In parts 1 and 2 of this series, I undertook a (much longer than anticipated) personal investigation into how scientists discuss the effects of cannabis as a way of trying to better it, both as a drug and as a cultural subject. The articles generated a great
deal of discussion and many intriguing points were raised. Jimmy is a much smarter young man now.

But even after all the reading, writing and discussion, I still had questions with unsatisfactory answers. So I decided to do the one thing that was even better than reading scientific articles: I talked to scientists.

Two scientists were kind enough to grant me interviews: Dr. Deepak
Cyril D'Souza, a psychiatrist and researcher at Yale University, and Dr. Steven
Laviolette, a neuroscientist at the University of Toronto.  Both are experts on the neurobiology of
cannabis, cannabinoids and the brain, and both were ideal and engaging interviewees
who have my sincere thanks. I posed to them many of the questions that had come up in the discussions, and added a few new ones that came up while I was learning about their research. 

Discussion with Dr. D'Souza

Dr. D'Souza  conducted the 2005 study that I cited in part 1, in
which different doses of THC were injected directly into the bloodstream. I
asked him specifically about his report of elevated anxiety rates in his
subjects, a finding which would seem to contradict the assumed affect of the
main component of cannabis. "We need to be clear that cannabis and THC are
not the same thing,…we did not fully appreciate this at the time that we
conceived the study" he said, and noted (as commenters have also noted)
that there are important differences in dosage and delivery between what he did
in his study and what smokers receive. Furthermore, he pointed out that there
are other chemicals which contribute to the net effect of smoking, including
the presence of the anti-anxiety, anti-psychotic cannabidiol, which we have
discussed elsewhere.

I also asked him about the use of the words
"psychosis" and "psychotic", and if what cannabis users
experienced could be described as a temporary experience as a schizophrenic. He
clarified, "Schizophrenia is a psychotic disorder. THC induces psychotic
symptoms. I don't believe that any drug can model a complex disorder like
schizophrenia. Elevated intravenous levels of THC can cause symptoms that
resemble schizophrenia." He referenced this video of a journalist being injected with THC on BBC, for anyone interested.

When I asked about his reports of paranoia and THC, and the
commenter response that anyone would feel paranoid in the lab, he noted that in
his double-blind study, people became paranoid only in the THC condition, not on
the placebo condition. He also noted that, again, the effect was dose-dependent.
He did concede that setting does matter a little in these studies.  He also cited the large anecdotal links
between cannabis use and paranoia. For example in some surveys between 20% and 50% of individuals have reported
paranoia, persecutory ideas, and hallucinations while under the influence of cannabis (see Here and Here).

I also asked about specific findings that he had published.
In one recent paper, (2012 Neuropsychopharmacology), he described that the
symptoms of time overestimation and underproduction in his THC subjects was
blunted in people who used 2-3 times a week. From what I've heard from users, the existence of tolerance does not come as a surprise. But he suggested that it was a
surprising finding because 2-3 times per week was considered "light
use," but that even that usage rate induced noticeable adaptive changes which weren't limited to the effects of how they experience time.  Behavioral effects, subjective
effects, cognitive effects including effects on memory, hormonal responses and
even EEG changes in response to THC were blunted in the 2-3 a week users. On
the topic of EEGs, his lab also found that gamma and beta frequency EEG
patterns were reduced in weekly cannabis users compared to non-users. What does
that mean? It is a bit too early to tell-- he can only speculate.

Discussion with Dr. Laviolette

Dr. Laviolette is a specialist in the effects of the
cannabinoid system on "emotional learning", which can mean a lot of
things, but in his lab, it refers to reward-seeking behaviors and learning
related to fear. He explained, “Cannabinoid transmission has a
long and important involvement in our understanding of emotional learning
because not only can modulation of cannabinoid receptors (either activation or
blockade) regulate the formation and expression of emotional learning and
memory, but the endocannabinoid system in general is a potent regulator of
neuronal plasticity mechanisms related to learning and memory."

I asked
about the lasting effects of high doses of THC. He replied that his lab was
focused on the acute effects, noting as an example that cannabinoid receptor
activators in the amygdala can "increase the emotional salience of fear
memories" and can affect activity in the prefrontal cortex remotely, but
that this occurs at higher doses only. 
His lab is undergoing further research into how higher doses of THC in
young rats affects the actions of cannabinoids in adulthood, as a way of
addressing "compelling evidence linking exposure to high levels of
marijuana during adolescence to an increased risk of developing
schizophrenia-related psychoses in young adulthood."

In 2006,
Dr. Laviolette published a review demonstrating the links between cannabinoid
and dopaminergic systems. This relationship is of interest since dopaminergic
systems are historically credited as the neurobiological root of addiction. And
yet, addiction seems to be a low risk in cannabis users. "That's a very
interesting and complex question," he responded.  He pointed out that the role of dopamine
isn't restricted to a single "pleasure" signal, and even has a role in
modulating aversive behaviors in the prefrontal cortex.  "I think we
are beginning to realize that dopamine serves more as a general signal for any
sort of emotionally 'salient' event, which acts to guide emotional learning and
memory formation, be it reward or fear-related."  He noted that cannabinoids strongly influence
dopaminergic signaling, but that the effects of their influence are still being
studied by their lab and others.

On How We
Talk About Cannabis

I asked Dr. D'Souza why it was that scientists
and doctors (like himself) tended to describe the effects of cannabis and THC
in negative terms. His answer was that his view of cannabis use was colored by
his surroundings. As a physician in a hospital, he only sees the people with
problems, but he is aware that there may be beneficial effects to cannabinoids.  In fact Dr. D’Souza’s lab is actively
studying potential beneficial effects of cannabinoids including the effects of
THC on pain, and on extinction learning.

I asked
both men if they thought that government agencies selectively emphasized
negative research findings over positive ones. Dr. Laviolette said, "I
think considering how far both the U.S. and Canadian Governments have evolved
since the days of ‘Reefer Madness’ is generally quite encouraging. Indeed, the
fact that it is actually possible to obtain marijuana for medical purposes is a
massive leap forward considering the history of cultural hysteria that has
surrounded marijuana in both the U.S. and Canada." But he also recognized
that there was considerable trepidation by governments concerning marijuana.
When I asked Dr. D'Souza specifically about the language of NIDA, he replied
that he couldn't speak for the agency, but “I don’t get the
sense that NIDA will only fund studies designed to show that marijuana is
harmful.”

I asked
both men if they ever felt pressure to perform, publish or propose research
that cast cannabis in a negative light. Dr. D'Souza was emphatic. "No.
Absolutely not."  Dr. Laviolette
added, "Personally no, I have not
experienced any sorts of pressure one way or the other."

On The Future

One idea that was brought up during the article discussions was that cannabis has been around for so long that it's unlikely that we would learn anything new about it now. It turns out that there actually is a lot to learn. Dr. D'Souza pointed out that
there were three historical phases of cannabis research. "There
are the thousands of years of uncontrolled data. Then, beginning in 1963, [when
THC was identified as the active ingredient] to the mid 1970’s, there was an
increase in research including controlled studies. Then not much happened for
about 15 years because the mechanism of action of THC remained an enigma.  Then in 1988, the cannabinoid receptor was
discovered." From that point, studies on cannabinoids have increased
exponentially.

Dr. Laviolette explained that
"the formal
identification of the brain's endocannabinoid system is relatively recent.
However, the progress over the last few years has been remarkable," citing
as an example the increased understanding of not just Cannabinoid Receptor 1 in
the brain, but also Cannabinoid Receptor 2. 
He noted that there is still a great deal of work to be done to discover
the anatomical and functional roles of the endocannabinoid system, specifically
as they relate to how they modulate synaptic plasticity, and how that
modulation translates into changes in behaviors.

Both
researchers are excited by the prospects of useful medical knowledge and
applications coming out of cannabinoid research.  In fact, both of them referenced the
potential therapeutic applications of cannabidiol. But they also strongly
suggested that there is much more research to be done on cannabis and
cannabinoids.

Dr.
D'Souza expressed concern because, although he believes that the majority of
people who use cannabis may not experience negative effects, the connection
between cannabis use and an increased risk of schizophrenia is still being
debated. "If there is a link between [cannabis] and schizophrenia, which
is a terrible disorder to have, then we should modify the risk factors."  He didn't know precisely what determines a
higher risk, but that "some are more vulnerable than others."
"The potential consequences of a lifelong disorder shouldn't be
minimized." He added that the move to legalize cannabis suggests that more
people will be using it. And that means "the studies need to continue.”

Taking a step aside, I wanted to make one (absolutely final) comment. An idea that was brought up in the commentary on the articles was that the only relevant debate about cannabis is its legalization, and that any studies on cannabis now are inconsequential to the sociopolitical discussion. Your opinions on this point are your own. But I've learned from this experience that the scientific debates in the study of cannabis, in neuroscience, in immunology, in pharmacology, and in other fields are not done. Not even close. That may not matter to users, or voters, but it should matter somewhere, and not just to the academics.

Dr.
Laviolette offered this fitting conclusion: "Those of us in the basic
neuroscience community go where our data takes us, both from the clinical and
basic research sides of the equations. I think there are extreme positions on
both sides of the debate and the best thing to do is to wait on the science.
Reliable, solid, peer-reviewed data is the best way to inform public health
policy."