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…
Associated Data
The microtorch was adjusted so that the flame was approximately 1.5 cm in length, and the tip of the flame was held in contact with the round-bottom flask. Using these procedures, inhalation of un-volatilized drug was unlikely because the salvinorin A residue left upon evaporation of acetone appeared strongly attached to the interior of the flask, and in tests with various rates of mechanical airflow (simulated inhalation) without heat, salvinorin A was observed to remain undisturbed. Tests with mechanical airflow and the application of the microtorch showed the method to result in the volatilization of salvinorin A with little scorching (small black marks presumably resulting from combustion).
5.2 Timecourse
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 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.
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But addictive drugs work by stimulating what scientists call mu opioid receptors. Salvinorin A works on the kappa opioid receptors, which have a depressive effect if activated. Today, we are facing a crisis in relation to the use and abuse of opiates and related molecules. In fact, new molecules are not being developed as analgesics, fundamentally because of the long time taken by the processes to position these new agents until they are properly marketed.
- Twelve healthy male participants (23–52 years) were recruited through advertisements and word-of-mouth referrals (see Table 1 for demographics).
- These receptors are part of the pain-dulling opioid system but are not the same receptors that addictive opiates target.
- Whole-brain dFC and eFC matrices were computed by calculating the variance and approximation to differential entropy, respectively, of each correlation timeseries (see Supplementary Fig. S4 and S5 for single participant dFC and eFC matrices, respectively).
- 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.
- Two participants (1 male, 1 female) provided the maximal rating of 10 at one or more time points during at least one session.
1 Participants
- Inhaled SA had its expected effects on the time course of drug strength ratings during the practice session similar to previous reports2–4, peaking 1–2 min post-inhalation, decreasing by approximately 50% at 10 min, and largely subsiding by 15–20 min, though the decay was somewhat variable (Fig. 1a).
- A kappa-like profile of antinociceptive and behavioral effects has also been demonstrated in rodents (Fantegrossi et al., 2005; Wang et al., 2005; Zhang et al., 2005; McCurdy et al., 2006; Carlezon et al., 2006).
- 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.
- Given the increasing trend and lack of plateau in drug strength ratings (see Figure 1b) and the lack of adverse effects in this study, future studies may also cautiously explore higher doses of salvinorin A.
- Despite these strong experiences, heart rate and blood pressure were unaffected.
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.
Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action
After a phone screen confirmed basic inclusion criteria (age, high-school-level education, and prior hallucinogen use), volunteers came study of controversial hallucinogen salvia shows intense and novel effects in humans 12 07 2010 to the laboratory for in-person screening. Participants were excluded who reported having a first or second degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or bipolar I or II disorder. Additional screening visits assessed general motivation for participation and established trust and rapport with the study staff.
“We have done the first human study with the drug and it could be the first examination fo a whole new line of drugs that have a therapeutic potential.” Johnson said learning about salvia’s effects on the brain could lead to medical advances in the treatment of Alzheimer’s disease, chronic pain and, though it seems counterintuitive, drug addiction. Divinorum, SA, and their analogues decrease the pain induced by neuropathy and inflammation.
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).
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.
Overall, these findings are strikingly similar to those of classic psychedelics and dissociative anesthetics. Once the inhalation procedure was sufficiently understood, a flask containing 15 µg/kg of SA was affixed to the delivery device (see Supplementary Information for description of drug and delivery device including analysis of tube deposition in Fig. S1). The inhalation procedure was then conducted during which an experimenter carefully moved the flames around the bottom of the flask and visually inspected that all SA was vaporized. Participants were then prompted by researchers to verbally rate the strength of subjective drug effects on a scale of 0 (no effect) to 10 (extreme, strongest imaginable) at 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, and 45 min post-inhalation.
“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.
Although Salvia divinorum leaves were traditionally administered orally by the indigenous Mazatecs of Mexico for ritualistic purposes1, the plant is now recreationally administered via vaporization or combustion. When inhaled, SA can produce intense feelings of depersonalization and derealization accompanied by drastic perceptual changes, with effects beginning within a minute of inhalation and subsiding by 15 min2–4. Also like classic psychedelics16,17, other drugs with κ-opioid agonist activity such as ibogaine are being explored for their potential to treat addiction18,19, and SA, specifically, has shown efficacy in the treatment of preclinical models of cocaine abuse20. Unlike classic psychedelics, inhaled SA appears to be more incapacitating, causing unique alterations in interoception4, dense amnesia3, and more closely mimicking near-death experiences (similar to ketamine)21. One study reported SA experiences to be more similar to dreaming than experiences under other hallucinogens22 (cf. 23).
Divinorum, their metabolites, and semi-synthetic analogs in the last decade has shown their potential as an analgesic agent. Divinorum is normally ingested by chewing fresh leaves or drinking an infusion for treating GI disorders like abdominal swelling, diarrhea, and intestinal spasms, illnesses that course with chronic inflammation. During the last decade, different studies have focused on proving the effect of S. Often the quantity of salvinorin A in the leaves has been boosted by the addition of a concentrated extract of the compound. More than a dozen states have outright bans on the product, and eight others have restrictions such as prohibitions for minors. The U.S. Department of Justice’s Drug Enforcement Administration has included it in a list of “drugs and chemicals of concern,” but to date there is no federal prohibition against it.
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.
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.