Salvia study shows intense, novel effects in humans

Two participants (1 male, 1 female) provided the maximal rating of 10 at one or more time points during at least one session. Both male participants were unresponsive (scores imputed as 10) on at least one time point for at least one dose. Specifically, one was unresponsive at the 2-minute time point in the 15, 16.5, 18, and 21 μg/kg conditions and the 4-minute time point in the 21 μg/kg condition. The other male was unresponsive at the 2-minute time point in the 18 and 19.5 μg/kg conditions. “A lot of folks don’t know what to do with this,” says study coauthor Matthew W. Johnson, an experimental psychologist at Johns Hopkins University School of Medicine in Baltimore.

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Prior to inhalation and 15 and 30 min post-inhalation, experimenters tested participants for tremors (see Supplementary Information for description of assessment). Other than these ratings, participants were encouraged to refrain from moving or talking until 30 min post-inhalation, and an experimenter kept a hand on participants’ shin to remind them of this. After 30 min, participants could remove their eyeshades and discuss their experience. After 45 min, participants completed several computerized questionnaires (see Supplementary Information for descriptions) and left the laboratory.

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This coadministration induced an analgesic effect in two of the main behavioral responses of this test, licking and escape, involved in the spinal and supraspinal nociceptive process (Figure 1). Classification based only on within- or between-network connectomes was mostly above chance, discriminating the first half of SA from all other conditions (Fig. 4b). However, dFC was by far more accurate with most network interactions performing well.

Matthew W Johnson

There was also some evidence that SA decreased within- but increased between-network sFC, especially in the first 10 min of the scan, a particularly prominent pattern of effects observed with LSD25,35. These effects were much subtler in our study, perhaps due to the short time course of peak SA effects. Nevertheless, nearly all uncorrected significant effects and 75% of within- and 88% of between-network changes numerically followed this pattern. Furthermore, using an extremely conservative thresholding procedure that largely returned bilateral within-network connections, it was found that several of these static connections were attenuated under SA. Twelve healthy male participants (23–52 years) were recruited through advertisements and word-of-mouth referrals (see Table 1 for demographics).

Studies in monkeys show salvinorin A produces discriminative stimulus effects similar to other high efficacy kappa agonists (Butelman et al., 2004). 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). Nonhuman research with salvinorin A has shown mixed results regarding abuse potential.

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• 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.
• A recent hypothesis suggests that classic psychedelics make the brain more “entropic,” particularly among interactions involving the DMN40,41.
• SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects).
• M.K.D. collected data, analyzed data, produced figures, and wrote the manuscript.
• 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.

Given the wide availability, continued popular use, and legal controversy, information is needed regarding the human psychopharmacology of salvinorin A. This is a report of preliminary findings of basic physiological, behavioral and subjective effects of inhaled salvinorin A across a range of doses, from sub-threshold to high, delivered under comfortable and interpersonally supportive conditions to healthy participants who reported histories of hallucinogen use. Shamans of the Mazatec people of Oaxaca, Mexico have used Salvia divinorum, a member of the mint family, for at least centuries in ethnomedical practices including divination and spiritual healing (Valdes, 1994; Ott, 1995, 1996; Siebert, 1994).

• 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.
• 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.
• SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections.
• In addition, salvinorin A produced dose-related increases on most subscales of the Hallucinogen Rating Scale and on the Mysticism Scale.

After filtering through a sterilized, acetone-approved 0.2 μm filter (Millex-LG Filter Unit, Millipore Corporation, Billerica, MA), 1 ml of solution was placed into a 5 ml round bottom chemistry flask and allowed to evaporate, leaving the dose of salvinorin A as a residue on the interior surface of the flask. Before the session, the flask was attached to the bottom of a chemistry vacuum adapter by ground glass tapered joint and secured by a metal Keck clip. A vinyl tube (23 cm long, 6.35 mm inside diameter) was connected to the vacuum line of the adapter for inhalation.

Therefore, one interpretation of the current data is that SA minimizes drastic changes in connectivity while increasing the number of qualitatively distinct states. Using methods that specifically identify recurring and unique brain states may help support such an interpretation44,49. Given the small sample, connectome-based classification (e.g., similar to connectome-based predictive modeling50–52) was used to test the internal validity of the data. This technique identifies the connectivity measures (sFC, dFC, eFC) and network interactions most predictive of drug effects. To this end, a partial least squares (discriminant analysis) model was trained using a “leave-two-participant-out” cross-validation. At each iteration, a model was trained on 10 participants, and data from the remaining two participants in each condition (i.e., placebo first half, placebo second half, SA first half, SA second half) were classified as one of the four conditions.

Dynamic and entropic functional connectivity

Compared to the commonly used sliding-window approach, DCCs do not suffer from artifacts introduced by arbitrary windowing practices, and dFC produced from DCC is far more reliable49. 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 split-half reliability of all functional connectivity measures was good (see Supplementary Fig. S2). The inhalation procedure described above began approximately 45 s after the beginning of each functional scan. Recorded audio prompts for the inhalation were presented through the headphones, and after each inhalation, music played through the headphones for the remainder of the scan.

Figure 3.

The study showed that the drug has no physically adverse effects on otherwise healthy people. Smoking the herb, which is related to mint, has been chronicled in countless YouTube videos. Now, researchers at Johns Hopkins University Medical School say it could open the door to a whole new class of drugs that have powerful analgesic properties. Currently, there are about 600 semisynthetic SA analogues that involve the substitution at the C2 acetate group, only a change at C2, or a change to the furan ring. These structural modifications of SA increase its efficacy and duration of action (for a complete review, see Roach and Shenvi).49 Some of these analogues have been proved in acute, inflammatory, and neuropathic pain models (Table 1, Figure 2). When comparing saliva to other drugs, participants said they had an awareness of the external world with drugs such as LSD and psilocybin — or so-called “magic mushrooms.”

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S.L.H. analyzed data, produced figures, and contributed to writing the manuscript. F.S.B. designed and had primary oversight of the study, collected data, advised on analyses, and edited the manuscript. “Heroin, morphine, oxycontin, the traditional pain killers all hit the mu opioid,” said Johnson. “But salvinorin A selectively hits the kappa receptors and it hits them more cleanly than any drugs have before.” Johnson says that subjects in the study reported very different experiences from those caused by hallucinogens such as LSD and so-called “magic study of controversial hallucinogen salvia shows intense and novel effects in humans 12 07 2010 mushrooms.” Those drugs, he says, tend to have powerful effects, but the person is typically still aware of the external world and can interact with it. “It might be a longer-acting version of the drug and one without the strong psychedelic effects, just the analgesic effects,” he said.

One female participant completed the first SA dose but due to excessive movement and amnesia, was not continued. Participants must have had ≥ 10 lifetime hallucinogen uses (e.g., 5-HT2A psychedelic, NMDA dissociative, SA), 1 lifetime inhaled hallucinogen use (e.g., DMT, nitrous oxide, SA), 1 past year hallucinogen use, and 1 past year inhaled psychoactive drug use. Exclusion criteria included meeting DSM-V criteria for schizophrenia, psychotic disorder, bipolar I or II disorder, dissociative disorder, eating disorder, past two-year moderate or severe substance use disorder, or current major depression.

In addition, study staff interviewed the participant before and after each session to determine how s/he felt about continuing to participate. Blood pressure (systolic and diastolic using oscillometric method with the blood pressure cuff placed on the arm) and heart rate were monitored using a Non-Invasive Patient Monitor Model 507E (Criticare Systems, Waukesha, WI). Data were collected at baseline (for at least 5 minutes before drug administration) and every 2 minutes during the 60 minutes following drug administration. The participants, all of whom were healthy, showed no changes in heart rate or blood pressure.

In order to reduce costs, a multi-session, crossover design was not implemented, which would have minimized possible expectancy and order effects. Finally, to ensure that participants were able to tolerate drug effects in the scanner, we only enlisted experienced hallucinogen users. The final sample of volunteers who both inquired and qualified for this study consisted only of males, thereby limiting generalizability. Additionally, the impact of chronic or extensive hallucinogen use on brain function is not well-understood, and may further limit the generalizability of these findings to potential effects in the brains of those naïve to hallucinogen use. 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). Although it is unknown whether salvinorin A effects are bodyweight dependent, doses in this study were adjusted for participant bodyweight based on knowledge that some but not all psychoactive drug effects are bodyweight dependent.

Evidence suggestive of no or low abuse potential includes research showing salvinorin A to elevate thresholds for intracranial stimulation and decrease extracellular dopamine concentrations in the nucleus accumbens in rats (Carlezon et al., 2006), and produce conditioned place aversion in mice (Zhang et al., 2005). Evidence suggestive of abuse potential are recent findings demonstrating intracerebroventricular salvinorin A self-administration and conditioned place preference in mice at relatively low doses (Braida et al., 2008). Subject-rated drug strength peaked at 2 minutes (first time point) and then progressively decreased toward pre-inhalation levels. By 20 minutes after inhalation, mean ratings indicated only a “possible mild” effect (see Figure 1a).