The primary chemical of clinical interest contained in C. forskohlii is the diterpine forskolin (Figure 80-1). In 1974, forskolin was discovered during a large-scale screening of medicinal plants by the Indian Central Drug Research Institute. The screening revealed the presence of a hypotensive and spasmolytic component, which was initially named coleanol.¹ Additional investigation determined the exact chemical structure, and the name was changed to forskolin. From 1981 to 2010, forskolin was used in more than 15,000 in vitro and in vivo experimental studies designed to better understand the cellular processes governed by cyclic adenosine monophosphate (cAMP). Although most of these studies used this isolated constituent, there is evidence that other components within the plant extract may have biological activity, as well as enhance the absorption and action of forskolin.

FIGURE 80-1 Forskolin.

History and Folk Use

C. forskohlii has a long history of use in Ayurvedic, Siddha, and Unani systems of medicine. Studies of the pharmacologic activity of forskolin substantiate the traditional uses of C. forskohlii in such conditions as¹:

• Cardiovascular disease

• Eczema

• Abdominal colic

• Respiratory disorders

• Painful urination

• Insomnia

• Convulsions

Pharmacology

As noted in a landmark experiment in 1981, the basic mechanism of action of forskolin is the activation of adenylate cyclase, which increases cAMP in cells.² cAMP is perhaps the most important cell-regulating compound. Once formed, it activates many other enzymes involved in diverse cellular functions.³

Under normal situations, cAMP is formed when an activating hormone (e.g., epinephrine) binds to a receptor site on the cell membrane and stimulates the activation of adenylate cyclase. This enzyme is found in all cellular membranes, and only the specificity of the receptor site determines which hormone will activate it in a particular cell. In contrast, forskolin appears to directly activate adenylate cyclase, bypassing hormonal transmembrane activation of adenylate cyclase.

The physiologic and biochemical effects of a raised intracellular cAMP level include the following:

• Inhibition of platelet activation and degranulation

• Inhibition of mast cell degranulation and histamine release

• Increased force of contraction of heart muscle

• Relaxation of the arteries and other smooth muscles

• Increased insulin secretion

• Increased thyroid function

• Lipolysis

Forskolin possesses additional mechanisms of action independent of its ability to directly stimulate adenylate cyclase and cAMP-dependent physiologic responses.⁴ Specifically, forskolin was shown to inhibit a number of membrane transport proteins and channel proteins through a mechanism that did not involve the production of cAMP. The result was a transmembrane signaling that resulted in activation of other cellular enzymes. Research is under way to determine the exact receptors to which forskolin binds.

Another action of forskolin is the inhibition of platelet-activating factor (PAF) by interfering with PAF binding to receptor sites.⁵ PAF plays a central role in many inflammatory and allergic processes, including neutrophil activation, increased vascular permeability, smooth muscle contraction (e.g., bronchoconstriction), and reduction in coronary blood flow. Treatment of platelets with forskolin before PAF exposure results in a 30% to 40% decrease in PAF binding. This decrease in PAF binding caused by forskolin was concomitant with a decrease in the physiologic responses of platelets induced by PAF. However, this forskolin-induced decrease in PAF binding was not a consequence of cAMP formation, as the addition of a cAMP antagonist did not inhibit the action of forskolin. In addition, the inactive analog of forskolin, dideoxyforskolin, which does not activate adenyl cyclase, also reduced PAF binding to its receptor. Researchers speculated that the action of forskolin on PAF binding was due to a direct effect of this molecule and its analog on the PAF receptor itself or to components of the postreceptor signaling for PAF.

Clinical Applications

The therapeutic ramifications of C. forskohlii based on the pharmacology of forskolin are immense. In many conditions, a decreased intracellular cAMP level is thought to be a major factor in the development of the disease process. C. forskohlii appears to be especially well indicated in the following types of conditions:

Although C. forskohlii can be used alone, it may prove to be most useful when combined with other botanicals or measures, or both, in the treatment of these disorders.

Inflammatory Conditions

Allergic conditions such as asthma and eczema are characterized by a relative decrease in cAMP in both the bronchial smooth muscle and the skin. As a result, mast cells degranulate and smooth muscle cells contract more readily. In addition, these allergic conditions are also characterized by excessive levels of PAF.

Asthma and Eczema

Current drug therapy for allergic conditions like asthma and eczema is largely designed to increase cAMP levels by using substances that either bind to receptors to stimulate adenylate cyclase (e.g., corticosteroids) or inhibit the enzyme phosphodiesterase, which breaks down cAMP once it is formed (e.g., methylxanthines). These actions are different than forskolin’s ability to increase the production of cAMP via transmembrane activation of adenylate cyclase. The cAMP-elevating action of forskolin supports the use of C. forskohlii extracts alone or in combination with standard drug therapy in the treatment of virtually all allergic conditions.

C. forskohlii extracts may be particularly useful in asthma, as increasing intracellular levels of cAMP results in relaxation of bronchial muscles and relief of respiratory symptoms. Forskolin was shown to have remarkable effects in relaxing constricted bronchial muscles in asthmatics.⁶^–⁸ This type of smooth muscle is also found in the gastrointestinal tract, uterus, bladder, and arteries. Forskolin was shown to have tremendous antispasmodic action on these various smooth muscles. This antispasmodic action of forskolin supports the folk medicine use of C. forskohlii in the treatment of not only asthma, but also intestinal colic, uterine cramps (menstrual cramps), painful urination, angina, and hypertension. In addition to forskolin’s ability to relax smooth muscle, its other antiallergic activities, such as inhibiting the release of histamine and synthesis of allergic compounds, are also beneficial in treating asthma.⁹

One double-blind clinical study sought to compare the antiasthmatic effects of forskolin with the drug fenoterol. Sixteen patients with asthma were studied using three different preparations: