The bite of a widow

What's inside a black widow's venom, and is it as deadly as feared?

👻Happy Halloween readers! I hope you’re all enjoying the night! The following isn’t too focused on Halloween, but it does follow the “nature be scary” concept. It also seems apt because is there really any other spider out there that can be associated with Halloween and horror?🕷

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There’s no animal, well real animal, that captures the spirit of Halloween more than the black widow. This spider of lore has made a lasting cultural impact far away from just being a guiding voice in Charlotte’s Web but is featured quite often in films. It’s curious why black widows have become such a staple when other venomous spiders are around. This may be owed in part due to its shiny black appearance which is only contrasted by the hourglass-like shape in red on its ventral (belly) side of this thorax which has become all-too iconic. The fact that it’s known as a “widower” may also help, given that black widows are known to cannibalize the smaller, more frail males of the species after mating.¹ It’s usually the females within this species that are known to be more toxic and bear larger fangs.

Black widows, or Latrodectus mactans, are known for the red hourglass markings on their underside. Interesting, black widows position themselves so that their red hourglass points upwards, and this may be due to the fact that predators may recognize the red markings from above and avoid attacking black widows. Image from Wikimedia.

The black widow belongs to the Latrodectus, or “widow” genus of spiders as these spiders are known to cannibalize the males. In particular, the black widow (Latrodectus mactans) comes from a mixture of Greek and Latin, combining to mean “deadly biting robber”.

There are over 30 different types of black widows found worldwide, with the most common one here in the US being the Southern black widow, being found predominately within the southeastern parts of the US, although the spider is known to inhabit regions such as New England and even Canada.

There’s a lot about this animal that raises serious questions, such as the red hourglass-like shape it bears. Not all widows bear a red hourglass. Some have red circles while others may have two triangles that may take the form of an hourglass.

But why do black widows have such a bright, contrasting image?

The answer may lie in aposematic signaling, or warning signals displayed by animals to indicate that they may be toxic and shouldn’t be eaten by predators. Most forms of aposematic signaling include bright, and often rather strange colors for animals, such as the highly conspicuous colors found in several species of toxic frogs. What’s also important is a strong contrast in colors, which may explain the bold red contrasted by the otherwise entirely black body of black widows.

A red-backed poison dart frog. Poison dart frogs are the most referenced animals when it comes to aposematic signaling, as they tend to show bright, bold colors with strong contrast. Image from Reptipidia

This has been the lasting position of biologists regarding the hourglass, and it was through a study from Brandley, et al.² that this hypothesis was validated, as the researchers found that wild birds may be less inclined to attack black widow models bearing the red hourglass than those that did not.

What’s interesting is that ancestors of the black widow may have had dorsal (back) red coloration as well, which may have been lost at some point for L. mactans. For instance, other widows, such as L. variolus, bear red colorings on both their ventral and dorsal side.

One explanation seems to suggest that a balance regarding conspicuousness is at play. Black widows present with their ventral side upward, and this may serve as a signal for predators that roam above that the black widow is dangerous. However, L. mactans, as suggested by Brandley, et al. tend to be closer to the ground relative to L. variolus, and therefore may be more prone to being recognized by prey that may wander directly below. As such, black widows may have lost the dorsal portion of their conspicuous coloring to prevent prey from recognizing and fleeing them.

In contrast, L. variolus seem to inhabit higher environments, and so for these widows bearing a red marking on both the dorsal and ventral side of the body may be a way to deter any predators that may roam both above and below the animal. In this case, preventing being eaten through signaling may outweigh the conspicuous color patterns and recognition by insects.

What’s the toxin?

Of course, the thing that concerns most people regarding black widows are their venomous nature. It’s been suggested that black widow bites are the most common form of envenomation here in the US, and they have been researched extensively due to how widespread and how dangerous they can be.

Like with many animals, black widow venom contains a mixture of various proteins, which was validated when isolated toxins from black widow were heated and showed no toxic effects.³ Further research would point to a group of neurotoxins called Latrotoxins as being the main culprit in widow toxicity.

Surprisingly, there are several Latrotoxins found within black widow venom, and they all appear to have different, rather exclusive targets. For instance, several of these Latrotoxins discovered include Latroinsectotoxins (LIT), which appear to elicit effects specifically in insects. There appear to be five so far discovered, differentiated by Greek lettering- α, β, γ, δ, and ε-LIT. There also exists a crustacean-specific toxin known as Latrocrustatoxin (LCT). For us vertebrates, the main toxin that targets us is just referred to as α-LTX, or Latrotoxin.

It's curious why such a tiny animal would produce such a wide array of toxins. The running hypothesis suggests that toxins that target insects and crustaceans are due to a predator relationship between widows and these animals, such that black widows will use these toxins to immobile or kill their prey.

In contrast, α-LTX may serve as a defensive deterrent for would-be predators of black widows. This would make sense, given that most human bites from black widows aren’t usually done from an aggressive position, but usually done as a defensive measure. It would make sense given that most mammals may not make good eating for black widows.

It’s interesting to think about this difference in toxicity across different phyla, as evidence from prior studies have noted either severely attenuated or even blunted toxic responses to isolated latrotoxins. For instance, some evidence suggests that exposure of C. elegans, a flatworm species commonly used in research, were not affected by isolated α-LTX even at a concentration of 2 micromolar.⁴ In animal studies where overlapping toxicity is found there’s generally a question of latrotoxin purity, as contamination with phylum-corresponding latrotoxin, or even of low molecular weight toxins found in the venom, can misconstrue results.

So, what exactly do latrotoxins do in the body?

The effects of latrotoxins are rather fascinating. Generally, toxicity from black widow venom starts off with local irritation, growing into muscle pain and cramping, and even possible autonomic issues such as tachycardia and hypertension. Patients may also progress into a state called Latrodectism⁵, in which cramping, tenderness, nausea and vomiting occurs. Generally, symptoms appear to progress from the site of envenomation and making their way to the chest, abdominals, and back.

There have also been several case reports of myocarditis following black widow bites⁶,⁷,⁸, which may provide insights into the role of hypercatecholamine release, at least as it relates to viral infection or COVID vaccines.

All of this appears to be due to a secretagogue effect of the toxin, defined as the massive purging of neurotransmitters by neurons. The science here is complex, but it appears that Latrotoxins target the presynaptic terminal of neurons and appear to either bind to proteins that aid in neurotransmitter release, or create porous regions of nerve terminals allow escape of neurotransmitters into the neighboring environment. It’s through this sudden onslaught of neurotransmitters and neuromuscular dysfunction that the symptoms of black widow envenomation manifest.

Silva, et al.⁹ summarizes these effects in the following manner:

From the pioneering study of the toxin’s action at the frog neuromuscular junction (NMJ) (Longenecker et al. 1970), it emerged that the venom causes exhaustive neurotransmitter release by acting specifically at the presynaptic nerve terminal. Later, in numerous experiments, this effect was unequivocally attributed to α-LTX. At low, subnanomolar concentrations, the toxin has no morphological effect on the nerve terminal; however, its action can be detected electrophysiologically as an increase in the frequency of miniature end-plate potentials (mepps) (Longenecker et al. 1970). At high, nanomolar concentrations, the toxin causes massive neurotransmitter release (Ceccarelli et al. 1979), which is sustained for a considerable amount of time and followed by substantial morphological changes in nerve terminals and even neuronal cell death. There is a concomitant dramatic drop in ATP levels and disintegration of the plasma membrane (McMahon et al. 1990), which is most strongly manifested in central synapses (Davletov et al. 1998; Ashton et al. 2001).

Again, there are several ways in which Latrotoxins elicit their neurotoxic effects, but it appears that the effect is both calcium dependent and independent, both of which elicit different responses in the body, and summarized as follows:

The data described above establish the following important facts: (1) α-LTX evokes exocytosis by two mechanisms, Ca²⁺-dependent and -independent; (2) these two mechanisms are distinct; (3) the tonic Ca²⁺-independent action develops slowly but ultimately leads to a total block of neurotransmitter release; (4) the Ca²⁺-dependent bursts of high frequency exocytosis appear abruptly and periodically but occur over a long time; (5) the Ca²⁺-independent exocytosis requires the presence of Mg²⁺; (6) synaptic vesicles carrying distinct neurotransmitters have different sensitivities to the two toxin actions.

This all sounds rather scary, as it suggests complete neuronal and autonomic dysfunction following envenomation.

At the same time, this mechanism of toxicity has been proven very useful within the field of neuroscience. Up until more widespread research into the effects of Latrotoxins there was an ongoing debate regarding how neurotransmitters are released from neurons. One proposed hypothesis at the time was the vesicle/exocytosis hypothesis, which suggests that neurotransmitters are contained within vesicles which are then released into the neuromuscular junction between neurons. This contrasted with a transporter-mediated release of neurotransmitters.

It was through research utilizing Latrotoxins in the absence of calcium that researchers were able to elucidate the significance of vesicles in neurotransmitter release:

One extremely important outcome of the first phase of toxin studies was its contribution to the debate regarding the nature of neurotransmitter release. At the time, transmitter exocytosis (as opposed to transporter-mediated outflow) was still a controversial idea, and the unique ability of α-LTX to cause sustained release of transmitters in the absence of Ca²⁺_e played a decisive role in this argument. As mentioned above, synaptic vesicles, fused with the plasma membrane, require Ca²⁺_e for their endocytosis (Ceccarelli and Hurlbut 1980). If α-LTX is applied in a Ca²⁺-free medium, fused vesicles become stranded in the membrane and eventually depleted from the terminal. This elegant paradigm, based on the peculiar features of α-LTX, was successfully employed in a series of cornerstone works (Ceccarelli et al. 1973; Gorio et al. 1978a). Finally, using electron microscopy and electrophysiological recordings, the authors concluded that quantal release at the NMJ occured as long as vesicles were present in the nerve terminal (Ceccarelli and Hurlbut 1980). This lent enormous support to the exocytotic theory of transmitter secretion (Hurlbut et al. 1990).

And so, as scary as these toxic effects appear, we should at least owe a bit of gratitude towards black widows in helping discover how our neurons operate. For more on the topic refer to the Silva, et al. piece for a deeper dive into research utilizing Latrotoxins.

How Deadly are Black Widow Bites, if at all?

The black widow is feared by many for a reason, and it’s not uncommon to hear of urban myths regarding someone who knew a guy who may have known a guy who got bitten by a black window and subsequently died.

As industrialization and further encroachment into nature occurred reports of hospitalizations and illness following black widow bites began to increase, especially around the turn of the 20^th century where reports of bites became more frequent.

For instance, a report from 1942¹⁰ details the growing recognition of Black Widow spider bites:

The article goes on to further elaborate on several cases of these black widow bites, which may make several readers wince, as many of these cases appear to have happened in outhouses…

Talk about true horror! It makes it worse that one of my irrational fears is having to use the bathroom and having a large spider just slowly crawl out of the toilet bowl…

If that’s not enough to make you feel squeamish, one man who was bitten on the penis was bitten twice with a 41-day window separating the two incidences.

In a more unfortunate circumstance, the one man who was bitten on the scrotum and later died, with the case report detailed below:

The report notes several instances of morphine being provided to alleviate the pain without much avail. The report also mentions the administration of calcium and magnesium, which were originally thought to be a first-line treatment, although over time it appears that there was no clear evidence that calcium would alleviate Latrotoxin toxicity.

Now, incidences such as the one above may validate the assumption that black widows are deadly.

However, evidence seems to suggest that deaths from black widow bites are rather rare. It’s hard to get an actual gauge on annual deaths, but out of the thousands of reported bites every year only a handful, if any, deaths appear to be attributed to the spider.

So why all the hysteria around black widows?

Part of this may be due to the lack of treatment available for Latrotoxins paired with the fact that not much was known about the spider bite including medical professionals. As such, there’s a question if deaths attributed to black widow bites may have been iatrogenic in nature.

Consider that many people may be unaware that they were bitten by a spider, usually not thinking much of the quick pain that comes from the initial bite. With symptoms progression to nausea and vomiting patients may ascribe their symptoms to something else. Smith, H. T, mentions that the abdominal pain associated with Latrodectism may incorrectly lead to unneeded abdominal surgery, noting a case report in which it was initially assumed that a man had a ruptured peptic ulcer requiring opening of the abdomen.

Who’s to say that some of these unneeded surgical procedures may have had some influence in black widow-related deaths?

Another article published by Cal State also raised a question regarding a construction worker who died following a black widow bite in 1900. This was another case of a man being bitten while using an outhouse.

However, in this case it appears that some of the methods of dealing with the spider bite may have led to the patient’s end:

It was reported that the patient, whose name was George, was convinced he was going to die when his condition did not improve with treatment. He took matters into his own hands by downing several six-ounce glasses of whiskey, Casem said. When his breathing became labored and he lost consciousness, Dr. Clark attempted to revive him using ammonia and camphor inhalation.

“When that did not work, Dr. Clark injected George with strychnine and whiskey,” Casem said.

Strychnine, a lethal poison, was used as a therapeutic agent at the turn of the century. The patient died 14 hours after being bitten. The cause of death was reported as blood poisoning. After George’s death, the black widow spider was discovered in the outhouse.

We can’t say for sure if it was the spider bite or the medications used that led to the patient’s death, but this scenario at least warrants considering that some treatments may have at least worsened the status of patients. This is made more likely given the fact that there was no known way to treat or manage black widow venoms.

And so, it’s likely that the black widow doesn’t quite live up to the hype that we’ve all been fed growing up. Again, it’s important to know that some individuals, especially those who may be allergic to the venom, may be more prone to worse outcomes and possible death. However, for most individuals, especially adults, the risk may not be as big as it’s made out to be.

Treatments for Latrotoxin

As of now, there doesn’t appear to be any clear treatment options for bite victims. Calcium gluconate was eventually deemed ineffective, with most people now being provided an opioid such as morphine along with muscle relaxants to help alleviate symptoms.

There are rare instances in which antivenoms may be administered to patients. Antivenoms are comprised of antibodies, usually from horse or sheep who produce an immunological response when exposed to Latrotoxin. The serum of these animals is then taken and the antibodies, usually IgG antibodies or Fab fragments, are what’s used as a treatment (Ryan, et al.¹¹):

Antivenoms are antibody preparations that are produced from the plasma of animals, usually horses or sheep, by injecting the animals with venoms. Due to their polyclonal nature antivenom is able to neutralize multiple toxins within the venom [23]. Antivenoms can be either whole IgG molecules, F(ab’)₂ fragments or Fab fragments. Proposed mechanisms of how antivenom works in humans includes blocking the active site of a toxin or binding to a toxin to prevent it interacting with its substrate thereby neutralising the toxin. Central vascular compartment antivenom-venom complex formation may prevent distribution of toxins to the target tissues such as the nervous system or cause redistribution of the toxins from target tissues back to the vascular compartment. Antivenom may also increase the rate of toxin elimination from the body depending on the relative clearance of the antivenom and toxin [23,24].

Hypothetically, this seems like it would be an effective treatment, however clinical trials utilizing antivenom would provide mixed results, at least when it comes to antivenom use and reduction in pain. It also doesn’t help that many of the trials which suggested that these treatments were effective were initially derived from the manufacturers of these antivenoms. However, case reports of allergic reactions to antivenom, including some instances of anaphylaxis following administration, has led to limited use of antivenom as a possible treatment.

Looks can be deceiving.

As scary as black widows may appear (and quite frankly all spiders), it’s possible that they’ve gotten a bad rep. Although people should be concerned about getting bitten, the risk of death following a black widow bite may be overexaggerated, likely relying on old reports that may have been biased by poor treatments.

Keep in mind that most black widow bites are defensive in nature, usually occurring when their habitat is disturbed, or they risk being harmed by an individual. This is more likely at night given that these animals are nocturnal.

But regardless, there’s no doubt that black widows are a Halloween staple. I doubt that the fears over black widows will ever dissipate. But really, who can blame anyone! It is a spider after all!

Image from Thermo Fisher

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1. It’s rather common for species that exhibit sexual dimorphism, to the extent that the females are larger than the males, to also exhibit some form of cannibalism. This is true for none other than the praying mantis. The question for why such cannibalism occurs is what’s worth considering. It could be due to energy resources, such that the females consume the males in order to gain more nutrients which may help with offspring. The females of cannibalistic species may also be less inclined to stray or exert unneeded energy if already fed. I recall that some researchers hypothesized that, at least in the case of praying mantises where the males’ heads are bitten off, that the sporadic movements of the males post-head removal may help with insemination, although I can’t recall to what degree this hypothesis was validated.

2. Nicholas Brandley, Matthew Johnson, Sönke Johnsen, Aposematic signals in North American black widows are more conspicuous to predators than to prey, Behavioral Ecology, Volume 27, Issue 4, July-August 2016, Pages 1104–1112, https://doi.org/10.1093/beheco/arw014

3. This seems to be a common occurrence in early toxicology studies relating to animal venoms. An easy way to find out if a toxin is protein-based is to heat the toxin up. In general, heat would denature the proteins, leaving them in conformation that doesn’t provide the ability to bind to receptors or other parts of cells.

4. Mee, C. J., Tomlinson, S. R., Perestenko, P. V., De Pomerai, D., Duce, I. R., Usherwood, P. N., & Bell, D. R. (2004). Latrophilin is required for toxicity of black widow spider venom in Caenorhabditis elegans. The Biochemical journal, 378(Pt 1), 185–191. https://doi.org/10.1042/BJ20031213

5. Williams M, Anderson J, Nappe TM. Black Widow Spider Toxicity. [Updated 2023 Aug 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499987/

6. Yaman, M., Mete, T., Ozer, I., Yaman, E., & Beton, O. (2015). Reversible Myocarditis and Pericarditis after Black Widow Spider Bite or Kounis Syndrome?. Case reports in cardiology, 2015, 768089. https://doi.org/10.1155/2015/768089

7. Dendane, T., Abidi, K., Madani, N., Benthami, A., Gueddari, F. Z., Abouqal, R., & Zeggwagh, A. A. (2012). Reversible myocarditis after black widow spider envenomation. Case reports in medicine, 2012, 794540. https://doi.org/10.1155/2012/794540

8. Kubena, B. E., Umar, M. A., Walker, J. D., & Harper, H. (2023). Case Report: Soldier With Latrodectism After Black Widow Spider Bite During a Field Training Exercise. Military medicine, 188(3-4), e870–e874. https://doi.org/10.1093/milmed/usab201

9. Silva, J. P., Suckling, J., & Ushkaryov, Y. (2009). Penelope's web: using alpha-latrotoxin to untangle the mysteries of exocytosis. Journal of neurochemistry, 111(2), 275–290. https://doi.org/10.1111/j.1471-4159.2009.06329.x

10. Kirby-Smith H. T. (1942). BLACK WIDOW SPIDER BITE. Annals of surgery, 115(2), 249–257. https://doi.org/10.1097/00000658-194202000-00008

11. Ryan, N. M., Buckley, N. A., & Graudins, A. (2017). Treatments for Latrodectism-A Systematic Review on Their Clinical Effectiveness. Toxins, 9(4), 148. https://doi.org/10.3390/toxins9040148