# _Cannabis sativa_ L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment
## 3 Chemical Composition
### Phytocannabinoids
#### 3.1.2 Compounds of the \(\Delta^{9}\)-Tetrahydrocannabinol Type  
The \(\Delta^{9}\)-tetrahydrocannabinol type includes many reduced cannabinoid forms that differ from each other in a stereochemical configuration or double-bond position. The most important and best-known compound in this group is, however, \(\Delta^{9}\)-THC, which is the main component of _Cannabis_[43,46]. Its structure is shown in Figure 3. The first isolation of \(\Delta^{9}\)-THC took place in 1942 [57]. Only over twenty years later, Messrs. [PERSON] and [PERSON] described its structure based on a Lebanese hashish sample using magnetic resonance spectroscopy [21]. The determined localization of the double bond had never been considered in studies before. [PERSON] defined the absolute configuration of the narcotic components, evidencing the relationship between the structure of \(\Delta^{9}\)-THC, \(\Delta^{8}\)-THC, and CBD [58,59]. The natural form of \(\Delta^{9}\)-THC in plants is a mixture of its acidic forms--THCA-A and THCA-B. They occur in plants in various concentrations, their decarboxylation takes place at different temperatures, and additionally, they have different crystalline forms. As a pure substance, \(\Delta^{9}\)-THC is unstable. It exists in an amorphous gum form and tends to brown. It shows greater stability in the unprocessed plant product, and it might be stored in a chilled methanol solution. The degradation rate of \(\Delta^{9}\)-THC in the plant product kept at room temperature is about 5%, while, for the pure substance, the value is around 10%. One of its degradation products is cannabinoid [46].  
As a partial agonist of CB\({}_{1}\) and CB\({}_{2}\) receptors, \(\Delta^{9}\)-THC adopts an agonist or antagonist profile, depending on the receptor expression, cell type, and the presence of full agonists or endocannabinoids. It is the compound responsible for the pharmacological effects of _Cannabis_. \(\Delta^{9}\)-THC also impacts other receptors. It is a GPR\({}_{55}\) and GPR\({}_{18}\) receptor agonist. It has anticancer activity, and it causes vascular relaxation, according to PPAR-\(\gamma\) receptor agonism. Moreover, its analgesic properties might result from the influence on glycine receptors. Some studies have proven the agonism of \(\Delta^{9}\)-THC against TRPV2, TRPV3, and TRPV4 channels, but no response to TRPV1 was observed [52]. The detailed activity of \(\Delta^{9}\)-THC on individual receptors is included in Table 2.  
Even in early studies, the narcotic properties of _Cannabis_ sp. were linked to the reduced form of cannabinoid--the first structurally known cannabinoid [46]. \(\Delta^{9}\)-tetrahydrocannabinol is known for the ability to induce psychotropic effects. Its chronic administration causes various central and peripheral effects, confirmed in humans and animal models [41]. It exhibits anti-inflammatory, antiemetic, and neuroprotective properties, and it seems to be effective in the fight against chronic and neuropathic pain [60]. THC is also responsible  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Receptor** & \(\Delta^{9}\)**-THC Activity** & **Receptor** & \(\Delta^{9}\)**-THC Activity** \\ \hline CB\({}_{1}\) & Partial agonist & opioid receptors & Allosteric modulator \\ CB\({}_{2}\) & Partial agonist & PPAR-\(\gamma\) & Agonist \\ GPR\({}_{55}\) & Agonist & TRPV2, TRPV3, TRPV4 & Agonist \\ GPR\({}_{18}\) & Agonist & TRPA1 & Agonist \\
5-HT\({}_{3\text{A}}\) & Antagonist & TRPM8 & Antagonist \\ \hline \hline \end{tabular}
\end{table}
Table 2: The effect of \(\Delta^{9}\)-tetrahydrocannabinol (\(\Delta^{9}\)-THC) on the receptors [52].  
for the addictive effect of _Cannabis_[29]. However, its acidic counterpart has antibiotic and neuroprotective potential [41; 43]. Interestingly, compared to other cannabinoids, \(\Delta^{9}\)-THC has low acute toxicity at the median lethal dose (LD\({}_{50}\)) level of 100 mg/kg [46].