2010: the year in reviewDecember 18, 2010 5:53 pm entactogen, hallucinogen, human, in vivo
Faithful readers will notice that we had a long hiatus here as I completed my dissertation and then recovered from the resulting snake-fight injuries. Meanwhile, the year 2010 saw a number of landmark papers and subtle shifts in the scientific terrain.
Franz Vollenweider and Michael Kometer published a commentary (article behind pay wall) in Nature Neuroscience Reviews that, among other things, used the word “psychedelic” in its title. With few exceptions, this word has been notably absent from reputable scientific journals. Psychedelic (“mind manifesting”), I suspect, always seemed a little too approving. For years, “Hallucinogen” has been the term of choice in science and, even if it sounds vaguely disapproving to some, it can boast lovely roots (“to wander in the mind”). Vollenweider and his colleagues, however, began publishing studies using the term “psychotomimetic”, which makes their use of the word psychedelic particularly noticeable. Maybe this was just an editorial decision by the journal, but it is hard for me not to see this as symbolic.
2010 may turn out to be the year that “psychedelic” returned to the mainstream as a term to highlight the potential of hallucinogens as medicine. Two long-anticipated clinical trials were finally published. First, Michael Mithoefer, Mark Wagner, Ann Mithoefer, Lisa Jerome, and Rick Doblin reported impressive results in a pilot study of MDMA-assisted psychotherapy for PTSD. Second, Charles Grob, Alicia Danforth, Gurpreet Chopra, Marycie Hagerty, Charles McKay, Adam Halberstadt, and George Greer reported on their efforts to use psilocybin to reduce suffering in late stage cancer patients, although their outcome measures mostly failed to achieve statistical significance. Grob also published a review in Scientific American with Roland Griffiths, lending further weight to the view that this psychedelic medicine topic had mainstream interest. Perhaps most improbably, the dissociative anesthetic ketamine, a drug that acts as a NMDA receptor antagonist and combines hallucinogen phenomenology with an addictive allure, gained recognition as a promising fast-acting antidepressant.
Given the excitement of these first few studies, 2011 may be a year of disappointment. I see a danger that more small pilot studies, which only have enough statistical power to see really big effects, will fail to convincingly cure anything before society’s excitement wears off. Under the best of circumstances, treatment trials for complex diseases are difficult. As someone with more focus on psychedelic mechanisms than medicine, I do not envy my colleagues who are trying to graft psychedelic culture onto clinical drug development. The next year or two may well disabuse everyone of the hope that psychedelics are miracle cures. As with every other treatment, some patients will get better, while others will not. The question will be, why?
This question will reverberate not just in science but also in the media. To date, clinical trials with hallucinogens have gotten a bit of a free ride in the press. News reports have understandably gone with a “doctors say bad drugs could be good medicine” discourse. As these studies lose their “man bites dog” surprise value, a new not-yet-determined story will emerge.
Just what story emerges will depend on the theories and mechanisms that researchers develop to describe hallucinogen effects. Right now, we lack any widely accepted plausible theories for how hallucinogens might be helpful. As Neuroskeptic put it, psychotherapy has changed a lot since the 60s and it remains to be seen what cognitive-behavioral therapy will make of LSD. Yet looking over the recent literature, I see a few ideas emerging.
A nascent (yet also old) theory for explaining the potential of psychedelics as medicine is that mystical-type experiences may be particularly effective for catalyzing dramatic life changes. The landmark 2006 paper by Griffiths, William Richards, Una McCann and Bob Jesse demonstrated that psilocybin made mystical-type experiences likely (at least in carefully selected and prepared volunteers). A great strength of that study was that the researchers showed the experiences had lasting impact on the participants. A follow-up study of the same volunteers suggested that this lasting impact was specifically mediated by the acute mystical-type experience and was not a more generic effect of high-does hallucinogen. This suggests that these drugs might occasion lasting life changes under some circumstances by producing mystical-type experiences. Years ago, Richards, Rhead, DiLeo, Yensen, and Kurland (1977) had found that cancer patients undergoing hallucinogen-assisted psychotherapy had better outcomes if they had peak experiences, which may have been a different label for the same mystical-type experience. (That article does not appear to be available online, but Richards sketches the basic idea in this 1980 paper.) Given the variability in hallucinogen effects, I think clinical trials of psychedelic medicine are likely to fail unless the researchers can identify these sorts of acute outcomes that predict therapeutic success.
A lingering question has been whether these mystical-type experiences only occur in people with a religious or spiritual bent or whether scientists can see them in more typical research volunteers. Two papers from this year address this question by showing that robust increases in self-report mystical-type experience are produced by volunteers given MDA (in a study I conducted with my colleagues, about which Brad at Oscillatory Thoughts kindly interviewed me) or Salvinorin A (in a hot-off-the-press study conducted by Matthew Johnson, Katherine MacLean, Chad Reissig, Thomas Prisinzano, and Roland Griffiths). Thus, it is becoming increasingly obvious that these sorts of transcendent experiences are pretty reliable with hallucinogens in controlled clinical settings with well-screened volunteers (and not only those with high religiosity).
Of course, the theory of transformative mystical-type experiences is a little unsatisfying to those of us who (for better or worse) have grown to expect stories of neurotransmitter imbalance and fMRI blobograms. It’s a theory with a lot of heuristic value, but it’s the wrong kind of theory for science circa-2011. In their Nature Neuroscience Reviews paper, Vollenweider and Kometer give the kind of theory that neuroscientists like. They suggest that hallucinogens might have beneficial effects on depression, anxiety, and pain by down-regulating prefrontal 5-HT2A receptors and enhancing neural plasticity, the latter possibly achieved by increasing AMPA-type glutamate receptor trafficking and raising brain derived neurotrophic factor (BDNF). Because BDNF can be measured in the blood, this is an easily testable hypothesis.
Perhaps the near future will see a synthesis of these theories, with pharmacologically enhanced neural plasticity (possibly indexed by blood BDNF levels) allowing mystical-like experiences (when they occur) to work their alleged lasting liminal magic. The safe bet, however, is that the truth will be much messier.
We are also beginning to see a theory emerging from the studies administering MDMA to healthy volunteers. As Vaughan Bell at Mindhacks blogs, Gill Bedi, David Hyman, and Harriet de Wit have just published an important article in Biological Psychiatry, comparing two doses of MDMA to methamphetamine and placebo in order to ask “is MDMA an empathogen?” Their tentative answer, that MDMA does not increase empathic accuracy but may decrease (what I would call) harm sensitivity, represents important steps toward a theory of how MDMA-like drugs work. Combined with comparisons of how MDMA and methamphetamine affect speech (by Gina F. Marrone, Jennifer S. Pardo, Robert M. Krauss, & Carl L. Hart) and early comparisons of self-report effects of MDMA and amphetamine (by Jordi Camí, Magí Farré, Marta Mas , Pere Roset, Sandra Poudevida, Anna Mas, Lluis San, Rafael de la Torre), it is becoming obvious that MDMA is not just another stimulant. While high doses of stimulants make people feel energized and alert, higher doses of MDMA make people feel oddly sedated. The drug is also doing something different emotionally, but no one knows how to describe it with proper scientific constructs yet. The paper by Bedi and colleagues suggests that reduced sensitivity to threat-related emotions may be an important part of that description.
Finally, because theoretical advances are often based on methodological ones, I will conclude by noting the much-needed psychometric evaluation of the Altered States of Consciousness questionnaire published by Erich Studerus, Alex Gamma, Franz Vollenweider this year. This instrument has been a mainstay of European hallucinogen work for years now. But the small number of validated many-item scales that you get are difficult to interpret and contain all kinds of interesting and seemingly different individual items. Researchers have responded by reporting unvalidated “clusters” of scale items. The new open-access paper provides some reasonable scales and, importantly, publishes all the individual questions, making it much easier for researchers to use the questionnaire. There is still no single questionnaire that is adequate for measuring self-report hallucinogen effects, but this questionnaire is emerging as one of the defaults.
The Altered States of Consciousness questionnaire had three main scales that were hypothesized to describe fundamental dimensions of the phenomenology of altered states of consciousness: Oceanic Boundlessness, Dread of Ego Dissolution, and Visionary Restructuralization. People sometimes labeled these as “heaven”, “hell”, and “visions”. Contrary to this theory, careful psychometric evaluation by Studerus and colleagues in this new paper failed to confirm these experiential dimensions. Instead, hallucinogen-induced altered states turned out to be far more complicated and the authors propose a number of valid and reliable scales. And that may be the major lesson of 2010. These chemicals are not as good as some hope, nor as bad as some fear; the way they interact with consciousness is, however, a lot more complicated than any theory can explain.