reefer madness

“Doctor, I’m afraid I might have ruined my brain.” Mr D’s wide brown eyes bore a pleading expression.  He was a young law student with a cherubic dimple set in his left cheek.  He had had no history of psychiatric issues until six months prior to our appointment.  Then, one Saturday evening during his winter recess from school, he’d celebrated the end of the semester with friends by smoking an enormous amount of marijuana and attending a 3-D movie.  

During the movie, he told me, he had a terrifying experience.  “It was as if I’d lost all of my memories.  I knew nothing.  I was nobody.  I was starting over.” During the course of the movie he gradually regained his memories but retained a feeling of foreboding.  Ever since that time he had been having episodes of déjà vu in which otherwise innocuous situations would give him the sense that he was about to be catapulted back into the memoryless state he had experienced in the movie. 

Simple triggers like buying a cup of coffee at his favorite stand would give him a sudden, horrifying feeling that he had been there before, and that he knew what would happen next: He would be thrown back to the place of no memories.  Or, he was having a dream and he would be forced to relive this same sequence in an endless loop, forever.  The feeling would last a few minutes, and then dissipate as surely as it had come. 

He’d been having experiences like this up to thirty times a day, ever since that night at the movies.  They were interfering with his sleep, his work, and his love life. He hadn’t touched marijuana again since that night.  Still, they weren’t going away.  Finally he decided he needed help.  Could I help him?  He spread his hands nervously on his lap. 

Marijuana use has long been associated with increases in psychotic manifestations.   (For many years it was unclear whether marijuana truly tilted the brain towards psychosis, or whether marijuana was simply more appealing to the psychosis-prone brain.  Earlier this year, the results of a decades-long study of marijuana use and psychosis in 3800 individuals were released (McGrath et al).  They confirmed the results of two other large cohort studies that found the longer people had been using marijuana, the more likely they were to report psychotic symptoms.  In addition, this most recent study analyzed sibling pairs and found that the same relationship held true – weakening the argument that some other, unknown genetic or environmental factor might be stacking the deck.) 

However, Mr D.’s symptoms weren’t the classical psychotic signs of hallucinated voices or paranoid delusions.  The déjà vu reminded me more of neurological oddities such as temporal lobe epilepsy than of any psychiatric syndrome.  But this patient had neither a history of epilepsy nor any risk factors for seizure, and the link to marijuana use was too clear to ignore.  I decided to offer Mr D. an antipsychotic – the very sort of drug we give to people who insist that the aliens are after them, or the CIA has bugged their hospital rooms, or they are the Messiah.              

I made the offer tentatively, worried that the very word ‘antipsychotic’ would set alarm bells ringing in Mr D’s formerly entirely sane and rational young head.  I more than halfway expected him to refuse it.  But to my surprise he accepted it eagerly.  “I’ve been living with this for six months,” he explained.  “I just need it to stop.”            

And stop it did.  Two hours after his first dose, Mr D reported to me the next week, he could feel the grip of his illusions relaxing.  Within a few days he went from having thirty episodes per day to having fewer than ten.  After two weeks on the drug he felt he was his old self.  He discontinued the medication without incident.            

There is much we do not know about the neurobiological effects of marijuana.  The psychoactive ingredients, cannabinoids, come in dozens of varieties whose relative proportions vary from plant to plant, presenting a complexity of Gordian proportions to the would-be researcher.   

Our bodies’ cannabinoid receptors (built to respond to our own endogenous cannabinoids but, happily for college students the world over, also responsive to the herbaceous variety) are found generously distributed throughout the brain (Glass et al.), including the frontal cortical areas that are implicated in psychosis.  They seem to act as local modulators, damping the strength of signals coursing through the brain’s circuits – including the frontal dopamine circuits in which hyperactivity seems to underlie psychotic episodes.  Tire out the endocannabinoid ‘braking system’ by flooding it with ganja, and you have an unchecked river of dopamine signaling leading to hallucinations and paranoia (Fernandez-Espejo et al.). 

Why should this cause psychosis long after the marijuana is gone from the system?  I don’t know the answer, but I do know that for Mr D., the way to fix it was to use a dopamine-blocking antipsychotic.  He’s doing well so far, though perhaps a bit wiser and warier. 

biology vs psychology: false dichotomy?

I was speaking with a very intelligent and insightful patient today who mentioned that he'd felt his problems (depression, some obsessional traits, a mild eating disorder) were all 'psychological' until he found a drug that significantly improved them. From that point on he was convinced they were 'biological,' and embarked upon a quest for the Magic Pill that would solve all his neuroses at a single swallow.

I see references to this sort of split all the time, and not just from patients but also from highly educated physicians and scientists. Somehow they consider that our behavior* arises from two distinct sources: one composed of neurons, synapses, and neurotransmitters, and another composed of experiences, drives, and willpower.

If you buy the biological theory of behavior at all, then it makes little sense to imagine a dividing line between 'biological' and 'non-biological' causes of behavior. Experience alters neurochemistry just as surely as medications do.

Here's a nice (but somewhat technical) piece of work discussing some of the cellular-level changes that have been observed to be triggered by real-world experience (Takahashi, Svoboda and Malinow).

Evidence abounds for the utility of 'talk therapy' in psychiatry. In order to separate the 'biological' from the 'psychological,' one would have to believe that there exists an entirely separate underpinning of human behavior that operates on some ethereal plane, unrelated to the biomechanical world of synapses and neurotransmitters.

If you're going to accept that neurobiology underlies behavior, then there is no clear point at all where you can divide the biological from the psychological. If you accept that experience exerts its effects through alteration of our neuronal activity, and you accept that hearing your therapist is an experience, then there is no room for some nebulous 'non-biological' effect. Your therapist's words tickle your ear neurons, which tickle your brain neurons, which make subtle changes - sticking themselves to some of their neighbor cells, unsticking themselves from other neighbors, changing the rate at which they spit neurotransmitters at each other - and voila! You change your behavior.

That the line between biological and psychological is fuzzy to the point of nonexistence is indeed starting to permeate the general consciousness, at least to a degree. This usually arises in discussions of ethics, where the whole edifice of crime-and-punishment rests on an assumption of free will. This assumption is being radically challenged by evidence that our behavior is heavily determined by factors not under our direct control (genetics and medication in particular).

This opens up another can of worms, because we frequently associate 'biological' with 'beyond our control' and 'psychological' with 'within our control.'  Hence my patient (and many like him) and his Magic Pill search.

But I think the educated world at large is not yet ready to join Steven Pinker in declaring us will-less playthings of our genes and environment. Fine for now, but I'm curious to see what we'll make of coming scientific advances that will no doubt push us even closer to the will-free wall.

*I'm using "behavior" intentionally to encompass all of the workings of the human brain that are manifest to others. I'm doing this very deliberately because the question of whether mind is biological at all is a very sticky wicket and not something I can afford to get into in this limited space.

chemical love

One of my more interesting recent patients had a problem straight out of a daytime talk show. This was a young gay man in love with his heterosexual roommate. The two of them had a very close relationship, eating dinner together, going to movies as a couple, and generally engaging in very couple-like domestic activities. They also had a surprisingly open relationship. The gay man had confessed his ardor to the roommate, and the roommate, while he did not return the sexual feelings, was mind-bogglingly relaxed about the whole issue and the two of them remained as close as before.



Matters took a turn for the worse when the roommate acquired a girlfriend. Naturally the gay man could not stand the girlfriend and resorted to drinking alone in his room or going for long drives whenever she was around. Ultimately he became so depressed and consumed by the situation that he was unable to work, could not sleep, lost interest in his hobbies, and finally sought psychiatric help.


At first nobody on the treatment team could understand the situation, and in particular the behavior of the roommate. We speculated that perhaps he was a closeted homosexual who unconsciously returned the feelings, or else that he simply couldn't bring himself to give up the incredibly cheap rent offered by his lovesick roommate (who owned the apartment).


The answer turned out to be a bit more complicated. I sat down with both men for a frank discussion of the situation, and found that, at least to casual observation, their relationship appeared as close and open as had been described to me by the gay patient. Together we dissected the timeline of their relationship. It turned out they had been ordinary good friends until they began to use the drug Ecstasy (MDMA). Over the course of a summer they had used the drug weekly together - rarely with anyone else - in the process cementing a bond that ultimately became more like a love relationship than anything else.


It is likely impossible to convey the emotional power of Ecstasy to anyone who has not tried the drug. Roughly, it works by reversing the direction of the reuptake transporter that vacuums leftover serotonin out of the synaptic cleft. This dumps enormous amounts of serotonin into the synaptic cleft - far more than would ever normally be present there at one time. Just as chocolate cake overstimulates the taste receptors that evolved to detect the more mild and nuanced sweetness of fruit, Ecstasy overstimulates circuits designed to underlie the natural pleasures of romantic attachment and sensory experience.


In a stark demonstration that love really is just chemistry, Ecstasy can make you feel a gush of deep affection for just about anyone sharing the experience with you. It's Cupid's Arrow in chemical form.


In this particular case, these two men overstimulated their 'love circuits' together over and over again for an entire summer. It's no wonder the gay one fell in love with his friend. As for the straight roommate, evidently Ecstasy can't alter sexuality (unsuprising, as anyone who's tried it will tell you Ecstasy has little to do with sexual feelings, and in fact often inhibits them). But it did seem to have triggered many of the other hallmarks of romantic love. The man gazed affectionately at his roommate, expressed all manner of deep and abiding emotion for him, was wracked with guilt for the suffering he'd caused. Everything was there but the sexual attraction.


The chemical basis for emotion is nothing new, and at this point carries little shock value. Yet it is still difficult to believe how easily we can manipulate our deepest emotions with a little diddle to the neuropharmacological machinery.


What was the cure for this young man? Fighting fire with fire, I prescribed him Prozac. Prozac works by paralyzing the same reuptake transporter that is reversed by Ecstasy. Instead of being vacuumed back out of the synaptic cleft when their job is done, the serotonin molecules loiter around in the cleft. The simple way to think about this is that more serotonin in the cleft equals more happiness, duh - though in fact the biological effects of SSRIs such as Prozac are somewhat more complicated than that (see Nutt et al for a useful summary).


As one might expect, then, Prozac blocks the effects of Ecstasy. With Prozac in your system paralyzing your reuptake transporters, a nice fat pill of E has no more effect than a sugar tab. That was one little-known side effect I thought might be useful in this particular patient's case.


A more well-documented side effect of SSRIs is inhibition of sexual function, including the ability to orgasm (see Rosen et al. for review). In addition to this, there are some anecdotal reports that SSRIs such as Prozac have adverse effects on romantic love. This is a much mushier and less well-documented realm. I found nothing about it on PubMed, though I did find a bit of schlock in Psychology Today that discusses the phenomenon. If this latter bit did turn out to be true, I would wonder whether the effect were secondary to inhibition of sexual desire or whether it involved a distinct group of neural circuits.





Based on anecdotal reports from people who have used them, it sounds as if SSRIs may in fact dull the capacity for deep emotion. You don't feel sad anymore, you even feel kind of happy, but the happiness is a sort of pleasant zoning out rather than a meaningful joy. Indeed, by some reports the entire spectrum of emotion is flattened out (see, for example, comments posted by readers on this WebMD blog).


Much has been made of the possibility that we are depriving ourselves of essential human experiences by medicating away our emotions (see, for example, this review of Eric Wilson's book Against Happiness). Of course, many others more articulate than I have also argued the opposite side of the story (see this other review of Peter Kramer's Against Depression).


As is often true, I find myself taking a position somewhere in the middle. I don't want my patient to be zoned out forever, but I can't help but think that he's already had more than enough character-building for a while. A little Prozac in this case is probably a good thing.