α- and β-pinene are the most widely found monoterpenoids, and can be found in EO of many plant species, such as conifers, e.g.,
Pinus sp. (pine), many
Salvia sp. (sage),
Rosmarinus officinalis (rosemary),
Helichrysium sp.,
Pistacia vera (pistachio), black plum, lesser galangal,
Cannabis sativa, etc. [
110,
111]. Nevertheless, only a limited number of clinical trials are available up to date on EO, which contains α- and β-pinene in considerable amounts and indicates these monoterpenes as active constituents. A very early clinical study with
α-pinene was conducted using a capsule preparation called Gelomyrtol forte (one capsule = 0.3 g myrtol, standardized to at least 20 mg of α-pinene, 75 mg of limonene, and 75 mg of 1,8-cineole) in patients with chronic pulmonary obstruction [
112]. The trial with a 7-day duration of therapy with 3 × 30 mg ambroxol (reference) or 4 × 1 capsule of gelomyrtol forte led to a marked amendment in mucociliar clearance. In a latter placebo-controlled, double-blind, and parallel-grouped clinical study including 676 male and female outpatients (aged > or = 18 years) with acute bronchitis undertaken by another research group [
113], the same preparation was revealed to be tolerated very well after two weeks of treatment. Furthermore, effect of preparation was found to be superior to those of cefuroxime and ambroxol, based on several ancillary parameters, so authors concluded that it could be a very effective option to treat acute bronchitis.
EO have shown to possess powerful insecticidal effects [
114]. However, only a small number of clinical studies referring to α- and β-pinene are available on this subject. For instance, the EO of
Eucalyptus globulus and
Cinnamomum zeylanicum, which contain α- and
β-pinene as the major components, were tested in a single-blind clinical study consisting of 95 cases infested with head louse (
Pediculus humanus capitis) as compared to permethrin as reference drug [
115]. The most effective one was found to be
E. globulus EO-containing shampoo (
p < 0.06), while
C. zeylanicum showed equal efficacy to that of permethrin (
p = 0.139). On the other hand, the difference was non-significant between
E. globulus-permethrin groups and
C. zeylanicum-permethrin groups (
p > 0.28). The data obtained revealed that
E. globulus in combination with permethrin or itself could be a beneficial solution for head lice.
Relatively more clinical studies have been found in scientific literature considering
α- and β-pinene-containing plants. In a very recent review, potential activity of EO was scrutinized against Alzheimer’s disease (AD) related to cholinergic hypothesis, amyloid hypothesis, oxidative stress, and other mechanisms searching well-known scientific databases including PubMed, ScienceDirect, Scopus, and Google Scholar from 1998 to 2018 [
116]. In that review,
Salvia species (sage) with over 900 species from all over the world, was examined to determine its effect on AD. As some
Salvia species are known to be used for memory enhancement in traditional medicine in Europe and some other countries, their EO, rich in α-and β-pinene, were tested in several clinical studies. The triggering point for those clinical studies was that several
Salvia species (Lamiaceae) have been found to inhibit cholinesterase (ChE) (acetylcholinesterase and butyrylcholinesterase) in vitro and in vivo—the key enzyme in AD pathogenesis. Perry et al. designed an open label clinical study including 11 patients aged 76–95 years diagnosed with mild -to-moderate AD [
117]. Patients received capsules containing 50 µL EO of
S. lavandulaefolia in sunflower oil. After 6 weeks use of this EO, a statistically significant decrease in neuropsychiatric symptoms and an enhancement in attention were recorded. In a similar clinical study, Tildesley et al. also tested the EO of
S. lavandulaefolia Vahl. (Spanish sage) given as capsulated in sunflower oil to healthy volunteers (24 adults, mean age: 23 years) in two groups in a placebo-controlled, double-blind, and crossover study [
118]. The first group consisted of 20 healthy adults (mean age: 20 years) who received the EO at doses of 50, 100, and 150 µL, while the second group included 24 healthy adults (mean age: 23 years) having EO at 25 and 50 µL. Data indicated that the EO of
S. lavandulaefolia was effective at 50 µL in both groups, which led to a marked improvement in mood and cognition. EO composition of this species consisted of α-pinene (6.5%), camphene (6.3%), β-pinene (5.4%), myrlene (1.9%), limonene (1.2%), 1,8-cineole (25.8%), and camphor (24.4%) as major terpenoids. Consistently, the plant has also been reported to contain 1,8-cineole and
α-pinene as main substances in other studies [
119], which were linked to the anti-Alzheimer activity of plant through inhibition of ChE enzymes activity, triggered by both synergistic or antagonistic interactions between camphor, 1,8-cineole, and α- and β-pinene [
120,
121,
122,
123,
124]. In particular, the EO of
S. officinalis and
S. lavandulaefolia have been noted to show high efficacy to inhibit these enzymes, leading to the conclusion that the high ChE inhibitory effect of these EO comes from synergistic and antagonistic interactions among the major monoterpenes (camphor, 1,8-cineole, borneol, α- and β-pinene) [
124]. Later,
S. lavandulaefolia EO was revealed to be significantly effective in a pilot open-label study consisting of patients with mild-to-moderate level of AD [
123]. However, it was found to be unsuccessful in another clinical study, which may due to several reasons, such as lack of standardization, etc. [
125].
On the other hand, the EO composition of
S. lavandulaefolia and
S. officinalis L. is known to be similar to some extent, except for their thujone content, while that of
S. officinalis usually possesses higher content of thujone, which is toxic [
126,
127,
128]. Accordingly, in a clinical study, the EO of
S. lavandulaefolia and
S. officinalis were comparatively investigated in a single-blind randomized controlled trial with healthy volunteers (135 healthy adults, mean age: 22 years) [
125]. The scores based on Bond–Lader mood scales and cognitive drug research system indicated that the group treated with EO of
S. officinalis displayed a better outcome for mood and memory performance, compared to the control group. Kennedy et al. also showed the positive action of
S. lavandulaefolia EO (50 mL) prepared in soft gel with olive oil in a double-blind, placebo-controlled clinical trial including 36 healthy adults with a mean age of 24 years. The results obtained pointed to the fact that
S. lavandulaefolia EO enhanced secondary memory performance along with attention, whereas it led to a decrease in mental fatigue and an increase in alertness, which were observed to be more obvious 4-h post-dose [
129].