DMT and S-Ketamine given during fMRI
July 31, 2008 3:34 pm admin fMRI, hallucinogen, human
Jörg Daumann and colleagues have published a functional magnetic resonance imaging (fMRI) study comparing the effects of N,N-Dimethyltryptamine (DMT) and S-Ketamine on fMRI-measured neural activity and performance during an attention task. Although the main findings aren’t dramatic, this paper is noteworthy in another way: I believe it is the first publication to combine fMRI and serotonergic hallucinogen administration in humans. This makes their use of ultra-short-duration DMT impressive.

So what did they find? They report that DMT (but not S-ketamine) blunted Inhibition of Return (IOR). IOR is a well-studied phenomenon. It turns out that if you are doing a task where you respond to visual targets, a cue (another stimulus appearing in the same location ahead of time) can either speed or slow your response to the target depending on the length of time between the target and cue. The cue makes people faster when the target comes right after the cue, but a little slower if the asynchrony is longer than about 250ms. This suggests that some attentional and/or oculomotor mechanism is inhibiting return to the recently evaluated location (hence the name, IOR). Hallucinogens have long been known to alter attention, so studying IOR may useful for understanding this.

Interestingly, even though DMT impaired IOR, they didn’t find any significant fMRI changes. And while S-ketamine didn’t change IOR (contrary to previous research by the same group), there were changes in fMRI measures. This isn’t really all that surprising; there are lots of reasons to get differences between fundamentally different measures. But it may useful to take the time to remind ourselves that it is amazing that fMRI works at all. There’s a whole lot of signal processing that goes on to find the slow changes in blood oxygenation that somehow correlate with fast neural changes. And sometimes you don’t get anything because you’re looking in the wrong area (among other things, IOR is thought to involve the subcortical superior colliculus, which the researchers note they couldn’t really see). Or maybe the drug changes something the fMRI measurement relies on (hallucinogens often change cerebral blood flow). Or maybe you just don’t have enough data points for the statistics because changes are so variable.

Daumann et al work within a ‘psychotomimetic’ paradigm, comparing and contrasting hallucinogens with schizophrenia. They suggest that different drugs can model different aspects of schizophrenia. Schizophrenia is often described as having two main types of signs and symptoms: positive (things that are present, such as delusions) and negative (things that are absent, such as lack of motivation). (These days many authorities would also mention a third category of signs and symptoms relating to cognitive disorganization.) Daumann and colleagues propose that DMT can imitate many of the positive symptoms while ketamine models both positive and negative. (And over the years, they and other researchers have collected data consistent with this proposal.) The psychotomimetic paradigm has its critics (and it is not an approach I pursue). But I suspect that objective scientific comparisons of different altered states can only be helpful in the long run. And people with schizophrenia surely are high on the list of populations we’d all like to help.

Plus, experiencing hallucinogens with your head inside a metal ‘mind-reading’ bucket that sounds like it is being hammered on may increase the validity of the hallucinogen-schizophrenia comparison. So how did they get DMT and S-ketamine to last long enough to study in a scanner? They used long intravenous infusions:


The appropriate dosages for both DMT and S-ketamine were determined in a previous study so as to evoke psychosis-like symptoms, such as hallucinations and transient delusional misinterpretations of the experimental situation (Gouzoulis-Mayfrank et al. 2005). The individual dosages were titrated during every experiment within the defined ranges so as to obtain relatively uniform psychopathological profiles across subjects. The two dose regimens were: (1) DMT: bolus injection of 0.15 mg/kg over 5 min followed by a break of 1 min, followed by continuous infusion with 0.01 up to 0.01875 mg/kg min over 20 min, (2) S-ketamine: bolus injection of 0.1 mg/kg over 5 min, followed by a break of 1 min, followed by continuous infusion with 0.0066 up to 0.015625 mg/kg min over 20 min. With these doses, the psychological effects of both drugs developed fully within about 10 min from the start of the injection and were then kept relatively constant over the functional magnetic resonance imaging (fMRI) scanning session.


This level of technical finesse is part of why neuroscientific human hallucinogen research is both difficult and expensive. The key is to add in all the technical aspects without fundamentally altering the thing you’re trying to study. This may be easier if you’re studying attentional impairments during paranoid psychotomimetic trips, but may be harder when you’re trying to study other aspects of hallucinogen-induced changes in consciousness. Even in its ‘easiest’ form, just getting this research done is a real achievement.


Daumann J, Heekeren K, Neukirch A, Thiel CM, Möller-Hartmann W, Gouzoulis-Mayfrank E.
Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT(2A) agonist and NMDA antagonist model of psychosis.
Psychopharmacology (Berl). 2008 Jul 24. DOI 10.1007/s00213-008-1237-1 Online Preprint

Abstract: RATIONALE: Attentional deficits are common symptoms in schizophrenia. Recent evidence suggests that schizophrenic patients show abnormalities in spatial orienting of attention, particularly a deficit of inhibition of return (IOR). IOR is mostly thought to reflect an automatic, inhibitory mechanism protecting the organism from redirecting attention to previously scanned, insignificant locations. Pharmacologic challenges with hallucinogens have been used as models for psychosis. OBJECTIVES: The aim of this study was to investigate the neural correlates underlying orienting of attention in the human N-methyl-D: -aspartic acid antagonist and 5-HT(2A) agonist models of psychosis. MATERIALS AND METHODS: Fourteen healthy volunteers participated in a randomized, double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. We administered a covert orienting of attention task with nonpredictive peripheral cues, and we scanned the subjects on two separate days at least 14 days apart with a placebo and a verum condition on each day. RESULTS: DMT, but not S-ketamine, slowed down reaction times significantly. IOR was blunted after DMT, but not after S-ketamine. Relative to placebo, S-ketamine increased activation in the IOR condition in the right superior frontal gyrus, left superior temporal gyrus, and right midfrontal frontal gyrus. CONCLUSIONS: The discrepancy between the behavioral and functional imaging outcome indicates that pharmacological fMRI might be a sensitive tool to detect drug-modulated blood oxygenation level-dependent signal changes in the absence of behavioral abnormalities. Our findings might help to further clarify the contradictory findings of IOR in schizophrenic patients and might, thus, shed more light on possible differential pathomechanisms of schizophrenic symptoms.