Clementines, Oranges, Satsumas and Tangerines have subtle differences based on size, colour, taste and presence or absence of pips between them. Yet they are all types of Mandarins, so you can use it as a generic definition to describe all of them. On top of this, there are many other citrus fruits out there that are highly similar to these, but the Mandarine type does not include them.

Controlled drug legislation aims to clarify what is an ‘orange’ or a ‘satsuma’ among organic compounds, defining the differences between the molecules in the language of chemical structures.

Identifying a controlled compound in a pharmaceutical library, often feels like trying to work out which orange coloured citrus fruit you are eating. It is all about subtle differences.

Evolution of controlled substance legislation

Historically legislation was based around specific molecules and later it was extended to their simple derivatives, for example isomers/ethers/esters. With the advent of multiple variations of a molecule around a core structure, identification has become much more complicated. In today’s world an unprecedented change has taken place in the legislation of controlled compounds from listing substances on a named basis to structure based generic definitions.  

An example of the new generic approach is typified by the fight against New Psychoactive Substances (NPS). These posed significant challenges for regulatory bodies due to the rapid emergence and evolution of these substances. NPS, often known as "designer drugs" or "legal highs," are synthetic compounds that mimic the effects of controlled drugs but are not classified under existing drug laws, making them difficult to regulate using traditional drug control methods.

In a previous blog post, the benefits and challenges of implementing generic definitions in controlled compound legislation were discussed. This blog will outline how the generic approach is being used to control Fentanyl derivatives, and explore the concept of controlled substance analogues. It will also discuss how the legal wording is interpreted and transformed into scientific nomenclature, i.e. words into chemical structures, and so more useful in a Pharma and other scientific environments.¹

The difference between ’controlled substance analogue’ and ‘generic control’ measures

Controlled substance analogue definition

Analogue control measures operate on a substance by substance basis. A substance that is both structurally similar and has a similar or greater effect on the central nervous system as an already controlled substance is deemed to be a controlled substance analogue and is therefore also controlled.

Generic control definition

Generic control measures relate to groups of substances. Starting from a core molecular structure, which does not itself need to be psychoactive, it specifies particular variations of the structure (particular substituent groups in specified positions in the molecule) which lead to a substance being controlled. Thus each substance does not have to be dealt with individually and new types of substances can be controlled through this approach.2

What is generic controlled substance legislation?

Generic controlled drug legislation refers to laws that control groups of substances based on their chemical structure rather than naming each substance individually.

The approach of controlling groups of substances through generic definitions has been used and adapted over the years in several countries. Recent years show a global rise in generic legislation.

Benefit of generic control

This approach allows for broader coverage of substances and can anticipate new variants that may emerge. For example, a navel orange is subject to the same legislation as a blood orange as would be a new orange variation.

Drawback of generic control

Generic definitions cover a large chemical space, potentially including millions of compounds. This combined with different legislative areas means that it is nearly impossible to manually find all the potential hits in a sizable compound library.

Examples for generic controlled substance legislation

New Psychoactive Substances

In Europe and North America, where a significant variety of New Psychoactive Substances (NPS) have been reported, generic control on various different groups of NPS have been introduced in at least 23 countries. Major examples of the generic legislation coming into play include, in the UK, Third Generation Synthetic Cannabinoids²; US, Fentanyl-related substance and Belgium, again, synthetic cannabinoids.  

Controlling fentanyl

More Americans are dying from fentanyl overdoses than ever. Around 100,000 deaths were caused by drug overdoses in 2022 of which 70% can be attributed to Fentanyl and other synthetic opioids³.  In  this article, there are no figures for deaths related to derivatives of Fentanyl, which is interesting and perhaps suggests that this, as yet, is not an issue.

To emphasise the fentanyl problem, this report⁴ in April 2024: Fentanyl and its derivatives: Pain-killers or man-killers, states that ‘fentanyl is considered as the number one cause of death for adults aged 18–45 in the US’ and that ‘more than 1400 fentanyl derivatives have been described in the scientific literature and patents’.

In the UK, the situation is slightly different with relatively fewer deaths being reported to be caused by Fentanyl. It is attributed to being a smaller population of people who have become habituated to strong opioids compared to the US.

The Advisory Council on Misuse of Drugs (ACMD), which is responsible for advising the UK government on controlled drug legislation, in a recent report⁵ from 2020, believe that ‘The long-standing UK generic control on fentanyls has proved to be robust and almost all ‘designer’ fentanyl variants being encountered are automatically controlled in the UK as Class A drugs’. It should be noted that since 2020, more fentanyl derivatives have been identified and reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

It is therefore imperative that as generic structure legislation is developed to cover these derivatives and potential derivatives as they arise on the streets, experts and compliance software within pharmaceutical and other scientific bodies are capable of correctly interpreting these derivatives.

Real-world challenges based on generic legislation

With generic legislation comes new obstacles for the Pharma, Contract Research Laboratories and Academia, how to identify them within a compound library. The sheer number and possibilities involved coupled with different policies in different legislative areas, means that it is virtually impossible for one in-house expert to manually keep track of all the potential hits within their library.

For commercial software, generic structures are digitalised by teams of experts into chemical queries, preferably represented by Markush structures. This allows for the timely and fast  identification of hits within pharmaceutical libraries, ensuring compliance with legislation at all times. 

What is a controlled substance analogue?

The analogue control extends the control to substances that are chemically or pharmacologically similar to already controlled drugs.

Benefit of analogue control

The benefits of analogue control, much like those of generic control, include the ability to regulate new psychoactive substances without the need for continual updates to the law.

Drawback of analogue control

On the other hand, the ambiguity in defining what qualifies as sufficient chemical or pharmacological similarity to a controlled substance makes practical implementation very challenging.

Examples for analogue-based legislation

This lack of clarity likely contributes to the fact that only six countries have adopted analogue control within their drug legislation⁶:

• Canada,
• Italy,
• Latvia,
• Luxembourg,
• South Africa,
• USA.

Federal Analogues Act

The United States introduced the first analogue control law in 1986 with the enactment of the Federal Analogue Act (21 U.S.C. § 813 ). The Act states that a compound “which is substantially similar to a controlled substance” (in Schedule I and II) “ is also controlled”.

Real-world challenges based on analogue control

As highlighted in a previous publication, an effective system for identifying controlled substances must operate both efficiently and swiftly, among other criteria. This requirement extends to the identification of substantially similar compounds. Such compounds must be identified with the same level of efficiency and promptness to ensure regulatory compliance and effective monitoring.

The efficiency of identifying similar compounds lies in ensuring that the majority of the substances that are flagged are truly analogous. This specificity is important because each compound requires a case-by-case assessment to determine if it qualifies as an analogue, necessitating expert evaluation from a chemist or pharmacologist. To minimize human workload, it is essential to effectively eliminate false positives.

Conclusions

The evolution from substance-specific control to structure-based legislation — encompassing both generic and analogue control strategies — has introduced significant complexity into regulatory compliance across the pharmaceutical and life sciences sectors. As demonstrated, seemingly minor structural modifications can lead to regulatory classification shifts, much like distinguishing between closely related citrus fruits. The identification of these structurally similar or generically defined compounds, particularly in large libraries, exceeds the scope of manual review and necessitates advanced cheminformatics solutions.

Commercial platforms such as Compliance Checker operationalize this need by transforming legislative text into computable chemical queries, including highly expressive Markush representations. These structures, coupled with algorithmically driven search strategies, enable the exhaustive interrogation of compound libraries for both explicit and implicit controlled substance matches. The use of Markush search technology, Extended Connectivity Fingerprints (ECFP), and pharmacophore-based filtering collectively provides a robust framework for identifying both directly regulated entities and structurally or functionally analogous compounds.

The case studies presented in the linked Markush search and similarity calculation sections, including the comprehensive screening of the ChEMBL database, underscore both the scalability and accuracy of these methodologies. Furthermore, the inclusion of dynamic regulatory updates ensures that libraries remain compliant as legislation evolves—an increasingly critical consideration in light of expanding global restrictions on fentanyl analogues and synthetic cannabinoids.

Looking forward, continuous refinement of similarity detection methods, including hybrid fingerprint strategies and machine learning-enhanced consensus models, will further enhance specificity and reduce false positives. In this rapidly changing landscape, the integration of expert-curated regulatory knowledge with computational precision is essential to maintaining compliance, mitigating risk, and enabling uninterrupted R&D in pharmaceutical and academic environments.

References

1. https://www.ukdpc.org.uk/wp-content/uploads/Analogue-control-19.06.12.pdf

2. https://chemaxon.com/blog/generic-definitions-cat-and-mouse

3. https://www.dea.gov/press-releases/2024/05/09/dea-releases-2024-national-drug-threat-assessment

4. https://doi.org/10.1016/j.heliyon.2024.e28795

5. https://www.gov.uk/government/publications/misuse-of-fentanyl-and-fentanyl-analogues

6: https://syntheticdrugs.unodc.org/syntheticdrugs/en/legal/national/analogueleg.html