Salvia: From Grandma Anna to Hannah Montana?
By Craig Schneider, MD. Dr. Schneider is Director of Integrative Medicine, Department of Family Medicine, Maine Medical Center, Portland, ME; he reports no financial relationship to this field of study.
Salvia is back in the news, but is well known to healer's through the ages. At least as far back as Pliny the Elder (23-79 C.E.), Salvia species have been purported to have memory-sparing effects. Salvia officinalis (common sage), Salvia lavandulaefolia (Spanish sage), and Salvia mittorrhiza (Danshen) all have been evaluated to some degree for dementias, although there are few well-designed clinical trials in humans. As with the majority of pharmaceutical approaches to managing Alzheimer's disease, salvia appears to inhibit acetylcholinesterase (AChE) and increase levels of acetylcholine in the brain. Constituents of salvia demonstrate this both in vitro (human brain) and in vivo (rats).1-3 "Rosmarinic acid, an active ingredient of common sage, also reduces several deleterious events induced by amyloid-β, including the formation of reactive oxygen species, lipid peroxidation, DNA fragmentation, caspase-3 activation and tau protein hyperphosphorylation."4
Thus far the only double-blind randomized controlled trial of salvia use for dementia was of S. officinalis in 2003, which was previously reviewed in Alternative Medicine Alert (May 2003). This study evaluated 30 Iranian subjects (aged 65-80 years) with mild-to-moderate Alzheimer's, randomized to trial intervention over 4 months. Their current dementia medications were discontinued and replaced with 60 drops per day of an extract of S. officinalis (1 kg dried leaf to 1 L of alcohol) or placebo. Cognitive function was measured at baseline and every two weeks by a neurologist. At 16 weeks, those who received S. officinalis had significantly better scores on Alzheimer's Disease Assessment Scale (ADAS-cog) and < 2 on the Clinical Dementia Rating (CDR) than subjects in the placebo group, (ADAS-cog: F = 4.77, d.f. = 1, P = 0.03) (CDR-SB: F = 10.84, d.f. = 1, P < 0.003). Side effects related to use of S. officinalis were related to cholinergic stimulation, primarily agitation (P = 0.09) as would be expected. The study was criticized for small numbers of participants, unclear exclusion criteria, and brief duration, etc.
So, why is salvia back in the news? The salvia that has stepped onto the stage of late is a different member of the genus, Salvia divinorum. S. divinorum or "divining sage" originated in Oaxaca, Mexico, where it has been used orally for hundreds of years by Shamans for healing and divination. Over the past decade S. divinorum has become a popular hallucinogenic with youth in America who smoke or inhale a vaporized version. It is widely available for sale on the Internet and in drug paraphernalia shops; as of 2006, about 1.8 million people had tried S. divinorum, with the heaviest use among males 18-25, 3% of whom had used S. divinorum in the previous year.5 Users report brief, intense hallucinogenic effects and more persistent effects as improved moods and insight.6
a.retrospective review of California Poison Control Centers revealed 37 calls involving S. divinorum exposures with gastrointestinal, cardiovascular, and neurologic complaints. There are several cases of extended psychotic reactions, but interpretation is complicated by concurrent drug use,7 or suspected genetic predisposition.8
Most recently S. divinorum swept into media consciousness as a video on YouTube revealed "tween" idol Miley Cyrus of Disney's Hannah Montana celebrating her 18th birthday smoking a bong filled with S. divinorum, resulting in "uncontrollable laughter" and "garbled speech."9 Its use has been banned or regulated in 15 states, and there are moves to ban it in more, but the Drug Enforcement Administration currently considers it a "drug of concern" not a controlled substance. Researchers have taken an interest in its potential medical uses and are concerned that "criminalization would make it burdensome to obtain and store the plant, and difficult to gain government permission for tests on human subjects."10 Apparently the herb's "presence on military ships and bases has even prompted the Armed Forces Institute of Pathology to develop the first urinalysis for salvia."10
a.ound the same time, an article in press reported on recent work at Johns Hopkins focusing on salvinorin A, a neoclerodane diterpene considered to be the most active component of S. divinorum.11 A kappa opioid receptor agonist in the brain, salvinorin A works differently than other common hallucinogens. The researchers wanted to study this drug due to its "wide availability, continued popular use, and legal controversy" as well as the belief that "studying the effects of salvinorin A may assist in identifying new opioid receptor modulators that may have therapeutic applications in certain psychiatric disorders (e.g., Alzheimer's disease, schizophrenia, bipolar disorder, cocaine abuse)."11
Four participants who previously had used a hallucinogen, but had no drug or alcohol dependence and no personal or family history of mental illness were included. Their mean age was 29 and they completed a medical exam prior to participation including a physical exam, ECG, CBC, CMP, and cholesterol profile. Subjects were given 16 doses of inhaled salvinorin A isolated from S. divinorum leaves and placebo inhalations across 20 sessions over 8-14 weeks. An unblinded staff member monitored the sessions but blinded staff collected drug-strength ratings and other pre- and post-session data. Subjects rested in easy chairs (semi-upright or reclined), listened to "a relaxing instrumental music track, and wore eyeshades 3-5 minutes prior to and for 10-30 minutes after administration of salvinorin A. They completed questionnaires and assessments 1 hour after administration of drug. Blood pressure, heart rate, and tremor were monitored during the sessions. No tremor nor significant impact on blood pressure and heart rate was observed. Time- and dose-related effects were observed, with peak drug strength occurring at 2 minutes and then progressively weakening over 20 minutes to near baseline.
In this recent high-profile but tiny human trial, in healthy participants with histories of hallucinogen use the authors report a safe physiological and psychological safe profile, with no adverse events. They were able to demonstrate that in a comfortable and supportive environment, salvinorin A elicited a "unique profile of subjective effects" that included "changes in spatial orientation, feelings of energy or pressure on different parts of the body, and unusual and sometimes recurring themes across sessions, such as revisiting childhood memories, cartoon-like imagery, and contact with entities."11 Unlike the online videos demonstrating "chaotic effects," these subjects remained behaviorally inactive.
Salvia, salvia, salvia. Salvia divinorum is a popular hallucinogenic drug among today's youth. Salvia officinalis has no hallucinogenic effects and might be helpful for people with mild-to-moderate dementia. We don't yet know if either will yield new approaches to dementia, but do know that people considering using salvia should become familiar with plant taxonomy.
References
1. Savelev SU, Okello EJ, Perry EK. Butyryl- and acetyl-cholinesterase inhibitory activities in essential oils of Salvia species and their constituents. Phytotherapy Research 2004;18:315-324.
2. Perry NS, Houghton PJ, Sampson J, et al. In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease. J Pharmacy Pharmacol 2001;53:1347-1356.
3. Perry NS, et al. Salvia lavandulaefolia essential oil inhibits cholinesterase in vivo. Phytomedicine 2002;9:48-51.
4. Iuvone T, De Filippis D, Esposito G, et al. The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity. J Pharmacol Exp Ther 2006;1143:1143-1149.
5. Substance Abuse and Mental Health Services Administration. The NSDUH Report: Use of Specific Hallucinogens. Rockville, MD; 2008.
6. Baggott ME, Erowid E, Erowid F, et al. Use patterns and self-reported effects of Salvia divinorum: An internet-based survey. Drug Alcohol Depend 2010;111: 250-256.
7. Singh S. Adolescent salvia substance abuse. Addiction 2007;102:823-824.
8. Przekop P, Lee T. Persistent psychosis associated with Salvia divinorum use. Am J Psychiatry 2009;166.
9. Detrick B. Salvia Takes a Starring Role. The New York Times 2010.
10. Sack K, McDonald B. Popularity of a Hallucinogen May Thwart its Medical Uses. The New York Times 2008.
11. Johnson MW, Maclean KA, Reissig CJ, et al. Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug Alcohol Depend 2010. In Press.
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