veins in the area producing the seizure turned red.  Recall that oxygenated blood is red while the deoxygenated blood in veins is darker and somewhat blue.  This implied that more blood was getting to the convulsing area than it could use.

BOLD depends on slight differences in the way oxygenated hemoglobin and deoxygenated hemoglobin interact with the magnetic field used in magnetic resonance imaging (MRI).  The technique has had a rather checkered history, because very small differences must  be measured, and there is lots of manipulation of the raw data (never seen in papers) to be done.  10 years ago functional magnetic imaging (fMRI) was called pseudocolor phrenology.

Another newer technique called arterial spin labeling perfusion also measures blood flow.

Both techniques were used on 15 ‘experienced’ hallucinogen users, who received either placebo or psilocin (the active metabolite  of psyilocybin) IV.  The druggies also rated the intensity of their experiences.

The surprising finding is that decreases in blood flow (implying decreased neuronal activity) occured in areas of the brain ‘implicated’ (e.g. not proven) in psychedelic drug actions.  Even more interesting is that the intensity of the experience  correlated with decrements in blood flow.

This constitutes yet another example of why drug discovery is hard.  Even when we know the observable effects of a given drug, our theories of how the drug does what it does, can be widely off base — in this case bass ackwards.  So if you were screening for an antihallucinogen, the incorrect theory would lead you seriously astray.  This is why big pharma is dropping research on CNS drugs — they haven’t had much success, and the theories to guide them may be flat out wrong.