This procedure was repeated by leaving out all possible combinations of two participants (66 training/testing cycles) to create confusion matrices. This analysis was first performed using full connectomes of sFC, dFC, and eFC alone and in all combinations. Then, to determine whether within- or between-network connections were particularly predictive of SA effects on brain function, the classification procedure was repeated by training models on within- or between-network connectomes.
- With the increasing acceptance of hallucinogens as potential therapeutics, exploration of different pharmacological tools and their combinations will be a necessary avenue in future research.
- The researchers saw no changes in blood pressure or heart rate, even at the highest doses of salvinorin A.
- Because weighing the very small doses of salvinorin A required for this study is difficult, a larger quantity was weighed on an analytical balance and then dissolved in a measured volume of HPLC grade acetone.
- Long-lasting pain has been among the major therapeutic challenges of the 21st century due to its disabling effects, especially with the growing population of the elderly.
- “We did document the very intense nature of the drug, even among those who are used to strong hallucinogenic drugs,” Johnson told ABCNews.com.
- “We’re opening the door for systematic study of this class of compounds, about which we know precious little,” said Roland R. Griffiths, a professor of psychiatry and behavioral sciences in the Johns Hopkins School of Medicine and the study’s senior investigator.
Data Availability Statement
Participants were cued when there were 20, 10, 5, 4, 3, 2, and 1 s remaining after which they were prompted to exhale and drop the tube. Johnson and the Hopkins team say they undertook the research to try and put some rigorous scientific information into current concerns over the growing recreational use of Salvia divinorum, which is an herb in mint family. Though little is known about the compound’s effects in humans, some legislators have been spurred to action after watching one of thousands of online videos chronicling the uncontrolled behavior that sometimes follows its use. However, because animal studies show that salvinorin A has unique effects in the brain, some scientists believe that the drug or a modified version of it may lead to medical advances in the treatment of diseases such as Alzheimer’s disease, chronic pain and drug addiction…
3 Drug administration
“We’re opening the door for systematic study of this class of compounds, about which we know precious little,” said Roland R. Griffiths, a professor of psychiatry and behavioral sciences in the Johns Hopkins School of Medicine and the study’s senior investigator. We are at a critical time and supporting climate journalism is more important than ever. Science News and our parent organization, the Society for Science, need your help to strengthen environmental literacy and ensure that our response to climate change is informed by science.
With the increasing acceptance of hallucinogens as potential therapeutics, exploration of different pharmacological tools and their combinations will be a necessary avenue in future research. Similar to previous reports2,3, the average subjective drug strength rating from the practice session dropped by approximately half from the peak rating by 10 min (i.e., equivalent in time to halfway through each scan; Fig. 1a). Therefore, after preprocessing (see Supplementary Information for preprocessing methods), the timeseries of all brain regions were split into first and second halves, creating a drug (placebo, SA) by time (first half of scan, second half of scan) design. Analyses repeated without partitioning timeseries did not change interpretation of results. Because weighing the very small doses of salvinorin A required for this study is difficult, a larger quantity was weighed on an analytical balance and then dissolved in a measured volume of HPLC grade acetone.
- At baseline and at 15 and 30 minutes after drug administration, the study staff visually assessed kinetic tremor intensity as the participant bent both of his or her extended arms to touch middle finger to nose.
- The split-half reliability of all functional connectivity measures was good (see Supplementary Fig. S2).
- In this regard, finding new molecules or associations to decrease or alleviate pain is of utmost importance.
- Salvinorin A produced no significant changes in heart rate or blood pressure; no tremor was observed; and no adverse events were reported.
Quantum ‘echoes’ reveal the potential of Google’s quantum computer
The lowest dose in the sequence was 0.375 μg/kg of bodyweight and subsequent doses were 0.75 μg/kg, 1.5μg/kg, and thereafter increased by an increment of 1.5 μg/kg until the maximum dose of 21 μg/kg was reached. Four placebo doses were inserted in the ascending sequence of salvinorin A doses such that each consecutive block of 5 sessions included 1 placebo. The position of the single placebo within each block of 5 sessions was determined randomly for each volunteer. Participants were told that on any session they may receive a dose of salvinorin A or placebo but were not told about the ascending design or frequency of placebos. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain.
One solution in this regard is to look back at the ancestral ethnobotany and the repositioning of existing molecules for new clinical applications. Divinorum can be used as an alternative therapy for inflammatory and neuropathic pain, due in part to the presence of salvinorin A, a powerful KOR agonist and an allosteric modulator of CB1 receptors. Researchers think the kappa-opioid receptor is important for a type of chronic pain, so understanding salvinorin A’s effects on the receptor might lead to better pain treatments. What’s more, tweaking the kappa-opioid receptor with salvinorin A–like compounds study of controversial hallucinogen salvia shows intense and novel effects in humans 12 07 2010 might one day treat neurological disorders in which a person’s view of reality is altered, such as schizophrenia, depression or Alzheimer’s disease. Studies in animals have shown that salvinorin A acts on molecules in the brain called kappa-opioid receptors. These receptors are part of the pain-dulling opioid system but are not the same receptors that addictive opiates target.
But because the study used a small number of healthy volunteers, it can’t make broad statements about the overall safety or the long-term effects of the substance. Although not reported by users in retrospective analyses (Baggott et al., 2010; González et al., 2006), tremor has been observed in rhesus monkeys at a substantially higher dose (100 μg/kg) than our maximum dose (Butelman; personal communication, 2006). The Fahn-Tolosa-Marin Tremor Rating Scale (TRS; Fahn et al., 1993) was used to classify resting and kinetic tremor severity on a 5-point scale.
Procedure
Participants were asked to rate the strength of peak drug effect on a scale of 1 to 10. Participants were allowed to drop out of the study at any time if they felt they could not tolerate a stronger dose on the following visit. The study found that salvia’s effects begin almost immediately after inhalation; are very brief, with a peak of strength after two minutes and very little effect remaining after 20; and get more powerful as more of the drug is administered. Salvinorin A produced no significant changes in heart rate or blood pressure and no tremors, and no adverse events were reported. But, Johnson cautions, the sample size was small, and only healthy and hallucinogen-experienced volunteers participated, so conclusions of safety are limited. This study used fMRI to measure how inhaled SA alters brain functional connectivity in humans.
Discrimination scores (d’) for each connectome were then computed from the proportion of data correctly identified as SA first half and the proportion of data mislabeled as SA first half. Given the enormous search space, models were not trained on combinations of within- and between-network connectomes. The researchers saw no changes in blood pressure or heart rate, even at the highest doses of salvinorin A. Other hallucinogenic compounds, such as LSD and psilocybin, moderately raise blood pressure and heart rate, Johnson says.
Salvia Studies Hold Promise for Addiction
Other Johns Hopkins researchers involved in the study are Katherine A. MacLean and Chad R. Reissig. This section collects any data citations, data availability statements, or supplementary materials included in this article. Where f(xi) is the discretized frequency distribution after binning and w is the bin width. Statistics resulting from a range of bin widths (15–120 bins, in steps of 15) did not meaningfully differ.
Few emergency room visits have been linked to its use; researchers believe the reason is that it wears off so quickly. None withdrew from the study, but they were allowed to take breaks from the drug when sessions were too intense. “We did document the very intense nature of the drug, even among those who are used to strong hallucinogenic drugs,” Johnson told ABCNews.com. “That in itself is an area of danger — people can have accidents or do foolish things on the drugs.” Divinorum, SA, and its analogues in the chronic diseases that occur with inflammation and pain urge to consider the possible cytotoxicity after the prolonged use of these substances.
Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC).
Most of the understanding of salvia has come from YouTube videos and not scientific studies. Lead researcher Matthew W. Johnson, a psychologist and assistant professor of psychiatry, said the study was an attempt to “put some rigorous scientific information into current concerns over the growing recreational use” of salvia. Divinorum, SA, and its analogues, focusing mainly on their analgesic and anti-inflammatory roles, as well as their psychoactive properties. Animal data suggest that the drug is not addictive, Griffiths says, and its intensity could keep people from returning to the drug again and again. Long-lasting pain has been among the major therapeutic challenges of the 21st century due to its disabling effects, especially with the growing population of the elderly. In this regard, finding new molecules or associations to decrease or alleviate pain is of utmost importance.
Similarly, SA numerically reduced dFC and increased eFC within and between all networks (Fig. 3b,d), but only decreases in dFC during the first half of the scan survived corrections for multiple comparisons. Drug by time interactions for within- and between-network changes in dFC were also significant (see Supplementary Table S2 for all drug by time ANOVAs). When running these analyses without aggressively correcting for motion, individual differences in the degree of motion within a scan (i.e., framewise displacement) were correlated with individual differences in dFC and eFC for some within- and between-network cases. However, with more rigorous motion reduction (i.e., the data displayed here), these correlations were reduced, and the change in dFC became stronger (see Supplementary Fig. S6–S11 for motion-related analyses). Moreover, changes in eFC were negatively correlated with motion, suggesting that motion may have actually attenuated these effects. To assess psychological effects that might warrant discontinuing future sessions, participants were asked at the end of each session “Would you absolutely refuse to receive the same or higher dose of today’s drug in future sessions?
Moreover, despite discussions of variability and entropy in similar terms40, these measures should not be expected to be impacted similarly. For example, a functional connection or brain area that fluctuates between a very strong and a very weak state would produce high variability and low entropy. In contrast, an edge that fluctuates between several neighboring connectivity strengths would produce high eFC without necessarily producing high dFC.