Introduction
There are many different kinds of toads on earth, poisonous or not, in the earth’s ecosystem. One genus of toads that is poisonous is the genus Bufo. There are more than 200 species that are known in this genus of toads (Lyttle, Goldstein, & Gartz, 1996). This paper will focus on only two species of poisonous toads in this genus.
The first species of toad in the Bufo genus is Bufo marinus. It is indigenous to parts of North and South America, from areas in the state of Florida through Mexico and Panama, and extending into parts of northern South America (Davis & Weil, 1992). It spread rapidly through parts of South America along the pacific coast, and it spread inland as well into the Amazon (Davis & Weil, 1992). The second species of toad is Bufo alvarius. It is known as the Sonoran desert toad or formerly as the Colorado river toad (Davis & Weil, 1992). It is found only in the Sonoran desert, which stretches from southeast California through Arizona and into parts of Mexico. It is an amphibian which is active only at night, during the cooler hours of the desert. During the hot days in the desert, they bury themselves underground. At night when they become active, they gather around as much available moisture as they can find, be it leftover streams or little beds of water. The two species of toads are morphologically similar (Davis & Weil, 1992) and are difficult to distinguish. Both species of toads are of similar size and are bigger than other species of toads in the Bufo genus (Davis & Weil, 1992). Both Bufo marinus and Bufo alvarius also have large parotoid glands on their backs that secrete their venom (Lyttle, Goldstein, & Gartz, 1996; Davis & Weil, 1992). These parotoid glands are kidney-shaped and are also located on each side of their necks. They are the most prominent of all of the secretory glands on the toads. There are also elongated secretory glands located on the distal side of each hind leg of the toads called femorals, as well as a string of glands located between the knee and the ankle, called the tibeals (WWW1). There are also some on the forearms as well.
Toad Venom and its constituents
Toad venom contains a huge mixture of different classes of chemicals. There are over 26 different biologically active compounds in toad venom (Davis & Weil, 1992). Not all of them are toxic and poisonous (Lyttle, Goldstein, & Gartz, 1996), but the poisonous and the nonpoisonous chemicals in the venom exist side by side. Also, the concentrations of each of the different chemicals in toad venom (and therefore the toxicity of the venom) varies from species to species (Lyttle, Goldstein, & Gartz, 1996).
The first class of chemicals in toad venom are called the cardiac glycosides. There are two classes of cardiac glycosides, bufogenins and its derivative bufotoxin (Davis & Weil, 1992). The bufogenins and bufotoxins together are known as bufodienolides. These classes of chemicals in the venom are known for their effects on the cardiovascular system, including the heart and blood vessels (Lyttle, Goldstein, & Gartz, 1996; Davis & Weil, 1992; Chi et al, 1998; Lim et al, 1997). More on the effects of these chemicals on the cardiovascular system in animals and humans will be examined later.
The second class of chemicals in toad venom are the phenethylamines and their derivatives. These include catecholamines such as dopamine (DA), norephinephrine (NE), and ephinephrine (E). As much as 50f ephinephrine has been found in the venom of various Bufo toad species (Chi et al, 1998; WWW2). These classes of chemicals in the toad venom generally don’t have as prominent an effect as the bufodienolides in exerting a quick and obvious physiological effect in animals, but it is thought that they probably contribute to vasoconstriction in human placental fetal blood vessels (Lim et al, 1997).
The third class of chemicals are the tryptamines and its derivatives. One of these is 5-hydroxytryptamine (5-HT, serotonin). Serotonin is found endogenously in both humans and Bufo toads. Another compound is 5-hydroxy-dimethyltryptamine (5-hydroxy-DMT, bufotenine), which is found in all species of Bufo toads, but in different concentrations (Lyttle, Goldstein, & Gartz, 1996). Bufotenine is toxic physiologically because it is thought to have pressor effects, meaning that it can affect the cardiovascular system, such as the heart rate and/or blood pressure (Lyttle, Goldstein, & Gartz, 1996). But when inhaling the vapors of toad venom from Bufo marinus, the bufotenine in it was claimed by some scientists and people to have hallucinogenic and/or psychoactive effects. This is because scientists have found bufotenine in the snuffs of many ancient mesoamerican peoples. However, according to Lyttle, Goldstein, & Gartz (1996), there is no real scientific link between bufotenine and any psychoactive effects. Davis & Weil (1992) states that it is very unlikely that the venom of Bufo marinus, which contains bufotenine, will have any psychoactive agents because of the lack of any hallucinogenic contents found in the venom after its analysis. More information about bufotenine will be examined later.
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is also a tryptamine, and it is found only in the venom of one species of the Bufo genus, Bufo alvarius. There is evidence that it’s the only substance found endogenously in Bufo alvarius that have psychoactive and/or psychedelic effects when their venom are inhaled(Davis & Weil, 1992; Lyttle, Goldstein, & Gartz, 1996; WWW1). However, when toad venom is taken orally or topically (by touch), the venom can have toxic effects on animals and humans. This is most likely due to the presence of the bufodienolides in the venom (Davis & Weil, 1992; Lyttle et al, 1996; WWW2). More about comparing the psychoactiveness of bufotenine and 5-MeO-DMT will be addressed later.
The fourth class of chemicals in toad venom are the noncardiac sterols. These include cholesterol, provitamin D, ergosterol, and gamma sitosteral. They don’t have any toxic effects in toad venom (WWW2).
General physiological effects of toad venom
There are usually three general toxic effects associated with toad venoms (WWW2). The first is the effect on the cardiovascular system due to the bufodienolides in the venom. The second are the pressor effects that might be associated with certain catecholamines in the venom such as ephinephrine and/or norephinephrine. These can cause increased heart rates and/or increased blood pressure. The third effect of toad venoms (due to the 5-MeO-DMT in Bufo alvarius venom only) is to cause hallucinations and/or be psychoactive. This can only be experienced when the smoke from its venom is inhaled (Davis & Weil, 1992). This section focuses on the general physiological effects of the venom on different systems in animals and humans if the venom is ingested, touched, or exposed to mucus membranes. If the venom is exposed to the eyes or nose, pain and irritation of the mucus membranes will result (WWW2). If the venom is swallowed, the venom may also cause local anesthesia of the tissues in the throat as well as the oral mucosa (WWW2). This can lead to numbness. Ingested venom may also cause dyspnea, which is difficulty or labored breathing (Dorland’s med. dict., 1994). Reported neurological effects include paralysis, seizures, blurred vision, and dizziness (WWW2; Chi et al, 1998). It can also cause increased salivation and vomiting. Topical exposure to toad venoms can also lead to decreased perspiration in humans. Other effects such as fevers were also reported. The general effects of the venom on the cardiovascular system in humans and animals may include ventricular fibrillation and vasoconstriction (WWW2; Lim et al, 1997). More detail about the physiological effects of the venom on the cardiovascular system will be examined in the next section, because these symptoms are usually the most prominent with toad venom poisoning (WWW2, sec 5.2A). Later on the psychoactive/psychedelic properties of the venoms in Bufo marinus versus Bufo alvarius will be examined.
The Bufodienolides and their cardiovascular effects
The bufodienolides, as mentioned above, consists of two classes of chemicals, the bufogenins and bufotoxins. It was found that the bufodienolides present in toad venom from Bufo marinus are both similar in their chemical structures as well as their pharmacological properties to digitalis (Chi et al, 1998; Lim et al, 1997). Digitalis binds to a specific receptor site on the cardiac muscle, therefore inhibiting the Na+/K+ ATPase pump (Chi et al, 1998). Normally the Na+/K+ ATPase pump pumps sodium into a cell and potassium out of a cell. When the pump is inhibited, the cell relies on Na+/Ca2+ pumps to maintain its sodium gradient instead. This pumps sodium out and calcium in. Therefore there is an increased concentration of calcium in the sarcoplasm of the cardiac cell. This results in a positive inotropic effect that is caused by digitalis (Chi et al, 1998). A positive inotropic effect means that there is an increase in the strength of muscular contractions (Dorland's med. dict., 1994). Increased intracellular concentrations of calcium also causes transient depolarizations. Failure of the Na+/K+ ATPase pump also results in an increased extracellular potassium concentration, which is called hyperkalemia (Dorland’s med. dict., 1994). The toxicity of toad venom on the cardiovascular system is due primarily to bufodienolides, which duplicates the digitalis mechanism by causing inhibition of the Na+/K+ ATPase pump (Chi et al, 1998). According to Lim et al (1997), the exact mechanism of the bufotoxins are still being debated, but in general there is agreement among the scientific community that they inhibit the Na+/K+ ATPase found on cellular membranes.
Water extracts of toad venom from the skin of Bufo marinus also caused sustained vasoconstriction of human fetal placental blood vessels (Lim et al, 1997). Sustained vasoconstriction means that the placental blood vessels continue to contract even after the water extract is removed with a number of washings. It is unclear in the paper what exactly causes the vasoconstriction in the extract, the bufodienolides or the bufotenine, or both. However, Lim et al (1997) suggests that the bufodienolides probably plays more of a role in causing the vasoconstriction, because the vasoconstriction effects exhibited due to the water extract was consistent with the presence of a Na+/K+ ATPase inhibitor which directly inhibited the Na+/K+ ATPase located on the placental blood vessels. Lim et al (1997) also acknowledges the fact that other agents in the Bufo marinus skin water extract might also cause the vasoconstriction, agents which do not inhibit the Na+/K+ ATPase pump. Some agents include bufotenine (due to its potential pressor effects) and also the catecholamines (specifically ephinephrine).
Regulating Endogenous Digitalis-Like Compounds in Bufo marinus' body
The bufodienolides mentioned above are an example of an endogenous digitalis-like substance (EDLS). Bufotendienolides are found in the venom of Bufo marinus as mentioned above, and are also the most abundant EDLS in the toad's body (Matsukawa et al, 1998). Other EDLS's in the toad are present in lower concentrations in other tissues and locations, including the plasma. It turns out that the EDLSs located in toad plasma have similar properties to bufodienolides, which is the EDLS in the toad's venom (Butler et al, 1996). This means that the EDLS in toad plasma is also a Na+/K+ ATPase inhibitor as
well, and therefore also exhibits a positive inotropic effect and can cause hyperkalemia. However, even though plasma EDLS inhibits Na+/K+ ATPase, the Na+/K+ ATPase pumps located in most toad tissues are EDLS resistant, such as tissues in the toad's heart, bladder, and kidneys (Butler et al, 1996; Matsukawa et al, 1998). But according to Butler et al (1996) and Matsukawa et al (1998), the only Na+/K+ ATPase in Bufo marinus' body that is sensitive to the effects of EDLS is in their brain. This means that the brain Na+/K+ ATPases' are most easily inhibited by either digitalis or EDLSs. What this suggests is that there must be some mechanism or mechanisms that exists to protect the brain Na+/K+ ATPases from the effects of high concentrations of EDLSs (Butler et al, 1996), because maintaining the sodium gradient in the CNS is vital for CNS functions. Some mechanisms that Butler et al (1996) proposes include binding of the plamsa EDLSs to certain plasma proteins, or the metabolic inactivation of the plasma EDLSs by certain enzymes in the toad's tissues. Another possibility is that maybe plasma EDLSs are unable to cross the blood brain barrier, therefore preventing high concentrations of EDLSs to come in contact with the brain. These possible mechanisms suggest that toads like Bufo marinus can regulate the concentrations of EDLSs in various parts of their body. Keeping EDLSs mostly confined to the Na+/K+ ATPase inhibitor-resistant tissues of their bodies, and keeping EDLSs out of their brain may be the (or part of the) reason why toads like Bufo marinus are immune to their own poisonous venoms.
Bufotenine
5-hydroxy-DMT (bufotenine) is a compound found in the venoms of all species of toads in the Bufo genus. Its concentration in the venom varies from species to species, but it is found most abundantly in the species Bufo marinus (Davis & Weil, 1992). However, the name bufotenine was originally derived from the species Bufo vulgaris, when it was first isolated from its venom over a century ago (Lyttle, Goldstein, & Gartz, 1996). As was mentioned above, bufotenine in toad venom might contribute to increased heart rate and/or an increase in blood pressure because of its pressor effects. But this section focuses on its supposedly psychoactive effects, if any.
From the time that bufotenine was isolated from toad venom, people and even scientists have thought that bufotenine had hallucinogenic and/or psychoactive/psychedelic effects. This was because bufotenine was found in the snuffs of some South American tribes. But according to Davis & Weil (1992) and Lyttle, Goldstein, & Gartz (1996), bufotenine is not hallucinogenic nor psychoactive/psychedelic at all when smoked. There are some claims that bufotenine isolated from the venom of Bufo marinus do cause strange visual distortions or weird visual effects when injected into the human body, but this is merely due to oxygen deprivation of the optic nerve, not to any intrinsic psychedelic effects of bufotenine itself (Lyttle, Goldstein, & Gartz, 1996).
According to Davis and Weil (1992), the main weakness of the arguments supporting bufotenine as being hallucinogenic and/or psychoactive is the lack of any evidence demonstrating how any chemical components of the venom of Bufo marinus can be safely consumed. The main components of the venom include the bufodienolides, which can cause potent cardiovascular effects if ingested or touched, as described above. Other chemicals include catecholamines and sterols. Then there’s bufotenine. Because of its pressor effects on the cardiovascular system, it is deemed toxic and unsafe. However, these toxic effects are due to ingestion or handling of its venom. What if its venom is dried and smoked? It was found by a researcher named Harris Isbell that neither snuffs nor aerosols containing pure bufotenine induced any hallucinogenic and/or psychoactive effects whatsoever (Davis & Weil, 1992). Also, the Bufo marinus’ venom contains bufodienolies. Would they also exert their toxic effects through the vapors of the venom as well? It was agreed by Davis & Weil (1992) that: “Because of the toxicity of B. marinus venom, we considered it prudent not to experiment with smoking..”.
5-MeO-DMT
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a chemical component found exclusively in the venom of Bufo alvarius. It was first synthesized in laboratories in 1936. Before it was discovered endogenously in Bufo alvarius, it was discovered in the snuffs of many South American tribes and also in a couple of indigenous South American plants (WWW1). Bufo alvarius contains an enzyme called O-methyl-transferase which transforms the 5-hydroxy-DMT (bufotenin) in its venom into 5-MeO-DMT (Davis & Weil, 1992). This enzyme is unique in that it only exists in Bufo alvarius species among the Bufo genus. It generates 5-MeO-DMT in the venom, up to as much as 150f the dry weight of its venom (WWW1; Davis & Weil, 1992).
5-MeO-DMT is the only component of the toad venom in Bufo alvarius that exhibits a hallucinogenic and/or psychoactive effect on humans when smoked (Davis & Weil, 1992; Lyttle, Goldstein, & Gartz, 1996). Davis & Weil (1992) have smoked both synthetic 5-MeO-DMT and the venom extracted from Bufo alvarius, and they give their personal observations about the effects that they experienced. Davis reports feeling pleasant and experiencing "no disturbing physical symptoms..". Weil states that there is "no long-lasting effects to report". From these personal experiences and observations about the psychoactive effects of the Bufo alvarius toad venom, they were sure "..that the toxic consituents of B. alvarius are evidently denatured by smoking", because they didn't feel that smoking the venom had caused any physiological harm. Other experiences from smoking the venom include experiencing an initial intensity such as losing a sense of space and time, followed by hallucinations and distortions of shapes and sound (WWW1).
Bufotenine, 5-MeO-DMT, and the blood brain barrier
Bufotenine is similar in its chemical structure to serotonin. Both have a tryptamine core and an indole ring. However, there are differences between the two chemicals, and it is found that bufotenine is more water-soluble than serotonin. This might be due to the extra hydroxy (-OH) group at the number 5 position on bufotenine, which contributes polarity to the molecule. Therefore it cannot cross the blood brain barrier (Lyttle, Goldstein, & Gartz, 1996). This result is consistent with the fact that bufotenine is not hallucinogenic and/or psychoactive. On the other hand, 5-MeO-DMT is more lipid-soluble (compared to DMT). This is because 5-MeO-DMT has an extra methoxy (-OCH3) group on its indole ring. Therefore it crosses the blood brain barrier more readily than DMT, and accounts for its hallucinogenic and/or psychedelic effects (WWW1). The fact that it crosses the blood brain barrier faster than DMT also means that it must be more potent of a hallucinogen/psychedelic than DMT is. Davis & Weil (1992) states that: "When smoked, DMT produces a very rapid, intense intoxication of short duration that is marked by vivid visual imagery...By contrast, smoking of pure 5-MeO-DMT, a more potent tryptamine, produces an overwhelmingly powerful experience that can be unnerving".
Conclusion
This paper was a very brief and general look at the chemical components of toad venoms from two species of the Bufo genus, Bufo marinus and Bufo alvarius, and their physiological and psychoactive effects. Much more research about the chemical and pharmacological mechanisms of the components of toad venoms can be found in the scientific literature. However, the exact pharmacological and/or toxicological mechanisms of components like bufotenine in causing its toxic physiological effects in animals and humans are still unclear. Also, detailed research elucidating the pharmacological and/or neuromolecular mechanisms of 5-MeO-DMT in exerting its psychoactive/psychedelic effects in humans are difficult to find in the literature because it is an analog of DMT, which is listed as a Schedule I drug. Therefore, although it's not listed in Schedule I, the Drug Analog Act of 1987 potentially makes 5-MeO-DMT an illegal drug to have or possess. This makes doing the research on it very difficult.
Another avenue of investigation into toad venoms in general would be to see if any component (or components) of toad venoms have any potential for medical uses and/or therapeutic uses. Obviously this might be difficult given the above criteria, but maybe there might be some pharmacological and/or neuromolecular mechanisms that are overlooked which could be useful. There is no doubt that many ancient tribes and civilizations have used toad venoms for their medicinal and therapeutical uses (Lyttle, Goldstein, & Gartz, 1996). Perhaps modern investigators and researchers in the future will eventually figure out some medical or medicinal uses from toad venom and/or its components.
References
Butler, V.P. Jr. et al. Heterogeneity and lability of endogenous digitalis-like substances in the plasma of the toad, Bufo marinus. American Journal of Physiology 271 (2 pt 2): R325-32 (Aug 1996)
Chi, H.T. et al. Prognostic implications of hyperkalemia in toad toxin intoxication. Human and Experimental Toxicology 17(6): 343-6 (Jun 1998)
Davis, W. & Weil, A.T. Identity of a new world psychoactive toad. Ancient Mesoamerica 3: 51-59 (1992)
Dorland’s illustrated medical dictionary. W.B. Saunders Company. 28th Edition (1994)
Lim, T.H. et al. Effects of Bufo marinus skin toxins on human fetal extracorporeal blood vessels. Toxicon 35(2): 293-304 (Feb 1997)
Lyttle, T., Goldstein, D., & Gartz, J. Bufo toads and bufotenine: fact and fiction surrounding an alleged psychedelic. Journal of Psychoactive Drugs v.28, n.3: 267-290 (1996)
Matsukawa, M. et al. Isolation and characterization of novel endogenous digitalis-like factors in the ovary of the giant toad, Bufo marinus. Journal of Natural Products 61(12): 1476-81 (Dec 1998)
WWW1. Most, A. Part 1 & Part 2 in Bufo alvarius: the psychedelic toad of the Sonoran desert. (1984)
WWW2. Toad toxins.
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