The kappa opioid receptor and the sleep of reason: Cortico-subcortical imbalance following salvinorin-A

This double-blind, crossover, randomized, placebo-controlled neuroimaging study (n=42) investigated the neuropharmacological properties of salvinorin-A (1 mg) in healthy participants and found that its ability to induce unique bizarre hallucinations are attributed to drastic decreases in regional blood flow in the frontal, temporal, parietal, and occipital cerebral cortices.

Abstract

“Background: The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist.

Methods: Changes in multimodal EEG, SPECT, and subjective effects following the acute administration of salvinorin-A are reported. The study included two sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design.

Results: The EEG measures showed a marked increase in delta and gamma waves, and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding SPECT measures, significant decreases in regional cerebral blood flow (rCBF) were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant rCBF increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs, but with an evidently dissociative nature. No dysphoric effects were reported.

Conclusion: The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects, along with a generalized decrease in CBF and electric activity within the cerebral cortex.”

Authors: Genís Ona, Frederic Sampedro, Sergio Romero, Marta Valle, Valle Camacho, Carolina Migliorelli, Miguel Ángel Mañanas, Rosa Maria Antonijoan, Montserrat Puntes, Jimena Coimbra, Maria Rosa Ballester, Maite Garrido & Jordi Riba

Summary

The effects of salvinorin-A, a highly selective kappa opioid receptor (KOR) agonist, were studied in two sub-studies. Results showed that salvinorin-A induced dramatic psychotomimetic effects, along with a generalized decrease in CBF and electric activity within the cerebral cortex.

Opioid receptors are G protein-coupled receptors expressed by central and peripheral neurons. They were named for their interactions with morphine, codeine, and other active principles found in opium, a medicinal product made with the latex of the plant Papaver somniferum. All three opioid receptors modulate pain and analgesia, but MOR has been studied most extensively. Several ligands for other opioid receptors have been designed to have potent analgesic effects without these side effects.

Interest in KOR agonists for the treatment of pain has increased considerably, but the selective activation of KOR is associated with dysphoria and psychotomimetic effects. However, the mechanism through which psychotomimetic effects are induced remains unknown. Human studies involving KOR agonists have shown that these drugs induce hallucinations, disturbances of space and time, racing thoughts, and feelings of body distortion, among other effects. These effects are unique in comparison to those induced by other hallucinogenic drugs.

Two independent, complementary studies were conducted with healthy volunteers to assess spontaneous brain electrical oscillations while individuals were under the effect of salvinorin-A. Subjective measures and single-photon emission computed tomography were used to characterize both clinical effects and changes in regional blood flow following the acute administration of salvinorin-A.

Twenty-four people participated in sub-study 1 (EEG), and twenty people participated in sub-study 2 (SPECT). One subject was removed from sub-study 1 due to an artifact rejection procedure, and one subject was removed from sub-study 2 due to technical problems. In two double-blind, randomized, placebo-controlled studies, volunteers inhaled 1 mg of vaporized pure (>99%) salvinorin-A to experience vivid visions with eyes closed, changes in dimensionality and time perception, and a complete blockage of external stimuli.

The HRS includes six sub-scales: somaesthesia, affect, cognition, perception, volition, and intensity. Self-administered VAS were used to retrospectively rate peak effects during the session, and a chart with 100 horizontal lines placed 1 mm apart was used to indicate intensity.

EEG readings were recorded at baseline, 0 min, +3 min, and +6 min after drug administration. Signals were recorded with a sample frequency of 100 Hz and analogically band-pass filtered between 0.1 and 45 Hz. The EEG signals were segmented into 5-s epochs and an automatic rejection procedure focused on saturation, muscle, and movement artifacts was applied. The sLORETA technique was applied to estimate 3D source distribution of the intracerebral current density function.

A digitized head model was used to estimate the current density values of 6239 cortical gray matter voxels with a spatial resolution of 0.125 cm3. MATLAB and LORETA software were used for statistical analyses. Brain 99mTc-HMPAO SPECT scans were conducted prior to and following the administration of salvinorin-A. The scans were acquired using a two-headed General Electric HELIX gamma camera equipped with fan-beam collimators, and the images were subsequently reconstructed using filtered back projection with the application of Metz filtering and attenuation-correction.

Neuroimaging analyses were performed using the SPM8 software package, and results are reported after Bonferroni correction. Statistical differences between drug and control groups were evaluated by paired-sample t-tests computed for the baseline-corrected and log-transformed LORETA power values in each voxel and for each frequency band at different time points.

To examine post-salvinorin-A rCBF changes, a SPECT voxel-wise paired t-test was performed. Significant increases or decreases in tracer uptake were found in the brain regions shown by the SPECT images. A single dose of salvinorin-A (1 mg) was assessed using EEG measures. Significant increases in delta and gamma bands were located at the temporal and occipital lobes, respectively, and decreases in alpha bands were restricted to the cingulate gyrus, precuneus, and superior parietal lobe.

A sample of 20 participants were recruited, aged between 23 and 46 years (M = 35.1 years), with previous experience in the use of hallucinogenic drugs. Salvinorin-A produced significant psychoactive effects, with the highest scores being obtained for “I liked the experience”, “I would like to take the substance again”, “good effects” and “changes in dimensionality”.

Salvinorin-A, a non-nitrogenous diterpene with high selectivity to KOR, was found to produce drastic changes in subjective effects, as well as EEG and SPECT measures. The highest scores were obtained for the scales of intensity and volition. The high scores obtained for hallucinogenic drugs include visual effects, modifications in dimensionality, and loss of contact with external reality.

The EEG measures showed an increase in delta waves along the temporal and parietal cortices, and in limbic regions, such as the parahippocampal gyrus, following the administration of salvinorin-A. This is in accordance with the subjective effects of salvinorin-A, which are commonly described as involving a dream-like state. Other studies have reported contradictory results, suggesting that different mechanisms of action underlie the hallucinogens’ psychotomimetic effects. However, a recent study has reported similar findings following the acute administration of DMT.

Salvinorin-A administration was associated with a widespread cortical decrease in rCBF in the frontal, parietal, and temporal lobes, as well as increases in rCBF in the cerebellum and in the medial regions of the temporal lobes of both hemispheres. The left prefrontal cortex, superior frontal gyrus, and premotor cortex showed decreases in CBF, which could explain the marked loss of contact with reality and body awareness reported by volunteers.

PET studies have shown that the precuneus is among the first regions to be deactivated in other states of consciousness, and that it is also among the first regions to show activity when individuals recover consciousness. The calcarine sulcus was the main region to show a relevant decrease in CBF, however, some previous studies found no effects in this region, while others found an increase in activity. This raises questions about the different mechanisms through which hallucinatory experiences can be induced.

The increase in CBF registered in the medial temporal lobe, especially in the amygdala, suggests differential mechanisms with serotonergic hallucinogens. This increase could be explained by the more abrupt and intense experience elicited by salvinorin-A, as well as by dynamics between the corticofrontal regions and amygdala. The small sample sizes used for both sub-studies and the fact that participants had previous experience with hallucinogens could be related to the absence of dysphoric effects. Therefore, further research is needed to fully elucidate the pattern of dysphoric effects of salvinorin-A in the general population.

The combination of EEG and SPECT allows the observation of brain perfusion, which is especially useful for drugs with rapid onset and short duration of effects, such as salvinorin-A, DMT, 5-MeO-DMT, and others that are currently being researched. Salvinorin-A induces psychotomimetic effects through the signaling of KOR, which suggests that disorders of cognition and perception, such as schizophrenia, may be associated with alterations in this receptor system.

This paper is dedicated to the memory of our dear colleague Jordi Riba, who recently passed away. Jordi, M.V., R.M.A., M.P., J.C., M.R.B., G.O., F.S., C.M., M.A.M., and S.R. wrote the paper.