Philadelphia is near the epicenter of the crisis. Some of the country’s largest open-air drug markets[3] can be found in the Kensington neighborhood. Heroin, prescription opioids and fentanyl aren’t the only drugs of concern. Xylazine, a powerful non-opioid also known as tranq, has an overwhelming presence[4] on the streets.
We are a group of Scandinavian[5]and[6]American[7] researchers who have studied drug treatment and harm reduction, and we have been watching the situation in Philadelphia from a variety of perspectives.
But Philadelphia’s City Council has overwhelmingly rejected the establishment of safe injection sites[12] – a potentially impactful, evidence-based tool in this fight. Overriding the mayor’s veto[13] on Sept. 28, 2023, council members have used zoning legislation to essentially prevent the opening of sites where people can take drugs under supervision across most of the city.
In May 2023, the Pennsylvania legislature[14] also overwhelmingly voted to ban safe injection sites in the entire state.
While much of the political discourse surrounding this decision has focused on protecting neighborhoods[15] where drug activity happens in parks and on the streets, ample evidence suggests that banning safe injection sites may instead jeopardize the people and communities the policy was intended to protect.
What is harm reduction?
Safe injection sites are an example of harm reduction, a general approach to addressing addiction and other public health crises. Ranging from efforts aimed at reducing incidences of HIV[16] to encouraging the safer consumption of alcohol[17], the concept has become integral to many global public health initiatives.
The goal of harm reduction[18] is to minimize the negative effects associated with drug use and other risky behaviors rather than solely focusing on eliminating the activity. This approach acknowledges the difficulty in breaking addictive behaviors and the fact that some individuals won’t – or can’t – stop regardless of policy and social efforts.
For drug use, harm reduction takes many forms. These include encouraging nonjudgmental approaches toward people who use drugs among social service workers and health care personnel, needle exchange programs, distribution of drugs that reverse overdoses, testing drugs for safety – and, in many parts of the world, safe injection sites.
Limitations in the United States
Safe injection sites have been a particularly controversial approach[19] to harm reduction not just in Philadelphia but across most of the U.S.
In the face of this uncertain legality[26], scant evidence from the U.S. is available. One unsanctioned site operating in secrecy was studied by academics[27]. They found that 90% of users reported they would otherwise have been injecting in parks, streets or public restrooms, meaning the site averted over 2,300 public injections and safely disposed of at least 1,700 needles over two years.
Beyond this, policymakers have limited research in the U.S. to draw upon – and so it is informative to look abroad.
Globally, over 100 safe injection sites[28] are currently operating in 10 countries, including Canada[29] and across Europe[30]. Researchers have looked to experiences in Denmark and Norway, in particular, to study drug consumption rooms. Despite clear differences between Scandinavia and Philadelphia, the research and evidence highlight the potential impact of this form of harm reduction.
The evidence from Norway
In Norway, as in the U.S., harm-reduction efforts first began with opioid substitution therapy[31], meaning the provision of less dangerous drugs like methadone for opioid users.
The Norwegian Institute of Public Health collected data on the impact of the safe injection site in Oslo. Just over 150 people used the site in 2005, the first year it opened. Two years later, demand had almost quadrupled. After just six months of operation, staff were recording over 900 injections per month, each diverted from the street. People using the facility told researchers[34] their sense of human dignity improved.
Staff reported that the site allowed them to directly connect more people to social and health services. Other data shows that the presence of the site has reduced the use of ambulances[35] and related public services, preserving those resources for the community.
Since then, several studies have shown the Copenhagen sites not only prevented many drug-related deaths, but improved overall health[37] by successfully connecting people to substance abuse treatment and other health care services.
An evaluation by the Danish Ministry of Health found that the number of needles and syringes discarded in the city’s public spaces was reduced by 70% to 80%[41], and residents in surrounding neighborhoods said their quality of life improved[42].
Property values stayed steady in Copenhagen neighborhoods with safe injection sites. Niels Ahlmann Olesen/AFP via Getty Images
Copenhagen’s experience also highlights the essential fact that safe injection sites alone aren’t a solution; they are only a part of an effective harm-reduction strategy and must be accompanied by social support and other programming.
For example, the Users’ Academy – or Brugernes Akademi[43] in Danish – is a national nonprofit led by people who use drugs that offers a wide range of harm-reduction services directly to their peers. They run a needle exchange program through the mail and raise awareness regarding the legal rights of people who use drugs. They also operate a mobile health clinic that seeks to prevent diseases like hepatitis C[44] and reduce barriers to health and social services.
Using the infusion of funding from national opioid settlements[46], Philadelphia could explore more politically acceptable approaches to harm reduction while collecting evidence and building support for a permanent safe injection site.
In some European cities, mobile safe injection sites have been adopted first. In Copenhagen, Fixelancen[47], an old ambulance, has been refurnished as a low-cost safe injection site. It can service different areas of the city as the drug scene rapidly evolves, avoiding the focus and burden on a particular neighborhood. Such an approach could easily complement other mobile[48]harm-reduction efforts[49] already operating in Philadelphia.
Philadelphia is near the epicenter of the crisis. Some of the country’s largest open-air drug markets[3] can be found in the Kensington neighborhood. Heroin, prescription opioids and fentanyl aren’t the only drugs of concern. Xylazine, a powerful non-opioid also known as tranq, has an overwhelming presence[4] on the streets.
We are a group of Scandinavian[5]and[6]American[7] researchers who have studied drug treatment and harm reduction, and we have been watching the situation in Philadelphia from a variety of perspectives.
But Philadelphia’s City Council has overwhelmingly rejected the establishment of supervised injection sites[12] – a potentially impactful, evidence-based tool in this fight. Overriding the mayor’s veto[13] on Sept. 28, 2023, council members have used zoning legislation to essentially prevent the opening of sites where people can take drugs under supervision across most of the city.
In May 2023, the Pennsylvania legislature[14] also overwhelmingly voted to ban supervised injection sites in the entire state.
While much of the political discourse surrounding this decision has focused on protecting neighborhoods[15] where drug activity happens in parks and on the streets, ample evidence suggests that banning supervised injection sites may instead jeopardize the people and communities the policy was intended to protect.
What is harm reduction?
Supervised injection sites are an example of harm reduction, a general approach to addressing addiction and other public health crises. Ranging from efforts aimed at reducing incidences of HIV[16] to encouraging the safer consumption of alcohol[17], the concept has become integral to many global public health initiatives.
The goal of harm reduction[18] is to minimize the negative effects associated with drug use and other risky behaviors rather than solely focusing on eliminating the activity. This approach acknowledges the difficulty in breaking addictive behaviors and the fact that some individuals won’t – or can’t – stop regardless of policy and social efforts.
For drug use, harm reduction takes many forms. These include encouraging nonjudgmental approaches toward people who use drugs among social service workers and health care personnel, needle exchange programs, distribution of drugs that reverse overdoses, testing drugs for safety – and, in many parts of the world, supervised injection sites.
Limitations in the United States
Supervised injection sites have been a particularly controversial approach[19] to harm reduction not just in Philadelphia but across most of the U.S.
In the face of this uncertain legality[26], scant evidence from the U.S. is available. One unsanctioned site operating in secrecy was studied by academics[27]. They found that 90% of users reported they would otherwise have been injecting in parks, streets or public restrooms, meaning the site averted over 2,300 public injections and safely disposed of at least 1,700 needles over two years.
Beyond this, policymakers have limited research in the U.S. to draw upon – and so it is informative to look abroad.
Globally, over 100 supervised injection sites[28] are currently operating in 10 countries, including Canada[29] and across Europe[30]. Researchers have looked to experiences in Denmark and Norway, in particular, to study drug consumption rooms. Despite clear differences between Scandinavia and Philadelphia, the research and evidence highlight the potential impact of this form of harm reduction.
The evidence from Norway
In Norway, as in the U.S., harm-reduction efforts first began with opioid substitution therapy[31], meaning the provision of less dangerous drugs like methadone for opioid users.
When overdose rates[32] kept rising, supervised injection sites where people who use drugs could get clean needles and be observed while using drugs[33] were piloted in 2005 and made permanent by 2009.
The Norwegian Institute of Public Health collected data on the impact of the supervised injection site in Oslo. Just over 150 people used the site in 2005, the first year it opened. Two years later, demand had almost quadrupled. After just six months of operation, staff were recording over 900 injections per month, each diverted from the street. People using the facility told researchers[34] their sense of human dignity improved.
Staff reported that the site allowed them to directly connect more people to social and health services. Other data shows that the presence of the site has reduced the use of ambulances[35] and related public services, preserving those resources for the community.
Since then, several studies have shown the Copenhagen sites not only prevented many drug-related deaths, but improved overall health[37] by successfully connecting people to substance abuse treatment and other health care services.
An evaluation by the Danish Ministry of Health found that the number of needles and syringes discarded in the city’s public spaces was reduced by 70% to 80%[41], and residents in surrounding neighborhoods said their quality of life improved[42].
Property values stayed steady in Copenhagen neighborhoods with supervised injection sites. Niels Ahlmann Olesen/AFP via Getty Images
Copenhagen’s experience also highlights the essential fact that supervised injection sites alone aren’t a solution; they are only a part of an effective harm-reduction strategy and must be accompanied by social support and other programming.
For example, the Users’ Academy – or Brugernes Akademi[43] in Danish – is a national nonprofit led by people who use drugs that offers a wide range of harm-reduction services directly to their peers. They run a needle exchange program through the mail and raise awareness regarding the legal rights of people who use drugs. They also operate a mobile health clinic that seeks to prevent diseases like hepatitis C[44] and reduce barriers to health and social services.
Using the infusion of funding from national opioid settlements[46], Philadelphia could explore more politically acceptable approaches to harm reduction while collecting evidence and building support for a permanent supervised injection site.
In some European cities, mobile supervised injection sites have been adopted first. In Copenhagen, Fixelancen[47], an old ambulance, has been refurnished as a low-cost supervised injection site. It can service different areas of the city as the drug scene rapidly evolves, avoiding the focus and burden on a particular neighborhood. Such an approach could easily complement other mobile[48]harm-reduction efforts[49] already operating in Philadelphia.
If you have ever gotten a vaccine or received an intravenous drug and did not come down with a potentially life-threatening fever, you can thank a horseshoe crab (Limulus polyphemus).
How can animals that are often called living fossils[1], because they have barely changed over millions of years, be so important in modern medicine? Horseshoe crab blood is used to produce a substance called limulus amebocyte lysate, or LAL, which scientists use to test for toxic substances called endotoxins[2] in intravenous drugs.
These toxins, produced by bacteria, are ubiquitous in the environment and can’t be removed simply through sterilization. They can cause a reaction historically referred to as “injection fever[3].” A strong concentration can lead to shock and even death.
Identifying LAL as a highly sensitive detector of endotoxins was a 20th-century medical safety breakthrough. Now, however, critics are raising questions about environmental impacts and the process for reviewing and approving synthetic alternatives to horseshoe crab blood.
We study science, technology[4] and public policy[5], and recently published a white paper[6] examining social, political and economic issues associated with using horseshoe crabs to produce LAL. We see this issue as a test case for complicated problems that cut across multiple agencies and require attention to both nature and human health.
Protecting horseshoe crabs will require persuading the heavily regulated pharmaceutical industry to embrace change.
An ocean solution
Doctors began injecting patients with various solutions in the mid-1800s[7], but it was not until the 1920s that biochemist Florence Seibert[8] discovered that febrile reactions were due to contaminated water in these solutions. She created a method for detecting and removing the substances that caused this reaction, and it became the medical standard in the 1940s.
Known as the rabbit pyrogen test[9], it required scientists to inject intravenous drugs into rabbits, then monitor the animals. A feverish rabbit meant that a batch of drugs was contaminated.
The LAL method was discovered by accident. Working with horseshoe crabs at the Marine Biological Laboratory[10] at Woods Hole, Massachusetts, in the 1950s and ’60s, pathobiologist Frederik Bang and medical researcher Jack Levin[11] noticed that the animals’ blue blood[12] coagulated in a curious manner. Through a series of experiments, they isolated endotoxin as the coagulant and devised a method for extracting LAL from the blood. This compound would gel or clot nearly instantaneously in the presence of fever-inducing toxins.
Academic researchers, biomedical companies and the U.S. Food and Drug Administration refined LAL production and measured it against the rabbit test. By the 1990s, LAL was the FDA-approved method[13] for testing medicines for endotoxin, largely replacing rabbits.
Rabbits undergoing a pyrogen test in a laboratory in 1956 to determine a drug’s safety. Sherman/Getty Images)[14]
Producing LAL requires harvesting horseshoe crabs from oceans and beaches, draining up to 30% of their blood[15] in a laboratory and returning the live crabs to the ocean. There’s dispute about how many crabs die in the process[16] – estimates range from a few percent to 30% or more – and about possible harmful effects on survivors.
Today there are five FDA-licensed LAL producers[17] along the U.S. East Coast. The amount of LAL they produce, and its sales value, are proprietary.
Bait versus biotech
As biomedical LAL production ramped up in the 1990s, so did harvesting horseshoe crabs to use as bait for other species, particularly eel and whelk for foreign seafood markets. Over the past 25 years, hundreds of thousands – and in the early years, millions – of horseshoe crabs have been harvested each year for these purposes. Combined, the two fisheries kill over half a million[18] horseshoe crabs every year.
Conservationists are worried, and not just about the crabs. Millions of shorebirds migrate along the Atlantic coast[20], and many stop in spring, when horseshoe crabs spawn on mid-Atlantic beaches, to feed on the crabs’ eggs. Particularly for red knots[21] – a species that can migrate up to 9,000 miles between the tip of South America and the Canadian Arctic – gorging on horseshoe crab eggs provides a critical energy-rich boost on their grueling journey.
Red knots were listed as threatened[22] under the Endangered Species Act in 2015, largely because horseshoe crab fishing threatened this key food source. As biomedical crab harvests came to equal or surpass bait harvests[23], conservation groups began calling on the LAL industry to find new sources.
When possible, synthesizing these substances in laboratories – especially widely used medications like insulin[27] – offers many benefits. It’s typically cheaper and more efficient, and it avoids putting species at risk, as well as addressing concerns some patients have[28] about using animal-derived medical products.
In the 1990s, researchers at the National University of Singapore invented and patented[29] the first process for creating a synthetic, endotoxin-detecting compound using horseshoe crab DNA and recombinant DNA technology[30]. The result, dubbed recombinant Factor C (rFC), mimicked the first step in the three-part cascade reaction that occurs when LAL is exposed to endotoxin.
Later, several biomedical firms produced their own versions[31] of rFC and compounds called recombinant cascade reagents (rCRs), which reproduce the entire LAL reaction without using horseshoe crab blood. Yet, today, LAL remains the dominant technology for detecting endotoxins in medicine.
The main reason is that the U.S. Pharmacopeia[34], a quasi-regulatory organization that sets safety standards for medical products, considers rFC and rCR as “alternative” methods for detecting endotoxins, so they require case-by-case validation for use – a potentially lengthy and expensive process. The FDA generally defers to the U.S. Pharmacopeia.
A few large pharmaceutical companies with deep pockets have committed to switching from LAL to rFC[35]. But most drug producers are sticking with the tried-and-true method.
Conservation groups want the U.S. Pharmacopeia to fully certify rFC[36] for use in industry with no extra testing or validation. In their view, LAL producers are stalling rFC and rCR approval to protect their market in endotoxin detection[37]. The U.S. Pharmacopeia and LAL producers counter that they are doing due diligence to protect public health[38].
Change in the offing
Change may be coming. All major LAL producers now have their own recombinant products – a tacit acknowledgment that markets and regulations are moving toward Limulus-free ways to test for endotoxins.
Atlantic fisheries regulators are currently considering new harvest limits for horseshoe crabs[39], and the U.S. Pharmacopeia is weighing guidance[40] on recombinant alternatives to LAL. Public comments will be solicited over the winter of 2024, followed by U.S. Pharmacopeia and FDA review.
Even if rFC and rCR don’t win immediate approval, we believe that collecting more complete data on horseshoe crab populations and requiring more transparency from the LAL industry on how it handles the crabs[41] would represent progress. So would directing medical companies to use recombinant products for testing during the manufacturing process, while saving LAL solely for final product testing.
Making policy on complex scientific issues across diverse agencies is never easy. But in our view, incremental actions that protect both human health and the environment could be important steps forward.
