What terpenes are in Silexan?
Silexan is a patented active substance produced from Lavandula angustifolia flowers by steam distillation consisting of the main active constituents. linalool (36.8%) and linalyl acetate (34.2%). Silexan (active substance of Lasea®, has been available in Germany since 2009 for the treatment of anxiety and tension.  Schuwald and coauthors concluded that Silexan targets voltage gated calcium channels. [1`]
Voltage gated calcium channels introduction
This manuscript concluded that Silexan is targeting voltage gated Ca2+ channels. Pregabalin is also known as Lyrica. In simple terms, these channels allow Ca2+ to pass from the outside of the cell to the inside of the cell when the potential difference (voltage) from the inside to the outside of the cell becomes less inside negative. The L-type, found in muscle, are of less interest as targets for insomnia, analgesia, and stress relief.
1. Sleeping, rodent anxiety, and pharmaceuticals
While pregabalin is a amino butyric acid derivative, it does not bind to the GABAA or GABAB receptors. pregabalin selectively binds to alpha2delta (A2D) subunits of presynaptic voltage-dependent calcium channels (VDCCs) located in the central nervous system (CNS). Binding of pregabalin to VDCC A2D subunits prevents calcium influx and the subsequent calcium-dependent release of various neurotransmitters, Diazepam is a positive allosteric modulator of GABAA. In other words, it increases the GABA induced opening of GABAA channels by GABA without being an agonist itself. Phenobarbitol, on the other hand, is a direct agonist of GABAA.
2. Dose response in rat cellebellar synaptosomes
Synaptosomes are synaptic junctions between neurons that break away when the brain is being homogenized under control conditions. These vesicles can be loaded with the calcium sensing fluorescent dye Fura-2. They can also be depolarized using high external potassium chloride, KCl.
A. Silexan at a dose of about 10-7 g/mL seems to max out in preventing the KCl depolarization Ca2+ channel opening. This is equivalent to 10-4 g/liter. Linalool has a molecualr mass of 154g/mole. This is 6.5 x 10-7 M or 650 nM if Silexan were 100% linalool. Pregabalin doesn’t seem to be that impressive. C. While the concentrations are not exactly the same, Silexan works, perhaps better than pregabalin. D. Linalool also inhibits the KCl Ca2+ response in the synaptosomes, but not as much as straight Silexan. E. Ditto for linalool acetate. F. Related compounds do not work.
3. Just as good as Pregabalin in hippocampus neurons
This particular experiment used isolated neurons from rat hippocampus. The membrane potential was dropped with the use of high KCl on the outside of the cell. 
4. Which voltage gated Ca2+ channel?
Pertussis toxin, produced by the bacterium that causes whooping cough, inhibits Gαi subunits from inhibiting guanylyl cyclase. Agonists of the Cannabinoid 1 receptor, CB1, result in activation of Gαi and inhibition of cAMP production. AEA, aka anandamide, is a CB1 agonist. A. A dose response curve for gabapentin. B Silexan does nothing to get radioactive gabapentin off its receptor. C. In primary hippocampal neurons AEA inhibits Ca2+ current too, but this inhibition is reversed by adding pertussis toxin (PTX). PTX does nothing to reverse Silexan inhibition. Silexan is probably not operating through CB1 or a related G protein coupled receptor. Part of this came from a study showing that CB1 agonists inhibit N and P/Q type calcium channels in a manner that is dependent on cAMP and presumably protein kinase A. (PKA) That Silexan does not act via cAMP pathways could be exciting news for Cannabis in search of a THC/terpene entourage effect.
ω-agatoxin IVA “is a potent, selective P/Q type Ca2+ (Cav2.1) channel blocker with IC50s of 2 nM and 90 nM for P-type and Q-type Ca2+ channels, respectively. ω-Agatoxin IVA (IC50, 30-225 nM) inhibits glutamate exocytosis and calcium influx elicited by high potassium. ω-Agatoxin IVA also blocks the high potassium-induced release of serotonin and norepinephrine. ω-Agatoxin IVA has no effect on L-type or N-type calcium channels.” ω-conotoxin GVIA is an inhibitor of N-type channels.
D. That adding both toxins together suggests that both N- and P/Q-type channels are present in the synaptosomes. E. There is no additive inhibition between Silexan and the N-type channel inhibitor. F. There is no additive inhibition between Silexan and the P/Q type channel inhibitor.
5. clean expression in CHO cells
The authors did not know what other sorts of baggage came with the voltage gated Ca2+ channels in their isolated neurons and synaptosomes. They expressed the N-type (A) and P/Q type channels (B) in Chinese hamster ovary cells and then performed whole cell patch clamping. Note that these expression systems contained all the correct subunits to be fully functional channels. The inhibition was not quite as great as in less pure systems. The authors switched to N-type channels in panels C-F.
- Silexan reduced anxiety in rats at an equivalent concentration of 80 mg per day in humans.  This same dose has been tested in a human clinical trial for anxiety [3,4}. The first trial proved safety and similar results to GABAA receptor agonist lorazepam and SSRI paroxetine/Paxil.  Silexan out preformed the placebo and 20mg per day paroxetine/Paxil. 
- . The inhibitory concentration was in the nanomolar range.
- Silexan does not share the same α2δ subunit of P/Q type channels as Pregabalin/Lyrica.
- Silexan did not inhibit Ca2+-increase via VOCCs as a consequence of previous activation of Gi coupled receptors.
- Silexan does not appear to be selective. The authors drew the parallel to Pregabalin acting on the the α2δ subunit that is shared by N and P/Q calcium channels even though Pregalin is selective to P/Q. Note: that Silexan might contain more active ingredients than just linalool and linalool acetate was not addressed. No mention was made of whether other terpenes that were without an effect alone were (1) in Silexan or (2) effective in combination with the two main Silexan terpenes.
Another German publication speculated that MAPK and PKA pathways are involved.  The Schuwald study demonstrated that Gαi and inhibition of cAMP production is not part of the mechanism.  This site has reviewed work from the Streicher Lab showing that linalool can act as an agonist of CB1, see the CB1 tetrad post. “Although the main eCB activity involves inhibitory G protein (Gi/o), it is now well established that Gβγ subunits can directly interact with and inhibit the high-voltage-activated Ca2+ channels regulating neurotransmitter release at most synapses.”
Perhaps linalool is binding to CB1 and the N- and P/Q type voltage gated calcium channels. Perhaps there is some receptor bias when it comes between linalool and AEA when it comes to the βγ subunit leaving and returning to the CB1 receptor.
- Schuwald, A. M., Nöldner, M., Wilmes, T., Klugbauer, N., Leuner, K., & Müller, W. E. (2013). Lavender oil-potent anxiolytic properties via modulating voltage dependent calcium channels. PloS one, 8(4), e59998. PMC free article
- Twitchell W, Brown S, Mackie K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol. 1997 Jul;78(1):43-50. PMC free article
- Kasper S, Müller WE, Volz HP, Möller HJ, Koch E, Dienel (2018) A. Silexan in anxiety disorders: Clinical data and pharmacological background. World J Biol Psychiatry. 2018 Sep;19(6):412-420.
- Yap, W. S., Dolzhenko, A. V., Jalal, Z., Hadi, M. A., & Khan, T. M. (2019). Efficacy and safety of lavender essential oil (Silexan) capsules among patients suffering from anxiety disorders: A network meta-analysis. Scientific reports, 9(1), 18042. PMC Free article
- Müller WE, Sillani G, Schuwald A, Friedland K. (2021) Pharmacological basis of the anxiolytic and antidepressant properties of Silexan®, an essential oil from the flowers of lavender. Neurochem Int. 2021 Feb;143:104899. PMC free article
- Boczek T, Zylinska L. (2021) Receptor-Dependent and Independent Regulation of Voltage-Gated Ca2+ Channels and Ca2+-Permeable Channels by Endocannabinoids in the Brain. Int J Mol Sci. 2021 Jul 29;22(15):8168. PMC free article