Using controlled substances in in vitro research

A commen mis conception amongst researchers is that laws around controlled drugs permit the use of small amounts of a controlled substance for non-clinical/non-in vivo research without the need for special licenses or control.

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For instance, a typical scenario for in vitro screening may involve possession of a few milligrams or microlitres of a controlled substance within larger chemical collections (often 10 K’s or 100 K’s of chemicals).

Researchers often beleive that there is some form of “research exemption” for such small amounts. This is incorrect and further reinforced by R&D chemical suppliers making it a general rule to ask scientists to confirm that any controlled substances under purchase are for research purposes only.

Another misconception is that laws around controlled substances simply list a few hundred substances (e.g. MDMA, Fentanyl, Amphetamine, etc.), and to meet compliance, all is needed is to check a CAS number, chemical name, or similar.

However, the majority of countries legislate for “generic statement" or “chemical space” laws, which control all chemicals similar to the “named” substance. These either include comprehensive descriptions similar to Markushes or plainly state that analogs are also controlled. Moreover, control of almost all named substances also encompasses their ethers, esters, salts, and stereoisomers. 

A single example of a "chemical space" statement from the UK Misuse of Drugs Act 1971 (Amendment) Order 2013 is shown below:

Any compound structurally derived from 3–(1–naphthoyl)indole, 3-(2-naphthoyl) indole, 1H–indol–3–yl–(1–naphthyl)methane or 1H-indol-3-yl-(2-naphthyl)methane by substitution at the nitrogen atom of the indole ring by alkyl, haloalkyl, alkenyl, cyanoalkyl, hydroxyalkyl, cycloalkylmethyl, cycloalkylethyl, (N-methylpiperidin-2-yl)methyl or 2–(4–morpholinyl)ethyl, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent.

As the legislation is so complex, many companies and institutions depend on Controlled Substances Squared as even smaller research operations can typically have bioactive collections running into 100 Ks of molecules at the 1-5 mg scale. These are more than likely to include some controlled substances. Such substances may not have been controlled when initially developed, but they have been declared as controlled at a later date.

Scitegrity has collaborated with the Association of the British Pharmaceutical Industry (ABPI), The Pistoia Alliance, and many of its clients to directly communicate with global legislators and encourage the design and implementation of feasible in vitro research exemptions without compromising the legislation for illicit use, or producing extra licensing, policing, or approval work for regulators. Scitegrity's software covers around 30 countries and international conventions.

Overview of known research exemptions in a few of the countries Scitegrity covers

Switzerland: There are limited exemptions to several Directory E substances, but what the exemption permits depends on the substance and which substances are covered. This is not always transparent, for instance, compounds similar to Fentanyl allow for the following:

“Excluded from the control is the industrial and scientific use. Private use is not exempt from the control.”

The exemption wording for Cyclohexylphenols is:

“Cyclohexylphenols are exempted from the control under Chapters 5 and 6 of the Narcotics Control Ordinance of 25 May 2011 if they are used industrially by undertakings holding an operating license for the handling of controlled substances in Inventory e. For substance quantities of up to 100 g, these companies do not require an import or export license”.

In certain analytical scenarios, import or export authorization is not a requirement concerning controlled substances in concentrations up to 1 mg/ml. (Art 23, Abs. 2b, BetmKV). Further qualifications are applicable e.g. annual limits as well limits on individual shipments.

United Kingdom: There are no particular research exemptions in the Misuse of Drugs Act. However, the related Misuse of Drug Regulations 2001 does offer exemptions to products containing no more than 1 mg of a controlled substance (1 ug for lysergide and derivatives) under the provision that several requirements are strictly followed, including that it cannot be easily recovered by readily applicable means, poses no risk to human health, and will not be administered to a human or animal subject. These are all "and" statements, e.g, all must be adhered to.

Although this initially seems to cover research use, in most circumstances, the sample is, by definition, “recoverable”. To prepare the sample for use, it is ‘recovered’ into an assay buffer or solvent, such as DMSO or water.

Working with various companies and institutions, Scitegrity has been actively trying to clarify the laws surrounding research exemptions and use.

When directly asked whether a microtiter plate holding a controlled substance could be classed as unrecoverable, the Home Office (the UK competent national and licensing authority for controlled drugs) could not offer a definitive disclosure on the matter, instead stating "...this is ultimately a matter of legal interpretation in the individual circumstances of each case and is for a court to determine".

This statement is likely to be indicative of the fact that microtiter plates and racks can contain anywhere between 1 nL to 1.8 mL per well depending on usage.

However, the Home Office was able to declare that:

(a) the 1mg limit applies to the total amount of each controlled substance across the entire microtitre plate.

(b) regardless of the destination plate amount, any source stock that contains more than 1 mg of a controlled substance would be considered controlled and require permits, and any replication of these would class as production.

In light of this information, most companies and researchers tend not to rely on this exemption for stocks or shipment of uL amounts, even though using it for sending/receiving nanoliter volumes in DMSO is a grey area. 

However, Home Office licensing states that "University research departments generally do not require licenses to possess and supply drugs in schedules 2, 3, 4 part I, 4 part II and schedule 5, but they do require licenses to produce any of those drugs and to produce, possess and/or supply drugs in schedule 1.”

While government advisors recently recommended that a partial extension to the research exemptions should be allowed, the government has not indicated whether this will be supported.

United States of America: In the US, there are no common research exemptions known to exist, at least at the federal level and the Controlled Substances Act.

Germany. The Gesetz über den Verkehr mit Betäubungsmitteln (Betäubungsmittelgesetz - BtMG) / (Law on the Traffic in Narcotic Drugs (Narcotics Act - BtMG) outlines that a partial exemption may apply to specific research cases.

The act allows for the following:

die Zubereitungen der in dieser Anlage aufgeführten Stoffe, wenn sie nicht

a) ohne am oder im menschlichen oder tierischen Körper angewendet zu werden, ausschließlich diagnostischen oder analytischen Zwecken dienen und ihr Gehalt an einem oder mehreren Betäubungsmitteln jeweils 0,001 vom Hundert nicht übersteigt oder die Stoffe in den Zubereitungen isotopenmodifiziert oder

b) besonders ausgenommen sind;

This can be translated as:

the preparations of the substances listed in this Appendix if they are not

a) without being applied to or in the human or animal body, for diagnostic or analytical purposes only, and their content of one or more anesthetics not exceeding 0.001 per cent, or isotope-modified in the preparations, or

b) are particularly excluded;

The exact percentage varies for each schedule. It is also not clear whether the ‘0.001%’ allows the rest to be an assay solvent or medium, or whether a license is required if in possession of a solid, e.g. 1 mg of sample before it has been diluted. 

The German Neue-psychoaktive-Stoffe-Gesetz (NpSG), which sets out to determine areas of chemical space controlled across Germany has an exemption that can be translated to: “Excluded from the prohibition are recognized uses of a novel psychoactive substance for commercial, industrial or scientific purposes and in accordance with the current state of science and technology.” 

This is only applicable to the NpSG and not the Narcotics Act above. Austria has also put in place similarly broad and generic statements, but also permits usage in legitimate commercial, industrial, or scientific purposes. Given the nature of these exemptions, these legislations are not covered in Controlled Substances Squared.

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