Historical Context.

Botanical Description and Geographical Distribution of Salvia divinorum

Salvia divinorum is certainly the most unique and mysterious herb of the more than 1,000
species of Salvia that inhabit the world. The genus name Salvia is derived from the Latin
salvare, meaning “to heal” or “to save,” because of the medicinal properties of this species. S.
divinorum is a perennial and hydrophyte plant belonging to the mint family (Lamiaceae), and it
has a height about 1 and 1.5 meters. It has a square and hollow stem, with decumbent
secondary stems that enables the plant to reproduce vegetatively, and to regrow from
senescent stems. The velvety leaves are arranged in opposite pairs, and their shape is between
oval and lanceolate with dentate edges. The flowers have a slightly sigmoid hairy white corolla,
surrounded by a violet chalice with distinctive upper lips of three veins (see Figures 16.1a and
16.1b). Mexican biologist and botanist Arturo Gómez Pompa (1957) was the first to classify S.
divinorum as belonging to the Salvia genus, but no flowering material was available, so he
could not identify the plant further. The first flowering specimens of S. divinorum were
collected by Robert Gordon Wasson (1962) and Albert Hofmann. In the original identification
and description of the plant (Epling & Jativa-M, 1962), S. divinorum was classified within the
section Dusenostachys. Many years later, in a study using a molecular phylogenetic approach
by DNA sequencing (Jenks, Walker, & Kim, 2010), no evidence was found to include S.
divinorum in the Dusenostachys section or to consider it a hybrid. Epling and Jativa-M (1962)
also described the flowers with blue chalice and corolla, an error that persisted in the
literature including in Richard Evan Schultes’s Hallucinogenic Plants (1976), among others. The
official description was corrected by Aaron S. Reisfield in 1993. Although the exact origin of S.
divinorum remains a mystery, the results of the 2010 phylogenetic study suggest that Salvia
venulosa, a rare perennial plant native to a small region of the Colombian Andes, is the closest
relative of S. divinorum. The native distribution of S. divinorum seems to be limited to the
Mazatec Sierra, a mountainous area of tropical forests within the Sierra Madre Oriental of
Oaxaca, Mexico. S. divinorum prefers to grow near streams in extremely humid and semidark
areas. The first specimens of living and flowering S. divinorum that came out of Mexico were
collected at the Mazatec Sierra by psychiatrist and naturalist Sterling Bunnell, who introduced
them to the United States in 1962. Therefore, the most common variety of S. divinorum
commercially distributed around the world today is the “Bunnell strain,” not the “Wasson and
Hofmann strain,” which in fact does not exist: The specimens that they collected were dried
and pressed, remaining in Mexico (Siebert, 2003).

Ethnobotany of S. divinorum: Review of the Traditional and Nontraditional Uses.

In 1939, anthropologist Jean Basset Johnson discovered that the Mazatec used the juice of the
leaves of a plant called hierba de María for divination, in what constitutes the first academic
report on the existence of S. divinorum. Johnson also noted that the Mazatec employed
semillas de la Virgen (“seeds of the Virgin”) in their ceremonies, which were later identified as
seeds of the plant ololiuhqui, or “morning glory,” Turbina corymbosa. These seeds contain
ergine (LSA), an alkaloid similar in structure to lysergic acid diethylamide (LSD) (Hofmann &
Tscherter, 1960). The Mazatec people, who have been using S. divinorum for its medicinal and
psychoactive properties for hundreds of years, know the plant in their language as ska pastora
[sic]. As the Mazatec language is a tonal one, the word ska (meaning “herb” or “leaf”) has been
reproduced in the literature as it sounds. However, it seems that a more appropriate form of
writing herb in Mazatec, closest to the actual sound of the word, would be xkà (Maqueda,
2018). The Mazatec also refer to this plant with names in Spanish, such as hojas de la pastora
(“shepherdess’s leaves”). The names are related to the Virgin Mary, who they believe is
incarnated in the plant. The lack of an indigenous name and the fact that some Mazatec have
stated that the plant is foreign to their region (Wasson, 1962), suggest that S. divinorum could
be a postcolonial introduction, or that the original name in Mazatec could have been modified
by Christian influence (Ott, 1995). In 1945, anthropologist Blas Pablo Reko mentioned the use
by the Mazatec and the Cuicatec of a “divination leaf,” which probably was S. divinorum. In
1952, Robert J. Weitlaner reported the therapeutic and divinatory use among the Mazatec of
Jalapa de Díaz of a potion made by rubbing in water between 50 and 100 leaves of hierba de
María, the highest dose being used for alcohol addicts. In addition to curing, Weitlaner (1952)
observed that the leaves were employed to guess where an animal or person had been lost, or
who had committed a robbery. For ceremonies, the leaves of S. divinorum are well chewed
and swallowed, or the mixture of crushed leaves with water is drunk for a softer effect. Before
and after the ritual, both healer and patient must refrain from eating certain foods, drinking
alcohol and cold beverages, and from having sex for a period ranging from several days to
several weeks. The ceremonies last for about 5 hours and take place in front of an altar at
night in complete darkness. The effects are felt after 20 minutes and last for about an hour,
but more leaves could be consumed if the healer consider it needed. After the ceremony, the
healer prepares an amulet of plant leaves for the patient in order to complete the ritual. Since
the 1960s, the spread of S. divinorum worldwide has led to the development of new methods
to consume the leaves. These new forms of administration include (1) the sublingual route
using tinctures, which provides the most similar experience to that of the traditional method;
(2) vaporization of the dried leaves; (3) vaporization of dry leaves potentiated with the active
principle, salvinorin A; and (4) vaporization of concentrated extracts. The latter two methods
are the most effective way of attaining strong psychedelic effects. The labeling of the
concentrated extracts, which are commercialized online or in smart shops, roughly indicates
the potency of the products, ranging from the lowest (“3×,” “5×”), to the highest potencies
(“50×,” “100×”). Some researchers who have analyzed these products have found a high
variability in the concentration of the active principle (Wolowich, Perkins, & Cienki, 2006).
Baggott, Erowid, and Erowid (2004) carried out the first survey to know the patterns of use of
S. divinorum. Most participants were male (93%) from the United States (77.4%), and the
average age was 23.4 years old. The researchers found that of the 500 respondents, 61.4% of
them vaporized concentrated extracts, and 37.3% vaporized dried leaf. Commonly expressed
reasons for S. divinorum use were to explore consciousness (86.2%), to satisfy curiosity
(76.6%), to have a spiritual experience (74.0%), to pursue personal growth/self-understanding
(69.2%), and for contemplation/ meditation (52.0%). The survey showed that most users
regarded the S. divinorum experience as very different from cannabis and classical
hallucinogens, and from most other inebriants, reporting it to be unique and intense. The main
effects that lingered after the consumption were increased insight, improved mood, calmness,
increased connection with the Universe or Nature, or weird thoughts, among others. The
researchers did not find persistent adverse effects.
Bioactive Compounds Present in S. divinorum

Salvinorin A: Chemical Structure and Biological Targets.

S. divinorum owes its psychoactive properties to its active ingredient, the diterpene salvinorin
A (SA). SA was isolated and identified for the first time in 1982 in Mexico by Alfredo Ortega and
his group, and shortly thereafter by Valdés and collaborators (Ortega, Blount, & Manchand,
1982; Valdés, Butler, Hatfield, Paul, & Koreeda, 1984). Daniel Siebert (1994) was the first
researcher to study SA in humans. SA is very lipophilic, so it is easily soluble in organic solvents
such as acetone, acetonitrile, chloroform, and methanol, but it is practically insoluble in water.
Thanks to receptor binding studies, it has been possible to determine that SA has a highly and
selective affinity for the k opioid receptor (KOR), exerting an agonist action at this receptor
(Roth et al., 2002). The involvement of KORs in the effects of SA in humans has been recently
confirmed (Maqueda et al., 2016). On the other hand, it differs from other compounds capable
of modifying perception, the so-called “classic” hallucinogens, such as psilocybin (a
psychoactive component in many species of fungi) or LSD. The latter are alkaloids (nitrogen
compounds) and have affinity for serotonin 5-HT1A and 5-HT2A receptors. The endogenous
agonist of KOR is a family of peptides known as dynorphins, widely distributed throughout the
central and peripheral nervous system. The KOR/dynorphin system is found in the spinal cord,
in neurons that transmit nociceptive signals, and in the cerebellum. It is also present in the
prefrontal and insular cortex, and in various subcortical areas. Thus, this system participates in
the regulation of physiological functions essential for life, such as breathing, wakefulness, and
cardiovascular functions. It also regulates neuroendocrine functions among which are the
modulation of pain/ analgesia, and acute and chronic stress. The KOR/dynorphin system also
modulates high cognitive functions such as perception, cognition, behavior, and memory.
There is a high density of KORs in brain circuits involved in the control of motivation, anxiety,
and the hedonic and aversive responses mediated by the reward system to natural and
chemical stimuli. KORs also modulate mood by means of projections to limbic areas, although
they have received much less attention than the monoamine systems, with which they interact
directly. In the case of drugs of abuse, the activation of the m opioid receptor
(MOR)/endorphins system induces euphoria in humans and produces reinforcement in
animals, by increasing the release of the neurotransmitter dopamine (DA). On the contrary,
the activation of the KOR/dynorphin system by endogenous or exogenous agonists produces
dysphoria in humans and aversion in animals, antagonizing the actions mediated by the
activation of MORs, by reducing the release of DA in structures innervated by the mesolimbic
pathway. In this manner, the KOR/dynorphins system exerts a direct and complementary
modulation on the reward system. In the specific case of SA, this compound regulates DA
neurotransmission by two different mechanisms: (1) inhibiting its release in the dorsal striatum
(Gehrke, Chefer, & Shippenberg, 2008), and in the nucleus accumbens (Carlezon et al., 2006)
and (2) up-regulating the expression of its transporter. The final result of this second
mechanism is an increase in the reuptake of the neurotransmitter (Kivell, Ewald, & Prisinzano,
2014). Despite the great relevance and potential clinical application that k-agonists would have
in view of the previous discussion, these compounds have undesired side effects that have
greatly restricted their clinical use. However, there are important differences between the
actions of synthetic k-agonists and SA, and it has been found that SA has effects on behavior
other than those caused by synthetic k-agonists (Wang et al., 2005). Additionally, the dose of
SA plays a key role in the final profile of effects: While at high doses (3.2 mg/kg) it triggers
some of the adverse effects of traditional k-agonists, at lower doses no such effects are
observed. Specifically, the anti-addiction, antireward, antidepressant, and anxiolytic effects of
SA are observed at moderate doses, and when it is administered acutely and not chronically
(Braida, Capurro, & Zani, 2009). The activation of KORs transmits not only inhibitory signals but
also excitatory ones, modulating the release of several neurotransmitters. SA facilitates the
exocytosis of noradrenaline, and inhibits the release of serotonin (Grilli et al., 2009). It also acts
as an allosteric modulator of MORs, and the similarity between the receptor binding profiles of
SA and ketamine (KOR and Nmethyl-d-aspartate [NMDA], respectively), could imply that SA
has some interaction with glutamate (Rothman et al., 2007). It has been described an indirect
action of SA on cannabinoid receptors, specifically on CB1 (Braida et al., 2007). An in vitro
experiment suggested that SA binds to DA D2 receptor with high affinity (Seeman, Guan, &
Hirbec, 2009). About the brain targets of SA, different studies in animals have shown that the
compound is distributed throughout the brain in areas with a high KORs density, among them,
in the cerebellum, involved in the integration of sensory perception and motor control, and in
the visual cortex, probably due to the hallucinogenic properties of SA. Other SA targets are
regions involved in the modulation of pain, in the regulation of the response to stress and
anxiety, in visual perception, in addiction and motivation, in proprioception, in areas involved
in mood and motivated behaviors, in emotional processes, and in areas responsible for
cognition, executive functions, and the perception of the self (Chartoff et al., 2008; Hooker et
al., 2008; Hooker, Patel, Kothari, & Schiffer, 2009). Some regions with very few KORs also
showed activation, so it cannot be ruled out that SA may also exert its actions through the
activation of one or more molecular targets not yet discovered. Another brain target of SA is
the insular cortex (Coffeen et al., 2018), which is densely populated by KORs and believed
perhaps to be involved in consciousness. It has an important role in cognitive processes and is
involved in emotional processes such as compassion and empathy, and interpersonal
experience. In particular, the insula modulates interoception, that is, body awareness: the
perception of what happens in our bodies and the sensation of owning a body. The subjective
effects observed in human studies may reflect this influence of SA in the insula, since high
doses of the compound modify body awareness powerfully or directly suppress it. In contrast,
low and medium doses of SA led to acute increases in body awareness and body-listening skills
(Maqueda et al., 2015). Stiefel, Merrifield, and Holcombe (2014) have suggested that the
disruption in consciousness observed in humans taking high doses of SA may be due to an
inhibition of the role of the claustrum as a conductor of consciousness. In laboratory animals,
no changes in heart rate, body temperature, or the galvanic skin response have been observed
after chronic administration of SA at high doses. Analyses of the organs did not reveal
histological changes. The data from this study suggest that the toxicity of SA is very low, even
at doses much higher than those that a human could ever consume (Mowry, Mosher, & Briner,
2003). The neoclerodane nucleus of SA provides an excellent structural template from which
to synthesize structural derivatives and analogues. To date, there are more than 600
compounds analogous to SA (for a review, see Roach & Shenvi, 2018).

Other Terpenes Present in S. divinorum.

The initial phytochemical investigation of S. divinorum identified SA and salvinorin B (SB). In

the subsequent work carried out by several different groups of researchers (see the review of
Casselman, Nock, Wohlmuth, Weatherby, & Heinrich, 2014), other diterpenes were isolated,
such as salvinorins C–J, salvidivins A–D, divinatorins A–F, and salvinicins A and B, whose role in
the pharmacological effects is not yet elucidated. The leaves of S. divinorum also contain
loliolide (a potent ant-repellent), and hardwickiic acid and (E)-phytol, both with antimicrobial
and antibacterial properties (Staphylococcus aureus and Candida albicans), and nepetoidin B,
with antifungal properties.
Pharmacological Effects in Humans.

Subjective Effects.

The available literature indicates two effective administration routes: through the oral
mucosa, and through inhalation. There are marked differences between these two methods
regarding the subjective effects and the final experience attained. Through oral consumption,
the leaves of S. divinorum must be well chewed and retained in contact with the inner part of
the mouth and with the gums for at least 10 minutes to effectively obtain the effects. If the
plant material is ingested, the active principle is rapidly degraded in the gut. It has been
reported little or no effects on the first attempts consuming the leaves, which could be
explained due to personal sensitivity or to genetic differences in KOR distribution. However, it
seems that on consecutive attempts, there is an increased awareness of the plant’s effects,
followed by a gradual inversed tolerance if the leaves are consumed frequently. Buccal
consumption of S. divinorum provides a gradual onset of the experience (starting at 10
minutes) and it has a duration of about an hour. The subjective effects can be interrupted by
sounds or touch. Some of them include sensations of floating and of movement; changes in
temperature and dysphoric effects; the feeling that one is becoming a plant; amplified sound
perception; dream-like states; organic visions of animals and the forest, and inorganic visions
of ornamented buildings or machinery; contact with entities that speak and interact with
oneself; increased understanding of personal problems or insights about the nature of reality;
and sensations of calm and relax (Aardvark, 2002; Bücheler, Gleiter, Schwoerer, & Gaertner,
2005; Díaz, 2013; Siebert, 1994; Valdés, Díaz, & Paul, 1983; Valdés, Hatfield, Koreeda, & Paul,
1987). Interestingly, it has been found that the sublingual route is not effective for pure SA at
doses of up to 4.0 milligrams (Mendelson et al., 2011). This suggests that oral absorption
requires a larger surface area, such as that offered by the inside of the cheek, or that there are
other compounds present in the leaf that help with the absorption of SA. Through inhalation of
the vapors of pure SA or concentrated extracts, the peak effects are attained very fast, in less
than a minute, and last 15–20 minutes (Addy, 2012). The subjective effects of pure SA are
blocked by prior administration of the k-antagonist naltrexone (Maqueda et al., 2016). Taking
into account individual sensitivity to the substance, this could elicit more robust or weaker
effects; with a low dose of 0.25 mg of pure SA, the subjective effects include increased
connection with the body, relaxation, calm, closed-eye visions, and changes in bodily
sensations. With a medium dose (0.50 mg), there is an increased interoceptive awareness,
closed-eye visual imagery including carnival or fantasy scenes and kaleidoscopic or fractal
visions, and somatic-dysphoric effects. Some of the somatic effects consist of changes in
temperature and tingling; sensations of being pulled or twisted by forces; sensations of being
glued to a side of reality while trying to join another reality with the other half of the body; and
visual-proprioceptive synesthesia that consists of merging with the objects present in the
surroundings or in the mind. This special type of synesthesia is very rare compared with other
psychedelics, and the perception of auditory phenomena is another peculiar feature of SA. It is
interesting to note that the somatic effects are usually felt starting from the left side of the
body, or they seem to come from a particular side of reality, affecting the body, then passing
through it like a wave; this lateralization of the effects is another unique characteristic of SA
inebriation (Maqueda et al., 2015). And with a high dose (1 mg), depersonalization,
dissociation, and out-ofbody experiences are much more common and a typical hallmark of
high doses of SA. Volunteers report a profound immersion in the experience, not being able to
stay present on consensus reality, which usually folds and creases at the beginning of the
experience. Subjects describe their bodies as being pushed by forces or by entities, as being
twisted, folded, or unzipped while passing through narrow conducts, before being thrown to
other dimensions, where they no longer have a physical body. On those other dimensions,
they describe the sensation of being pure mind, pure consciousness or energy. Once the
experience has ended, as abruptly as it started, some volunteers report vague memories of the
trip other than it being extremely weird, scary or difficult to explain scenarios that seemed to
be repeated endlessly, and that it did not obey the laws of physics to which we are typically
accustomed. On the other hand, other subjects can detail having visited remote and wondrous
universes and having spoken with entities and achieved new and valuable personal or
philosophical insights, all wrapped in a dream-like sensation. Volunteers universally affirm that
SA experience is unique, intense, and difficult to compare with other psychedelics. The first
human to experiment with pure SA, the pioneer researcher Daniel Siebert, vaporized for the
first time 2.6 mg of the compound and related his experience as “tearing apart the fabric of
reality”: Then quite suddenly I found myself in a confused, fast moving state of consciousness
with absolutely no idea where my body or for that matter my universe had gone. . . . Suddenly
I realized that I had no memory of ever having lived in another state of consciousness, but in
the disembodied condition in which I was at that moment. In this state, all points of time in my
personal history coexisted. None preceded the next. (in Turner, 1996) In his classical study with
volunteers, Siebert (1994) reported other SA themes: (1) uncontrollable hysterical laughter; (2)
visions of various two-dimensional surfaces, films and membranes; (3) revisiting places of the
past, especially childhood; and (4) overlapping realities, the perception that one is in several
locations at once.

Pharmacokinetics.

After being vaporized, SA is transported through the blood–brain barrier with relative ease
and accumulates in the central nervous system (CNS). The compound is metabolized at the
intestinal and hepatic levels and excreted by the kidneys. The original product is hydrolyzed,
which results in the formation of SB, which would be the main inactive metabolite of SA. That
SA is rapidly metabolized is supported by the finding that only approximately 0.8% of a 0.5-mg
dose of the compound was extracted from urine in human volunteers (Pichini et al., 2005). SA
metabolism seems to depend on gender, being slower for females than for males, which may
be the reason why females experience less dysphoric effects with KOR agonists (Russell et al.,
2014). The perceived intensity of the subjective effects is correlated with the plasmatic
concentration of the compound (Johnson, MacLean, Caspers, Prisinzano, & Griffiths, 2016;
Johnson, MacLean, Reissig, Prisinzano, & Griffiths, 2011; Maqueda et al., 2016).

Cardiovascular and Autonomic Effects

In the study of Maqueda and collaborators (2016), at the 1-mg dose, SA elicited a short-lived
increase in systolic blood pressure. No other significant effects have been found in
cardiovascular measures in other human studies. However, the differences between the
studies, such as the number of participants (Johnson et al., 2011, 2016; MacLean, Johnson,
Reissig, Prisinzano, & Griffiths, 2013), the time between measurements (Addy, 2012), and the
differences in the method of vaporization employed (Ranganathan et al., 2012), could imply
different absorption and levels of the compound in plasma.
Neuroendocrine Effects.

KORs regulate hormonal processes. There are sex differences in terms of distribution and KOR
levels. SA increased plasma concentrations of prolactin and cortisol 5 minutes after inhalation,
peaked at minute 15, and gradually decreased after 90 minutes (Johnson et al., 2016;
Maqueda et al., 2016). However, these studies showed variations in individual measures,
which could be explained due to the different responses of men and women to SA. Some
participants did not show any cortisol response at all (Johnson et al., 2016).

Psychophysiology.

Ranganathan and colleagues (2012) performed an electroencephalographic (EEG) analysis of

the eight volunteers of their study. They found that inhalation of SA decreased b frequency in
both high doses (8 and 12 mg), and q frequency also showed a decrease with a tendency
toward statistical significance. These results of very high doses of SA would be indicative of a
reduction in the waking state, similar to deep sleep or a state of sedation. In our laboratory
(Valle et al., 2016) we also measured EEG before and after the vaporization of 1 mg of SA. The
results showed that SA suppressed a rhythm and markedly increased slow d activity. Less
prominent effects included increases in q and low g bands. While SA shares with serotonergic
psychedelics the a-suppressing action, its main neurophysiological signature is an atypical
enhancement of slow d activity, associated with non-rapid eye movement (NREM) sleep.

Adverse Reactions.

In regard to laboratory studies, the literature shows that inhaled doses of up to 12 mg of pure
SA are safe in terms of physiological measures. Of the 112 subjects in total, summing all the
participants of the controlled studies performed until today, carried out in six laboratories in
six different countries, no adverse reactions have been found in volunteers. In the case of the
recreational use of potentiated extracts of S. divinorum, several published anecdotal reports
suggest that SA could occasionally produce psychotic symptoms that required treatment by
emergency care personnel. In one of these reports, the patient reported that the psychotic
symptoms began after smoking a cannabis cigarette, to which material from a S. divinorum
extract had been added without her knowledge (Paulzen & Gründer, 2008). However, relative
to subjects of the reports, their prior psychiatric status, their personal and family background,
or whether there was concomitant use of other drugs were not reported. In general, the side
effects induced by the vaporization of S. divinorum, if produced, do not elicit excessive
discomfort. These somatic–dysphoric effects include subjective changes in body temperature,
sensations of electricity and tingling in the body, heaviness of head, and tiredness, which are
transient and similar to those of classic hallucinogens. Respecting harm reduction, it is very
important to have an attentive and sober sitter to maintain safety of the user during the trip,
and to start with low doses, until the individual’s personal sensitivity to the compound is
known. The intensity of the experience can be overwhelming, and the person may lose touch
with reality. The effects of S. divinorum are exceptionally sensitive to context. Because of the
particular synesthesia with the material world that this compound may induce, to be in a
pleasing and comfortable context is recommended. A recent survey on wise-salvia users who
smoked extracts remarked on the existing synergy between the substance, the context, and
the sitter or guide (Hutton, Kivell, & Boyle, 2016). The respondents of the survey preferred to
be at home or in isolated outdoor settings and accompanied by friends. The management of
these considerations help in tackling unhelpful stigma surrounding this plant. In the case of
buccal consumption of S. divinorum, users have 10 minutes before feeling any effects, which
allows a progressive adaptation to them. In fact, the effects have a very subtle onset, so they
may even be missed if the user is distracted, or in a noisy or too luminous environment.

Other Short- and Long-Term Psychological Effects.

At the present moment there are no studies on the effects of long-term consumption of S.
divinorum. One reason may be the low number of users who employ the plant repeatedly.
Several surveys have revealed that nontraditional use of S. divinorum is sporadic due to
unrewarding effects for the typical recreational consumption, and because many users find the
effects too intense or unpleasant (Baggott, Erowid, Erowid, Galloway, & Mendelson, 2010). In a
retrospective survey of recurrent recreational users of the plant, 13 respondents claimed to
have gained a greater connection with others, and to have increased creativity and connection
with nature, as well as a greater understanding about the nature of reality (Nygård, 2007).
MacLean and his group (2013) carried out a 1-month follow-up of their study, finding no
evidence of lasting negative effects such as depression, anxiety, psychiatric symptoms, or
visual disturbances. Four of the eight participants reported specific positive changes that they
attributed to the experiences on the day of the session, including greater self-confidence, a
feeling of greater physical comfort and calmness, less emotional reactivity, improvements in
interpersonal relationships, and renewed interest in daily responsibilities. There is a report of a
young man who chewed or smoked dry leaves of the plant twice a week for 6 months, without
reporting any detrimental effects on his health or social or academic life (Bücheler et al., 2005).
The Mazatec have been consuming the leaves of S. divinorum for centuries. For them, this
herb is a key piece of their culture and a sacred medicine that can be consumed for extended
periods without any harmful effects on their mental or physical health. In fact, S. divinorum is
the initiation plant or training herb for the future healer because it is considered the plant that
is easiest to handle, with the least psychoactive power, followed by morning glory seeds, and
finally, by the management of hallucinogenic mushrooms.

Therapeutic Potential of S. divinorum and SA.

Neither S. divinorum nor its active constituent has yet been approved for medical use in the
United States. Currently, S. divinorum is controlled in 22 U.S. states and listed as a “drug of
concern” by the U.S. Drug Enforcement Administration (2017). As reviewed in this chapter, S.
divinorum is a nontoxic, non-addictive plant with multiple medicinal applications. There is no
scientific justification based on research or on any public health concern to maintain this
herb’s criminalized status. Instead, a smarter approach is to keep S. divinorum legal while
establishing age-control restrictions and other regulations. Outright prohibition of S. divinorum
deters scientists from studying its medical benefits, and replaces a legal market that can be
strictly and sensibly be regulated with an underground economy. Still, S. divinorum is legally
and commercially available in many states and countries, so it could be possible to have a safe
medicine and a Master Plant at home. Cuttings are relatively easy to cultivate, and dry leaves,
tinctures, and concentrated extracts can be bought online.
Therapeutic Potential of S. divinorum.

As with many psychoactive plants, there is scarce research about the mental and behavioral
effects of S. divinorum, but there are much more detailed data about its active principle.
Fortunately, we have the centenary knowledge of the Mazatec to guide us in the use of this
wonderful herb. I have created a nonprofit, the Center for Research and Ethnobotanical
Conservation of Salvia divinorum (xkapastora.org), to compile and divulge the traditional uses
of Salvia of the Mazatec. From articles published by the researchers who visited the Mazatec
Sierra and participated in ceremonies with S. divinorum, we know that the Mazatec use the
plant as a treatment for arthritis and inflammation, headaches, gastrointestinal problems,
elimination dysfunctions, and as general relief or tonic for the sick, anemic, or the dying.
During my own fieldwork conducted with the Mazatec (Maqueda, 2018), I learned that the
leaves of S. divinorum are applied in poultices to treat insect bites, eczema, fungi, candidiasis
and other vaginal diseases, and that the leaves are eaten to treat cystitis, menstrual cramps,
bronchitis, and fever. For the treatment of pain, back contractions, water retention, and
inflammation, the juice of 40 leaves or more is drunk right before going to sleep. The users
that I interviewed reported vivid dreams, and a significant and lasting remission of the
symptoms. For the treatment of addictions, the early literature has reported on use of the
leaves for the treatment of alcoholics. I lived with a traditional healer and his family, whose
older son had been addicted to inhalants and cocaine. The father treated his son successfully
using S. divinorum in ceremonies, as well as with the administration of fresh leaves on
alternate days for 1 month (Addy & Maqueda, 2015). I know, too, that S. divinorum is
employed for treating symptoms of low mood, by eating a small pair of fresh leaves in the
morning until the symptoms disappear. Hanes (2001) presented the clinical case of a 26-year-
old woman with treatment-resistant depression, who showed improvement after taking
subpsychoactive oral doses of S. divinorum. The patient chewed and kept in her mouth from
0.5 to 0.75 g of dried leaf for 15–30 minutes, two or three times a week, and also claimed to
benefit from occasional psychoactive doses consisting of 2–4 g of leaves. Dr. Hanes reported
on the total remission of depressive symptoms of the patient in the last 6 months, as well as a
considerable improvement in self-esteem and psychospiritual development. Later, Hanes
(2003) published a follow-up report on six additional patients who achieved a complete
remission of the symptoms of treatment-resistant depression using the leaves. A growing body
of research indicates that the endogenous opioid system is directly involved in the regulation
of mood and is dysregulated in mayor depressive disorder. This involvement of the
endogenous opioid system may underlie the disproportionate use of opioids among patients
with mood disorders. The use of the leaves of S. divinorum for mood disorders could provide
safe and nonaddictive treatment, instead of the highly addictive opioid medicines massively
prescribed today. This would help to alleviate the opioid crisis that the United States is
currently facing. S. divinorum produces a state of increased self-awareness. For this reason,
some psychotherapists use it in tincture form as an adjuvant to psychotherapy, and some
people use it as an aid to meditation, contemplation, and spiritual reflection (Soutar &
Strassman, 2000). Future research could explore the profile of effects in humans and the
potential of S. divinorum for psychotherapy. In animal research, only one study has explored
the administration of a hydroponic extract of S. divinorum (Simón-Arceo et al., 2017). The
authors found that the extract significantly reduced nociceptive and inflammatory processes.
Therapeutic Potential of SA.

The medicinal applications of the Mazatec using the leaves of S. divinorum are well supported
by recent pharmacological findings with SA. 1. Medications for addictions. As previously
mentioned, k-agonists modulate dopaminergic activity. These compounds have been shown to
decrease opioid withdrawal in both animals and humans, to decrease cocaine-, amphetamine-,
and heroin-induced DA release, to decrease many behavioral effects of nicotine, and to
attenuate self-administration of cocaine, morphine, and heroin, all of which supports the role
of k-agonists as pharmacotherapeutics for treating addictions (Morani, Kivell, Prisinzano, &
Schenk, 2009). The compound SA has been shown to inhibit the hyperlocomotive activity, the
rewarding effects, the reestablishment of self-administration, and the altered expression of
genes induced by cocaine. The reduced profile of side effects compared to k-agonists makes SA
a compound of high therapeutic promise in treating drug abuse (Dos Santos, Crippa, Machado-
de-Sousa, & Hallak, 2014). Regarding the low addictive potential of S. divinorum,
demonstrated by animal research (Serra et al., 2015), we have seen that the stimulation of
KORs causes dysphoria, the opposite effect of the euphoria that entails the typical drug of
abuse. As described earlier, dysphoria implies a detachment of one’s own bodily sensations, an
annoying or unpleasant sensation, that lies at the opposite pole of a pleasant sensation or one
with addictive potential. 2. Antidepressants. Animal studies have demonstrated the
antidepressant properties of SA (Braida et al., 2009), and it has been proposed as a candidate
for the treatment of major depressive disorder (Taylor & Manzella, 2016). 3. Medications for
perceptive and cognitive disorders. Due to its acute action on KORs, compounds derived from
SA could offer new treatments for disorders that manifest alterations in perception and
cognitive dysfunctions, such as schizophrenia, bipolar disorder, and Alzheimer’s disease
(Butelman & Kreek, 2015). 4. Safe and nonaddictive analgesics. Some of the analgesics
employed in the current medical practice produce dependence (e.g., morphine). To find an
opioid-strength analgesic devoid of side effects, especially addiction, has eluded pain
researchers. Research supports the use of SA as a therapeutic alternative for the relief of
chronic pain without addictive properties (Guida et al., 2012). 5. Anti-inflammatories. SA has
ultrapotent effects on macrophages via KORs (Aviello et al., 2011), and it exerts an important
attenuation of inflammation and intestinal motility in irritable bowel syndrome (Capasso et al.,
2008). SA also inhibits the inflammatory response mediated by leukotrienes, which are crucial
in various autoimmune and inflammatory conditions such as bronchial asthma, allergic rhinitis,
urticaria, and cardiovascular problems (Rossi et al., 2016). 6. Medications to treat different
types of cancer. When there are tumors in the brain, one of the difficulties of therapeutics is to
get the drugs through the blood–brain barrier and reach the tumor. The terpene SA is able to
cross the blood–brain barrier and reach the brain and structures of the CNS in less than a
minute. SA analogues have demonstrated antiproliferative properties that inhibit the growth
of 77–86% of tumors in the MCF7 breast cancer cell line (Vasiljevik, Groer, Lehner, Navarro, &
Prisinzano, 2014). 7. Assisting psychotherapy. SA has several properties that would make it
effective as an adjunct to psychotherapy. In low doses, it helps to increase body awareness and
awareness of the interconnectedness of the body, emotions, and mental states. It also
produces a state of deep introspection, facilitates the recall of biographical episodes, and
offers access to areas of the psyche that are not easily attainable ordinarily. I have received
several personal communications from psychotherapists and patients about the extraordinary
potential of vaporizing low doses of SA for psychological healing. Other promising medications
are neuroprotectors for acute brain pathologies (Sun et al., 2018), and short-term anesthetics
that do not depress breathing (McCurdy, Sufka, Smith, Warnick, & Nieto, 2006).