THF-F : report on the risk assessment of N-phenyl-N-1-(2-phenylethyl)piperidin-4- yloxolane-2-carboxamide in the framework of the Council Decision on new psychoactive substances.
Date: 2018-07-17
Institutions: European Monitoring Centre for Drugs and Drug Addiction
Subjects: drug addiction, health control, health policy, health risk, psychotropic substance, public health, scientific report

RISK ASSESSMENTS

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THF-F

Report on the risk assessment of N-phenyl-
N-[1-(2-phenylethyl)piperidin-4-
yl]oxolane-2-carboxamide in the framework 
of the Council Decision on new psychoactive 
substances

About this series

EMCDDA Risk Assessments are publications 
examining the health and social risks of 
individual new psychoactive substances.

The Risk Assessment Report consists of an 
analysis of the scientific and law enforcement 
information available on the new psychoactive 
substance under scrutiny and the implications 
of placing it under control. It is the outcome of 
a meeting convened under the auspices of the 
EMCDDA Scientific Committee.

This process is part of a three-step procedure 
involving information exchange/early warning, 
risk assessment and decision-making in the 
framework of Council Decision 2005/387/JHA.

 
RISK ASSESSMENT I THF-F 

Contents 

Foreword ................................................................................................................................................. 3 

EMCDDA actions on monitoring and responding to new drugs.............................................................. 4 

Europol–EMCDDA Joint Report on tetrahydrofuranylfentanyl (N-phenyl-N-[1-(2-phenylethyl)piperidin-
4-yl]tetrahydrofuran-2-carboxamide; THF-F) — a summary ................................................................... 5 

Risk Assessment Report on a new psychoactive substance: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]oxolane-2-carboxamide (tetrahydrofuranylfentanyl; THF-F) ............................................................... 6 

Technical report on N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide 
(tetrahydrofuranylfentanyl; THF-F) ........................................................................................................ 22 

Participants of the risk assessment meeting,  7-8 November 2017...................................................... 48 

Acknowledgements  

The EMCDDA would like to thank the following for their contribution in producing this publication: 

 

 

the members of the extended Scientific Committee of the EMCDDA; the advisers to the 
Scientific Committee and the invited external experts who took part in the risk assessment 
meeting; 
the Early Warning System (EWS) correspondents of the Reitox national focal points (NFPs) 
and experts from their national EWS networks;  
the services within each Member State that collected the raw data for the risk assessment; 

 
  Europol, the European Medicines Agency (EMA) and the European Commission; 
 
  Dr Simon Brandt, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores 

the World Health Organization; 

University, Liverpool; 

  Dr Simon Elliott, Alere Forensics, Worcestershire; 
  Dr István Ujváry, hon. associate professor, Budapest University of Technology and 
Economics; hon. associate professor, University of Szeged; iKem BT, Budapest. 

Project team: Anabela Almeida, Rachel Christie, Helgi Valur Danielsson, Rita Jorge, Joanna De 
Morais and Sofía Sola (EMCDDA) and Werner Verbruggen (Europol). 

Project leaders: Michael Evans-Brown, Ana Gallegos and Roumen Sedefov (EMCDDA). 

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RISK ASSESSMENT I THF-F 

Foreword 

This publication presents the data and findings of the risk assessment on the new psychoactive 
substance tetrahydrofuranylfentanyl (THF-F) (N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-
carboxamide), carried out by the extended Scientific Committee of the EMCDDA on 7 and 8 
November 2017. 

The Risk Assessment Report, which was submitted to the European Commission and the Council of 
the European Union on 14 November 2017, examines the health and social risks of the substance, 
information on international trafficking and the involvement of organised crime, as well as a 
consideration of the potential implications of subjecting the substance to control measures. 
Tetrahydrofuranylfentanyl is the twentieth new psychoactive substance to be risk assessed under the 
terms of Council Decision 2005/387/JHA. 

On the basis of the Risk Assessment Report on a new psychoactive substance, and, on the initiative 
of the European Commission, the Council may decide that the substance should be subject to control 
measures across the Member States. This decision is adopted in the final stage of the three-step 
process — early warning, risk assessment and control of new psychoactive substances — 
established by the Council Decision 2005/387/JHA. This legal framework allows the EU institutions 
and Member States to act on all new and potentially threatening narcotic and psychotropic drugs 
which appear on the European drug scene, with the EMCDDA and Europol, in collaboration with their 
respective networks, playing a central role in the early detection of such substances as well as the 
harms caused by their use — information that underpins risk assessment, and, ultimately, decision-
making.  

In March 2018, at its 61st regular session, the Commission on Narcotic Drugs (CND) decided to place 
tetrahydrofuranylfentanyl in Schedule I of the Single Convention on Narcotic Drugs of 1961 based on 
a recommendation by the World Health Organization. This recommendation was substantially 
supported by European data provided by the EMCDDA.  

In this respect we would like to acknowledge the excellent work done by the networks of the 
EMCDDA and Europol, as well as those of the EMA — the Reitox national focal points, Europol 
national units and the national competent authorities responsible for medicinal products — who 
played an essential role in collecting and providing national data. 

Finally, we would like to thank all the participants in the risk assessment process for the high quality of 
work carried out. The resulting report is a valuable contribution at European level, which gives clear 
support to political decision-making.  

Dr Anne Line Bretteville-Jensen 
Chair, Scientific Committee of the EMCDDA 

Alexis Goosdeel 
Director, EMCDDA 

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EMCDDA actions on monitoring and responding to 
new drugs  

The EMCDDA has been assigned a key role in the detection and assessment of new drugs in the 
European Union under the terms of a Council Decision 2005/387/JHA on the information exchange, 
risk-assessment and control of new psychoactive substances. 

It establishes a mechanism for the rapid exchange of information on new psychoactive substances 
and provides for an assessment of the risks associated with them in order to permit the measures 
applicable in the Member States for the control of narcotic and psychotropic substances to be applied 
also to new psychoactive substances. 

The three-step process involves information exchange/early warning, risk assessment and decision-
making (see below). More detailed information can be found in the section ‘Action on new drugs’ of 
the EMCDDA’s website: www.emcdda.europa.eu/activities/action-on-new-drugs  

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RISK ASSESSMENT I THF-F 

Europol–EMCDDA Joint Report on 
tetrahydrofuranylfentanyl (N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]tetrahydrofuran-2-
carboxamide; THF-F) — a summary 

Europol–EMCDDA Joint Report on a new psychoactive substance: N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]tetrahydrofuran-2-carboxamide — in accordance with Article 5 of 
Council Decision 2005/387/JHA on the information exchange, risk assessment and control of 
new psychoactive substances 

In March 2017, the EMCDDA and Europol examined the available information on a new psychoactive 
substance N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]tetrahydrofuran-2-carboxamide, commonly 
known by the abbreviation ‘tetrahydrofuranylfentanyl (THF-F)’, through a joint assessment based 
upon the following criteria: (1) the amount of the material seized; (2) evidence of organised crime 
involvement; (3) evidence of international trafficking; (4) analogy with better-studied compounds; (5) 
evidence of the potential for further (rapid) spread; and (6) evidence of cases of serious intoxication or 
fatalities. 

The EMCDDA and Europol agreed that the information available on tetrahydrofuranylfentanyl satisfied 
criteria 4 and 6. The two organisations therefore concluded that sufficient information has been 
accumulated to merit the production of a Joint Report on tetrahydrofuranylfentanyl as stipulated by 
Article 5.1 of the Decision. Accordingly, the NFPs, the Europol national units (ENUs), the EMA and 
the World Health Organization (WHO) were formally asked to provide the relevant information within 
six weeks from the date of the request, i.e. by 6 June 2017. 

The resulting Joint Report on was submitted to the Council, the Commission and the EMA on 3 July 
2017. The report concluded that the health and social risks, caused by the use of, the manufacture of, 
and traffic in tetrahydrofuranylfentanyl, as well as the involvement of organised crime and possible 
consequences of control measures, could be thoroughly assessed through a risk assessment 
procedure as foreseen by Article 6 of Council Decision 2005/387/JHA. 

The full text of the Joint Report can be found at: 
www.emcdda.europa.eu/publications/joint-reports/thf-f 

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RISK ASSESSMENT I THF-F 

Risk Assessment Report on a new psychoactive 
substance: N-phenyl-N-[1-(2-phenylethyl)piperidin-
4-yl]oxolane-2-carboxamide 
(tetrahydrofuranylfentanyl; THF-F) 

Introduction  

This Risk Assessment Report presents the summary findings and the conclusion of the risk 
assessment carried out by the extended Scientific Committee of the European Monitoring Centre for 
Drugs and Drug Addiction (EMCDDA) on the new psychoactive substance N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]oxolane-2-carboxamide, (commonly known as tetrahydrofuranylfentanyl). 
The report is intended for policy makers and decision makers in the institutions of the European 
Union. 

The report has been prepared and drafted in accordance with the conceptual framework and the 
procedure set out in the risk assessment operating guidelines ( 1). It is written as a stand-alone 
document, which presents a summary of the information considered during the detailed analysis of 
the scientific and law enforcement data available at this time. The conclusion section of the report 
summarises the main issues addressed and reflects the opinions held by the members of the 
Scientific Committee. A list of the information resources considered by the Scientific Committee, 
including a detailed technical report on tetrahydrofuranylfentanyl, is provided below.  

The risk assessment has been undertaken in compliance with Article 6 of Council Decision 
2005/387/JHA of 10 May 2005 on the information exchange, risk assessment and control of new 
psychoactive substances ( 2) (hereafter ‘Council Decision’). The Council Decision establishes a 
mechanism for the rapid exchange of information on new psychoactive substances (hereafter ‘EU 
Early Warning System’ (3)) that may pose public health and social threats, including those related to 
the involvement of organised crime. Thus, it allows the institutions of the European Union and the 
Member States to act on all new narcotic and psychotropic substances ( 4) that appear on the 
European Union drug market. The Council Decision also provides for an assessment of the risks 

(1)  

(2) 

(3) 

(4) 

EMCDDA (2010), Risk assessment of new psychoactive substances: Operating guidelines, Publications Office of the 
European Union, Luxembourg. Available at: http://www.emcdda.europa.eu/html.cfm/index100978EN.html 

OJ L 127, 20.5.2005, p. 32. 

The information exchange mechanism laid down by the Council Decision is operationalized as the European Union 
Early Warning System on New Psychoactive Substances (‘EU Early Warning System’). It is operated by the 
EMCDDA and Europol in partnership with the Reitox national focal points and Europol national units in the Member 
States, the European Commission, and the European Medicines Agency. 

According to the definition provided by the Council Decision, a ‘new psychoactive substance’ means a new narcotic 
drug or a new psychotropic drug in pure form or in a preparation; ‘new narcotic drug’ means a substance in pure form 
or in a preparation that has not been scheduled under the 1961 United Nations Single Convention on Narcotic Drugs, 
and that may pose a threat to public health comparable to the substances listed in Schedule I, II or IV; ‘new 
psychotropic drug’ means a substance in pure form or in a preparation that has not been scheduled under the 1971 
United Nations Convention on Psychotropic Substances, and that may pose a threat to public health comparable to 
the substances listed in Schedule I, II, III or IV. 

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associated with these new psychoactive substances so that, if necessary, control measures can be 
applied in the Member States for narcotic and psychotropic substances ( 5). 

Tetrahydrofuranylfentanyl was formally notified on 23 December 2016 by the EMCDDA on behalf of 
the Swedish national focal point, in accordance with Article 4 of the Council Decision. The notification 
related to the seizure of 22 millilitres of pale yellow liquid seized on 29 September 2016 by police. 
Following an assessment of the available information on tetrahydrofuranylfentanyl, and, in 
accordance with Article 5 of the Council Decision, on 3 July 2017 the EMCDDA and Europol 
submitted a Joint Report on tetrahydrofuranylfentanyl ( 6) to the Council of the European Union, the 
European Commission, and the European Medicines Agency (EMA). Taking into account the 
conclusion of the Joint Report, and, in accordance with Article 6 of the Council Decision, on 14 
September 2017 the Council formally requested that ‘the risk assessment should be carried out by the 
extended Scientific Committee of the EMCDDA and be submitted to the Commission and the Council 
within twelve weeks from the date of this notification’. 

In accordance with Article 6.2, the meeting to assess the risks of tetrahydrofuranylfentanyl was 
convened under the auspices of the Scientific Committee of the EMCDDA with the participation of 
four additional experts designated by the Director of the EMCDDA, acting on the advice of the 
Chairperson of the Scientific Committee, chosen from a panel proposed by Member States and 
approved by the Management Board of the EMCDDA. The additional experts were from scientific 
fields that were either not represented, or not sufficiently represented on the Scientific Committee, 
and whose contribution was necessary for a balanced and adequate assessment of the possible risks 
of tetrahydrofuranylfentanyl, including health and social risks. A further four experts participated in the 
risk assessment: two experts from the Commission, one expert from Europol, and one expert from the 
European Medicines Agency (EMA). The meeting took place on 8 November 2017 at the EMCDDA in 
Lisbon. The risk assessment was carried out on the basis of information provided to the Scientific 
Committee by the Member States, the EMCDDA, Europol, and the EMA. A list of the extended 
Scientific Committee, as well as the list of other participants attending the risk assessment meeting, is 
annexed to this report (page 48). 

For the risk assessment, the extended Scientific Committee considered the following information 
resources: 

  Technical report on N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide 

(tetrahydrofuranylfentanyl) (Annex 1);   

  EMCDDA–Europol Joint Report on a new psychoactive substance: N-phenyl-N-[1-(2-

phenylethyl)piperidin-4-yl]tetrahydrofuran-2-carboxamide (tetrahydrofuranylfentanyl) (6); 

  Open source information including scientific articles, official reports, grey literature, internet 

drug discussion forums and related websites (hereafter ‘user websites’); 

  Additional information provided during the course of the risk assessment by the participants; 

  The EMCDDA operating guidelines for the risk assessment of new psychoactive substances 

(1); and, 

(5) 

(6) 

In compliance with the provisions of the United Nations Single Convention on Narcotic Drugs, 1961, and the United 
Nations Convention on Psychotropic Substances, 1971. 

EMCDDA (2017), EMCDDA–Europol Joint Report on a new psychoactive substance N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]tetrahydrofuran-2-carboxamide (tetrahydrofuranylfentanyl), Lisbon. Available at: 
http://www.emcdda.europa.eu/publications/joint-reports/thf-f 

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  Council Decision 2005/387/JHA of 10 May 2005 on the information exchange, risk 

assessment and control of new psychoactive substances (2). 

Finally, it is important to note that this risk assessment report contains a discussion of the available 
information on serious adverse events such as acute intoxications (typically presenting to hospital 
emergency departments) and deaths associated with tetrahydrofuranylfentanyl. Such information is 
critical to the identification of emerging toxicological problems associated with new psychoactive 
substances within the European Union. In this context, it is important to recognise that the capacity to 
detect, identify, and report these events differ both within and between Member States. In the past 
few years, programmes have been introduced in some Member States to strengthen these capacities. 
The EMCDDA’s toxicovigilance system, which is a central component of the EU Early Warning 
System, has also been strengthened resulting in more information being available regarding serious 
adverse events associated with new psychoactive substances. Nonetheless, it is likely that these 
events remain under-detected and under-reported.  

Physical, chemical and pharmacological description 

N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide (tetrahydrofuranylfentanyl or THF-
F) is structurally related to fentanyl, which is a propionamide. Tetrahydrofuranylfentanyl contains one 
basic nitrogen atom in the piperidine ring and readily forms salts with organic or inorganic acids. 
Fentanyl analogues (fentanils) have in common an aralkyl group attached to a 4-N-
acylanilinopiperidine. 

Until 2017, information about tetrahydrofuranylfentanyl could not be identified in the scientific 
literature, which suggests that this compound has no published history. Tetrahydrofuranylfentanyl is 
the saturated derivative of furanylfentanyl which was risk-assessed by the Scientific Committee of the 
EMCDDA in May 2017.  

Pharmacologically, tetrahydrofuranylfentanyl is an opioid receptor agonist. 

Synthetic opioids like fentanyl and related 4-anilinopiperidine derivatives are potent analgesics. 
Initially developed in the 1960’s as part of research efforts to develop safer and better opioid 
analgesics, a small number of this family of compounds—alfentanil, fentanyl, sufentanil and 
remifentanil—have become widely used in human medicine as adjuncts to general anaesthesia 
during surgery and for pain management. They are available in a wide variety of formulations, such as 
liquids for injection, tablets, transdermal patches, lozenges, and nasal sprays. Some are also used in 
veterinary medicine as general anaesthetics, for pain management, and, in the case of carfentanil and 
thiofentanil, to immobilise large animals.  

Fentanil analogues first emerged on the illicit drug market in the United States of America in 1979. At 
the time they were not controlled under drug legislation. They were manufactured in clandestine 
laboratories and sold on the heroin market as heroin or ‘synthetic heroin’.  

A total of fifteen fentanils are controlled under the United Nations Single Convention on Narcotic 
Drugs, 1961, as amended by the 1972 Protocol. 

The major pharmacological effects of the fentanils, including their analgesic activity, are due to their 
activation of opioid receptors, and, in particular, the µ-opioid receptor. Besides their analgesic 
properties, a notable feature associated with µ-opioid receptor agonists is that they cause dose-
dependent respiratory depression, which in overdose can be life-threatening. Other additional 

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RISK ASSESSMENT I THF-F 

pharmacological effects include miosis, sedation, bradycardia, hypothermia, constipation, physical 
dependence, and changes in mood such as euphoria. 

Tetrahydrofuranylfentanyl as free base or as its hydrochloride salt may occur as solids. Due to its 
similarity to fentanyl, the free base could be expected to be sparingly soluble in water; whereas its 
hydrochloride and citrate salt is expected to have greater aqueous solubility; the free base is expected 
to be lipophilic.  

In Europe, tetrahydrofuranylfentanyl has been seized as powder and in liquid solutions. In the latter 
case the available data suggests that tetrahydrofuranylfentanyl is sold online on the surface web as 
ready to use nasal sprays.  

The analytical identification of tetrahydrofuranylfentanyl in physical and biological samples is possible 
using several analytical techniques. These include chromatographic and mass-spectrometric 
techniques. Routine commercially available immunoassays may not detect this compound. 

Analytical reference materials are important for the correct identification and for facilitating the 
quantification of tetrahydrofuranylfentanyl in physical and biological samples. Such reference 
materials are commercially available. It should be noted that concentrations in blood samples can be 
in the sub-nanogram per millilitre range.  

As tetrahydrofuranylfentanyl has only been on the drug market for a short period of time it may not be 
part of most drug screenings and therefore may be under-detected and under-reported. 

Route of administration and dosage 

As with other fentanils, tetrahydrofuranylfentanyl can be administered orally as a powder (including in 
capsules), as tablets, or as a solution (using nasal sprays), or by insufflation of a powder; it can also 
be administered intranasally or sublingually via a spray; inhaled by smoking or vaporizing; and, 
administered by injection (intravenous and intramuscular). 

Limited information is available regarding the dose and the dose regimens of 
tetrahydrofuranylfentanyl. It is not possible to currently discern the ‘typical’ dosages administered by 
users. Doses appear to differ depending on factors such as the route of administration, the tolerance 
of the users, the use of other drugs, and the desired effects. 

Pharmacology 

Currently available data on the pharmacodynamics of tetrahydrofuranylfentanyl are limited to studies 
investigating its binding and functional activity at opioid receptors in vitro. These data show that 
tetrahydrofuranylfentanyl is a highly selective μ-opioid receptor agonist in vitro, and that it is less 
potent than morphine and fentanyl.  

A recent study indicates that the metabolic pathway of tetrahydrofuranylfentanyl shares some 
similarities with fentanyl. Consequently drug-drug interactions observed with fentanyl might equally 
apply. 

The concomitant use of other central nervous system (CNS) depressants, including other opioids, 
sedatives/hypnotics, ethanol, pregabalin, gabapentin, tranquillisers, and sedating anti-histamines, 
may produce additive depressant effects. 

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Psychological and behavioural effects 

From the available data, the psychological and behavioural effects of tetrahydrofuranylfentanyl may 
share some similarities with fentanyl and other opioid analgesics. These would include relaxation and 
euphoria; at higher doses, sedation and profound intoxication may occur. 

Legitimate uses 

Tetrahydrofuranylfentanyl is used as an analytical reference material in clinical and forensic case 
work/investigations as well as scientific research. There is currently no information that suggests 
tetrahydrofuranylfentanyl is used for other legitimate purposes. 

There are no reported uses of tetrahydrofuranylfentanyl as a component in industrial, cosmetic or 
agricultural products. In addition, a search of the Registration, Evaluation, Authorisation and 
Restriction of Chemicals (REACH) registered substances database hosted by the European 
Chemicals Agency (ECHA) using the available CAS Registry Numbers returned no hits. 

There is no marketing authorisation (existing, on-going, or suspended) for tetrahydrofuranylfentanyl in 
the European Union or in the Member States that responded to the request for information that was 
undertaken as part of the Joint Report process (6). 

There is no information to suggest that tetrahydrofuranylfentanyl is currently used in the manufacture 
of a medicinal product in the European Union (6). However, in the absence of a database on the 
synthetic routes of all medicinal products it is not possible to confirm whether or not 
tetrahydrofuranylfentanyl is currently used in the manufacture of a medicinal product. 

Chemical precursors that are used for the manufacture 

Information on the chemical precursors and the synthetic methods employed for 
tetrahydrofuranylfentanyl detected on the drug market within the European Union is limited. However, 
analysis of a collected sample of tetrahydrofuranylfentanyl that was test purchased from an online 
vendor apparently based in China also identified ‘4-aminophenyl-1-phenethylpiperidine’, i.e. N-phenyl-
1-(2-phenylethyl)piperidin-4-amine (4-ANPP), which is a commonly used precursor for synthesising 
many fentanyl analogues.  

A synthesis procedure for tetrahydrofuranylfentanyl could not be identified in the literature; however 
the manufacture of tetrahydrofuranylfentanyl most likely relies on precursors and synthetic methods 
similar to those used for the manufacture of pharmaceutical fentanyl. Accordingly, methods developed 
for the synthesis of fentanyl are applicable to tetrahydrofuranylfentanyl. Most of these are 
straightforward, make use of common laboratory equipment and precursors, and require only basic 
knowledge of chemistry. The substances 4-ANPP and tetrahydrofuran-2-carbonyl chloride could be 
used for the manufacture of the substance. It has been demonstrated that N-(2-furoyl)piperazine 
could be directly reduced to N-(tetrahydro-2-furoyl)piperazine, but whether this is applicable to the 
reduction of furanylfentanyl to tetrahydrofuranylfentanyl remains to be studied. If this were feasible 
then it would suggest that furanylfentanyl might serve as a precursor to tetrahydrofuranylfentanyl. 

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RISK ASSESSMENT I THF-F 

Two potential precursors of tetrahydrofuranylfentanyl and other fentanils, 4-ANPP as well as N-
phenethyl-4-piperidone (NPP, a pre-precursor), have been recently scheduled ( 7). 

Tetrahydrofuranylfentanyl poses a risk of poisoning if accidental exposure occurs during its 
manufacture. Extreme care must be taken when carrying out the final synthetic step as well as when 
purifying and handling the substance. 

Health risks 

Individual health risks 

The assessment of individual health risks includes consideration of the acute and chronic toxicity of 
tetrahydrofuranylfentanyl, as well as its dependence potential, and its similarities to and differences 
from other chemically or pharmacologically related substances. 

It is important to note that when interpreting the information from acute intoxications and deaths 
reported to the EMCDDA as well as information from user websites, that individuals may have used 
other substances in addition to tetrahydrofuranylfentanyl. The presence of and/or interaction with 
other substances or pre-existing health conditions may account for some of the reported effects. 

While specific information for tetrahydrofuranylfentanyl is limited, of note is the apparent popularity of 
selling ready-to-use or using homemade nasal sprays containing solutions for the administration of 
fentanils. These typically contain milligram amounts of dissolved substance. The preparation of such 
solutions is inherently prone to mistakes in weighing and dilution which may lead to solutions with 
higher (or lower) concentrations. This may constitute an increased risk of acute toxicity to the 
individuals, who are unlikely to be able to control the dose of fentanil being consumed. 

In addition, recent seizures in Europe of nasal sprays containing other fentanils found that these have 
been sold in some cases as unlabelled bottles. In other cases, users have also filled nasal sprays 
previously containing medicines (such as nasal decongestants) with fentanils. The lack of labelling 
increases the potential for accidental use by others and therefore poses a risk of poisoning. 

Tetrahydrofuranylfentanyl may be used in combination with other drugs (intentionally or 
unintentionally).  

Acute toxicity 

The acute toxicity of tetrahydrofuranylfentanyl and/or its metabolites has not been studied in non-
clinical and clinical studies.  

Although the pharmacology and toxicology of tetrahydrofuranylfentanyl remains largely unstudied, the 
available data suggests that the nature of its effects share some similarities with opioid analgesics 
such as morphine and fentanyl. The acute effects of these types of opioids include: euphoria, 
relaxation, analgesia, sedation, bradycardia, hypothermia, and respiratory depression. They also have 
an abuse liability and dependence potential. 

(7) 

Table I of the United Nations Convention against Traffic in Narcotic Drugs and Psychotropic Substances, 1988  

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While there is limited data on the clinical features of poisoning caused by tetrahydrofuranylfentanyl, 
they are likely to include reduced level of consciousness or unconsciousness, respiratory depression 
and arrest, and miosis. Similar to other opioid analgesics, the most serious acute risk arising from the 
use of tetrahydrofuranylfentanyl is probably respiratory depression, which can lead to apnoea, 
respiratory arrest, and death.  

The timely administration of the antidote naloxone should reverse acute poisoning caused by 
tetrahydrofuranylfentanyl. Recent clinical and community experience in treating poisonings caused by 
fentanils suggests that larger than normal doses and repeated doses of naloxone may be required to 
manage the poisoning in some cases; longer periods of observation may also be required. 

In general for fentanils, the risk of life-threatening poisoning may be exacerbated by: the difficulty in 
diluting/using fentanils (as they are typically highly potent), which can lead to a toxic dose being 
accidentally used; the apparent rapid onset of severe poisoning following use; using routes of 
administration that allow large amounts of the substance to rapidly reach the central nervous system 
(such as injecting, insufflation, and inhalation); availability of easy to use dosage forms (such as nasal 
sprays and e-liquids); lack of awareness and experience of users with these new substances (effects 
and dosage); use of other central nervous system depressants (such as other opioids, 
benzodiazepines, and alcohol); lack of tolerance to opioids in opioid-naïve persons (such as new or 
former users); use in environments where it may be difficult to summon help in the event of poisoning 
(e.g. alone in a home environment); and, limited availability of the antidote naloxone in community 
settings. 

In addition, and, often unknown to users, the fentanils are sold as heroin or mixed with heroin. They 
are also used to make counterfeits of highly sought-after analgesics and benzodiazepines. They have 
also been sold in or as drugs such as cocaine. Due to this, users may not be aware that they are 
using a fentanil; in some cases these individuals will have no tolerance to opioids nor access to 
community naloxone programmes. Overall, these factors may increase the risk of life-threatening 
poisoning. 

Acute intoxications 

A single case of acute intoxication with confirmed exposure to tetrahydrofuranylfentanyl was reported 
to the EMCDDA. The case occurred in Sweden and involved a 26 year old male who had 
administered 8 actuations of a 'fentanyl' nasal spray. The poisoning was classed as severe. The 
clinical features were consistent with the use of an opioid analgesic, and included reduced 
consciousness, respiratory depression and miosis. The patient was treated with 0.2 mg of naloxone 
(route of administration and response was not reported). The only other substance detected was 
flunitrazolam. The patient survived.  

Deaths 

A total of 14 deaths were reported by 1 Member State: Sweden. In all cases, tetrahydrofuranylfentanyl 
was analytically confirmed from post-mortem samples (femoral blood or muscle).  

The deaths occurred between September 2016 and March 2017 with 8 occurring in 2016 and 6 in 
2017. Of these deaths, 8 were male (57%) and 6 were female (43%). The mean age of the males was 
31 years (median 29) and ranged from 25 to 41 years; the mean age of the females was 32 years 
(median 30) and ranged from 29 to 38 years. 

12 

 
 
RISK ASSESSMENT I THF-F 

Cause of death and toxicological significance 

The cause of death was reported in 13 out of 14 cases. In at least 12 deaths, intoxication with 
tetrahydrofuranylfentanyl was reported either as the cause of death or as likely to have contributed to 
death (even in presence of other substances); other substances were detected in all 14 cases. 

Tetrahydrofuranylfentanyl was quantified in 5 cases. Post-mortem femoral blood concentrations 
ranged from 2 to 54 ng/g blood (median 18 ng/g blood). For a number of reasons, including variability 
in user tolerance, determination of a ‘fatal’ concentration based on a post-mortem blood concentration 
may not be reliable. In the majority of circumstances involving fentanils, the mere presence of the 
drug is of significance whether concentration has been determined or not, especially in situations of 
poly-drug use. 

A range of other substances were detected in the reported deaths, including: benzodiazepines, 
zopiclone, pregabalin, antidepressants, antipsychotics, antihistamines, synthetic cathinones, 
anticonvulsants, and ethanol. Other opioids were detected in 3 of the deaths: tramadol, 
benzodioxolfentanyl, and acryloylfentanyl. 

Overall, whilst other substances may have contributed some toxicity, a synergistic effect with 
tetrahydrofuranylfentanyl would have been likely with other central nervous system depressants such 
as ethanol, benzodiazepines, opioids, etc. Nevertheless, the apparent fentanyl-like nature of 
tetrahydrofuranylfentanyl means that the primary toxic contribution could be attributed to the 
tetrahydrofuranylfentanyl and death may not have occurred if tetrahydrofuranylfentanyl had not been 
used. An assessment of the toxicological significance score (TSS) (8) incorporating the above 
considerations showed that tetrahydrofuranylfentanyl had a TSS value of 3 (high) in 13 out of 14 of 
the deaths (where it was cited as the cause of death or is likely to have contributed to death). In the 
remaining death, an alternative pathological cause of death was cited (TSS value of 1, low). 

Circumstances of death 

In all but one case, the individuals were found dead (predominantly in a home environment). In all 
cases there was a lack of information regarding symptoms experienced by the deceased prior to 
death. Consequently, it was not possible to identify or evaluate ante-mortem symptoms (especially in 
relation to acute intoxication). 

Ability to operate machinery and drive 

There have been no studies of the effects of tetrahydrofuranylfentanyl on the ability to drive and 
operate machines. However, it is well established that opioid narcotic analgesics, such as fentanyl, 
impair the mental and physical ability required to drive and operate machines. This effect is likely to 
extend to tetrahydrofuranylfentanyl. 

Chronic toxicity 

No studies were identified that investigated the chronic health effects of tetrahydrofuranylfentanyl 
and/or its metabolites. 

(8) 

Elliott, S., Sedefov, R. and Evans-Brown, M. (2017), 'Assessing the toxicological significance of new psychoactive 
substances in fatalities', Drug Testing and Analysis. https://doi.org/10.1002/dta.2225 

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RISK ASSESSMENT I THF-F 

Abuse liability and dependence potential 

There have been no studies that have investigated the abuse liability and dependence potential of 
tetrahydrofuranylfentanyl. Given what is currently known about its pharmacology, including some 
similarities to other fentanils and opioid narcotic analgesics, it may have a potential for abuse and 
dependence. Further research will be required in order to determine such effects. 

Public health risks 

The public health risks associated with tetrahydrofuranylfentanyl may be categorised in terms of 
patterns of use (extent, frequency, route of administration, etc.); availability and quality of the drug; 
information, availability and levels of knowledge amongst users; and, negative health consequences. 
Detailed information, including data on sporadic versus chronic use, that allow for a determination of 
public health risks associated with tetrahydrofuranylfentanyl are not available. In addition, risk of 
accidental exposure needs to be considered.  

Extent, frequency, and patterns of use 

No studies were identified that have investigated the prevalence of use of tetrahydrofuranylfentanyl in 
the general population. Given its pharmacology and that it is sold openly as a ‘legal’ replacement to 
illicit opioids, it would be expected that users looking for substitutes for opioids, which would include 
individuals who use illicit opioids, such as heroin and/or prescription opioids, may seek out 
tetrahydrofuranylfentanyl and other fentanils. It also appears that there is interest in this substance by 
some psychonauts. Overall, the available information does not suggest widespread use of the 
substance. 

Tetrahydrofuranylfentanyl appears to be sold online in small and wholesale amounts as powders and 
ready-to-use nasal sprays (sometimes as a ‘research chemical’).  

Availability and quality on the market 

A total of 53 seizures have been reported by one Member State, Sweden. Of these, 26 seizures 
occurred in 2016, and the other 27 in the first 6 months of 2017.  

A majority of the seizures were made by police at street-level (50 cases), as liquids (48 seizures) and 
powders (5 seizures). 

It is important to note that detections of tetrahydrofuranylfentanyl may be under-reported since the 
substance is not routinely screened for. 

Nasal sprays claiming to contain tetrahydrofuranylfentanyl have been offered by online vendors within 
the European Union. The availability of tetrahydrofuranylfentanyl on the darknet is not currently 
known.   

Characteristics and behaviour of users 

No studies were identified that have examined the characteristics and behaviours of users of 
tetrahydrofuranylfentanyl. While no specific examples are available on the possible appeal of the 
substance to specific user groups (aside from psychonauts), it is reasonable to assume that it may 
may be sought by those looking for ‘legal’ substitutes for illicit opioids, such as heroin and/or 
prescription opioids.  

14 

 
 
RISK ASSESSMENT I THF-F 

The available information, including deaths reported by the Member States, suggests that of 
tetrahydrofuranylfentanyl is used in the home environment. In the majority of the deaths reported to 
the EMCDDA the individuals were found dead, often in a home environment (their own or someone 
else’s). It appears that in at least some of these cases the poisoning with tetrahydrofuranylfentanyl 
was so severe that they were unable to call for help.  

Information from the deaths reported to the EMCDDA found that in the majority of the deaths, 
tetrahydrofuranylfentanyl was the sole opioid present, suggesting that they may have had no 
tolerance to opioids. In addition, polydrug use was common, including the use of other CNS 
depressants. 

Nature and extent of health consequences 

In addition to the individual health risks that are discussed above, there are some further 
considerations related to the fentanils as a group that should be considered in respect to potential 
risks to public health. 

Mirroring the increased availability of fentanils on the drug market over the past few, there has also 
been an increase in the number of outbreaks of mass poisoning caused by fentanils, particularly in 
the United States and Canada. These types of outbreaks have had the potential to overwhelm 
emergency responders and other local healthcare systems, as well as deplete stocks of naloxone. 
Stocks and availability of the naloxone, as well as adequacy of training in how to resuscitate poisoned 
patients both in clinical and community settings may need to be assessed. This might also include a 
review of the availability of naloxone to users through take-home naloxone programmes. 

As noted, new dosage forms—such as ready-to-use nasal sprays and e-liquids for vaping—along with 
open sales on the surface web and darknet marketplaces add to the complexity of the problem 
caused by the fentanils. They have become easier to get hold of and easier to use. The Committee is 
concerned about whether the availability of ‘novel’ dosage forms has the potential to make the use of 
fentanils more socially acceptable. 

An additional challenge in respect to reducing risk in users and potential users is the balance between 
providing information to prevent harm and the unintended consequences of communicating the risks 
of opioids. There is evidence that using terms to describe them as 'potent', 'strong', 'deadly', and 'toxic' 
can lead some individuals to specifically seek out these substances. Such unintended promotion of 
the substances may also extend to former users and other groups. 

Adding to these challenges is evidence from Europe, the United States, and Canada that fentanils are 
being sold to unsuspecting users in/as heroin, counterfeit medicines (including commonly used opioid 
analgesics and benzodiazepines), cocaine, and other illicit drugs. As users will be unaware of this, it 
increases the risk of severe and fatal poisoning in both opioid users and especially other groups who 
may have no existing tolerance to opioids. Non-opioid users are unlikely to be aware of these risks 
and are unlikely to have access to community opioid overdose prevention programmes, including 
take-home naloxone programmes. 

Accidental exposure to fentanils may also pose a risk of poisoning to those who may come into 
contact with the substances. This includes the family and friends of users, law enforcement, 
emergency personnel, medical and forensic laboratory personnel, as well as those in custodial 
settings and postal services. Where necessary, specific risks should be identified and assessed, and, 
appropriate measures to reduce these risks should be implemented. This may include appropriate 
protective equipment, training in resuscitation, and making naloxone readily available to relevant 

15 

 
 
RISK ASSESSMENT I THF-F 

personnel in sufficient quantities in the event of poisonings. Any required measures should continue 
to ensure the delivery of prompt and appropriate care to patients with suspected overdose. 

Long-term consequences of use 

There is no information on the long-term consequences of use of tetrahydrofuranylfentanyl. 

Conditions under which the substance is obtained and used 

There is limited information on the conditions which tetrahydrofuranylfentanyl is obtained and used. 
Tetrahydrofuranylfentanyl appears to be sold on the surface web, typically as ready-to-use nasal 
sprays. 

Overall, tetrahydrofuranylfentanyl may be deliberately sought after by some users; others, such as 
those that purchase it at street-level, may be unaware that they are using the substance which 
presents an inherent risk to the individuals. 

Social risks  

While there have been no studies on the social risks of tetrahydrofuranylfentanyl, it is likely that some 
of the risks are similar to those seen with opioids such as fentanyl and heroin. 

Individual social risks 

There is no information on whether the use of tetrahydrofuranylfentanyl causes individual social risks; 
however, any such risks may have some similarities with those associated with the use of illicit 
opioids, including fentanyl. These may impact on education or career, family or other personal and 
social relationships and may result in marginalisation. 

Possible effects on direct social environment (e.g. neglect of family, violence) 

There is no information on the possible effects of tetrahydrofuranylfentanyl on the direct social 
environment; however, any such risks may have some similarities with those associated with the use 
of illicit opioids.  

Possible effects on society as a whole (public order and safety, acquisitive crime) 

There is no specific information on the possible effects of tetrahydrofuranylfentanyl on society as a 
whole.  

As discussed above, accidental exposure of fentanils may pose a risk of poisoning to those who may 
come into contact with the substances. This includes the family and friends of users, law enforcement, 
emergency personnel, medical and forensic laboratory personnel, as well as those in custodial 
settings and postal services. 

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RISK ASSESSMENT I THF-F 

Economic costs  

There are no data on the effects of tetrahydrofuranylfentanyl in respect to its health and social costs. 

Possible appeal to specific population groups 

Whilst no specific examples are available on the possible appeal of tetrahydrofuranylfentanyl to user 
groups, it is reasonable to assume that the substance may be sought by those looking for substitutes 
for illicit opioids, such as heroin and/or prescription opioids.  

As highlighted, concerns exist over the use of fentanils with novel dosage forms—such as ready-to-
use and homemade nasal sprays and e-liquids for vaping—which have the potential to make the use 
of these substances easier (with similar effects to injecting) and more socially acceptable. Further 
research is required on this topic to better understand the risks. 

Information on manufacturing, trafficking, distribution, and the level of 
involvement of organised crime  

There is no information to suggest the involvement of organised crime or established criminal groups 
in the manufacture, distribution, and supply of tetrahydrofuranylfentanyl.  

Slovenia reported a collected sample of tetrahydrofuranylfentanyl to Europol and the EMCDDA where 
the country of origin was reported as China ( 9). 

The seizure of an illicit laboratory producing fentanils in Europe in 2013 suggests that the capability to 
manufacture fentanils may exist within the European Union. 

Information on any assessment in the United Nations system 

The World Health Organization (WHO) is the specialised United Nations agency designated for the 
evaluation of the medical, scientific and public health aspects of psychoactive substances under the 
Single Convention on Narcotic Drugs, 1961, and the Convention on Psychotropic Substances, 1971. 
In May 2017, the WHO informed the EMCDDA that tetrahydrofuranylfentanyl will be reviewed at the 
39th meeting of the WHO Expert Committee on Drug Dependence (ECDD) that will be held in 
November 2017. 

Description of the control measures that are applicable in the Member 
States 

Five Member States (France, Latvia, Lithuania, Sweden, and the United Kingdom) reported that 
tetrahydrofuranylfentanyl is controlled under drug control legislation. 

 

In France, tetrahydrofuranylfentanyl is controlled as of 5 September 2017. 

(9) 

The sample also contained 4-aminophenyl-1-phenethylpiperidine (4-ANPP), a precursor that can be used for the 
synthesis of fentanyl and many fentanil analogues. 

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RISK ASSESSMENT I THF-F 

 

 

 

 

In Latvia, tetrahydrofuranylfentanyl is included in the Cabinet Regulation N 847 ‘Regulations 
regarding Narcotic Substances, Psychotropic Substances and Precursors to be Controlled in 
Latvia’ and the law ‘On the Procedures for the Coming into force and Application of the 
Criminal Law’.  

In Lithuania, tetrahydrofuranylfentanyl is subjected to control measures by The Republic of 
Lithuania Minister of Health Order No V-853 (07/07/2017) ‘On the amendment of the Ministry 
of Health of the Republic of Lithuania Order No. 5 of 6 January 2000’. 

In Sweden, tetrahydrofuranylfentanyl is regulated under the Act on the Prohibition of Certain 
Goods Dangerous to Health, as of 25 January 2017. 

In the United Kingdom, tetrahydrofuranylfentanyl is controlled under the Misuse of Drugs Act 
1971 by way of a generic definition.  

Three Member States (Austria, Belgium, and Poland) reported that tetrahydrofuranylfentanyl is 
controlled under specific new psychoactive substances control legislation.  

 

 

 

In Austria, tetrahydrofuranylfentanyl is covered by the phenethylamine generic definition 
within the Austrian Act on New Psychoactive substances. 

In Belgium, tetrahydrofuranylfentanyl is controlled by way of generic definition.  

In Poland, tetrahydrofuranylfentanyl is controlled according to the general definition of the 
‘substitute drug’ (Act of 8 October 2010 amending the Act on counteracting drug addiction 
and the Act on State Sanitary Inspection, Journal of Laws “Dz.U.” No. 213, item 1396). 
Pursuant to Article 44b of the Act on counteracting drug addiction, it is prohibited to 
manufacture and introduce substitute drugs to trade.  

Norway reported that tetrahydrofuranylfentanyl is controlled under medicines legislation. 

Nineteen Member States (Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, 
Germany ( 10), Greece, Hungary (10), Ireland, Italy, Luxembourg, Malta, the Netherlands, Portugal, 
Romania, Slovenia, and Spain) and Turkey reported that tetrahydrofuranylfentanyl is not subject to 
control measures at the national level. 

Slovakia did not provide information on the control status of tetrahydrofuranylfentanyl. 

Options for control and the possible consequences of the control 
measures 

Under Article 9.1 of the Council Decision, the option for control that is available at European Union 
level is for the Member States to submit the new psychoactive substance tetrahydrofuranylfentanyl to 
control measures and criminal penalties, as provided for under their legislation, by virtue of their 
obligations under the Single Convention on Narcotic Drugs, 1961.  

(10) 

As part of the Joint Report process, it was reported by the German and Hungarian national focal points that 
tetrahydrofuranylfentanyl is not controlled in Germany and Hungary, respectively (6). However, during the risk 
assessment meeting, two experts who were present informed that the substance is controlled under specific new 
psychoactive substances control legislation, by way of generic definition. As such, the control of the substance has 
been reflected in the totals that are presented in the conclusion. 

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RISK ASSESSMENT I THF-F 

There are no studies on the possible consequences of such control measures on 
tetrahydrofuranylfentanyl. If this option of control is pursued, the Committee considers that the 
following consequences are possible. Some of these may apply to any new psychoactive substance. 

  This control option could be expected to limit the availability of tetrahydrofuranylfentanyl and 

hence the further expansion of the current open trade in this substance. 

  A health consequence that might result from this control option is the benefit brought about by 

the presumed reduction in availability and use.  

  This control option could facilitate the detection, seizure and monitoring of 

tetrahydrofuranylfentanyl related to its unlawful manufacture, trafficking and use. In so doing, 
it could facilitate cooperation between the judicial authorities and law enforcement agencies 
across the European Union. 

  This control option would imply additional costs for the criminal justice system, including 

forensic services, law enforcement, and the courts. 

  This control option could lead to replacement with other (established or new) psychoactive 
substances, which may in themselves have public health consequences and social risks.  

  This control option could create an illicit market in tetrahydrofuranylfentanyl with the increased 

risk of associated criminal activity, including the involvement of organised crime. 

  This control option could impact on both the quality/purity and price of any 

tetrahydrofuranylfentanyl still available on the illicit market. The extent to which this will impact 
on public health, criminality, or levels of use, is difficult to predict. 

 

 

It is difficult to predict the impact of this control option on current or future research by the 
pharmaceutical or chemical industries. 

In order to examine the consequences of control, the Committee wishes to note that it will be 
important to monitor for the presence of tetrahydrofuranylfentanyl on the market post-control, 
should this control option be pursued. 

  Aside from the option for control under those stipulated in Article 9.1 of the Council Decision, 
other options for control may be available to Member States. These may include restricting 
the importation and supply of the substance as some Member States have already done.  

19 

 
 
 
 
 
RISK ASSESSMENT I THF-F 

Conclusion 

N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide (tetrahydrofuranylfentanyl) is a 
synthetic opioid and is structurally related to fentanyl, a controlled substance widely used in medicine 
as an adjunct to general anaesthesia during surgery and for pain management. Currently available 
information suggests that tetrahydrofuranylfentanyl is a narcotic opioid analgesic similar to fentanyl. 

Similar to other opioid analgesics, the most serious acute risk arising from the use of 
tetrahydrofuranylfentanyl is probably from respiratory depression, which can lead to apnoea, 
respiratory arrest, and death.  

Tetrahydrofuranylfentanyl has been available in Europe since at least September 2016 and has been 
seized in 1 Member State (Sweden). Fourteen deaths have been reported by Sweden where 
exposure to tetrahydrofuranylfentanyl was confirmed. In many of cases, other drugs were also 
detected with tetrahydrofuranylfentanyl. In at least 12 of the deaths, tetrahydrofuranylfentanyl was 
reported to be either the cause of death or to have contributed to death. 

It is likely that naloxone works as an antidote to poisoning caused by tetrahydrofuranylfentanyl. 

It is important to note that detections of tetrahydrofuranylfentanyl may be under-reported since the 
substance is not routinely screened for. Routine commercially available immunoassays may not 
detect this compound.  

Tetrahydrofuranylfentanyl appears to be sold online typically as a liquid (as a ‘research chemical’).  

Typically, the substance has been administered by nasal spray. Particular concerns exist over novel 
ways of administering fentanils including tetrahydrofuranylfentanyl. These include nasal sprays and e-
liquids for vaping. These may have the potential to make the use of fentanils easier and more socially 
acceptable.  

While no specific examples are available on the possible appeal of tetrahydrofuranylfentanyl to 
specific user groups, it can be assumed that it may be available to and being used by high-risk drug 
users, including opioid users. 

Accidental exposure to tetrahydrofuranylfentanyl, as well as to other fentanils, may pose a risk to law 
enforcement, emergency personnel, medical and forensic laboratory personnel, as well as to those in 
custodial settings and postal services. Where necessary, specific risks and appropriate measures to 
reduce these risks should be identified and implemented. Any required measures should continue to 
ensure the delivery of prompt and appropriate care to patients with suspected overdose. 

There is no information regarding the involvement of organised crime in the manufacture, distribution 
(trafficking) and supply within the European Union. There is limited information on the chemical 
precursors and the synthetic routes used to manufacture the tetrahydrofuranylfentanyl detected within 
the European Union. Most of the synthetic routes are straightforward, make use of common 
laboratory equipment and readily available precursors, and require only basic knowledge of 
chemistry.  

Information from seizures suggests that some tetrahydrofuranylfentanyl on the market in Europe has 
been produced by chemical companies based in China.  

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RISK ASSESSMENT I THF-F 

Tetrahydrofuranylfentanyl has no recognised human or veterinary medical use in the European Union, 
nor, it appears, elsewhere. There are no indications that tetrahydrofuranylfentanyl may be used for 
any other purpose aside from as an analytical reference standard and in scientific research. 

Tetrahydrofuranylfentanyl is not listed for control in the Single Convention on Narcotic Drugs, 1961, 
nor in the Convention on Psychotropic Substances, 1971. Tetrahydrofuranylfentanyl is currently under 
assessment by the United Nations system.  

Five Member States control tetrahydrofuranylfentanyl under drug control legislation. Five Member 
States and Norway control tetrahydrofuranylfentanyl under other legislation. 

As for any new psychoactive substance, many of the questions related to tetrahydrofuranylfentanyl 
that are posed by the lack of data on the risks to individual health, risks to public health, and social 
risks, could be answered through further research. Areas where additional information would be 
important include studies on: rationale for use, prevalence and patterns of use (including studies that 
examine user groups and risk behaviours); the market; chemical profiling; complete pharmacological 
profiling; metabolic pathways; behavioural effects; acute and chronic toxicity; the potential interaction 
between tetrahydrofuranylfentanyl and other substances; the dependence and abuse potential; and 
the public health risks associated with its use. 

The Committee notes that a decision to control tetrahydrofuranylfentanyl has the potential to bring 
with it both intended and unintended consequences. Potential intended consequences include 
reduced levels of availability and ultimately use. This may reduce the health and social risks and 
consequences arising from the use of tetrahydrofuranylfentanyl. It is important to recognise that a 
potential unintended consequence of control may be the manufacture and availability of other 
substances. Indeed, since tetrahydrofuranylfentanyl was first detected at least nine new fentanils and 
a number of other new opioids that may replace it are already being sold on the drug market. The 
implementation of control measures may also lead to the criminalisation of those who continue to use 
this substance with the possible attendant risks of socio-economic stigmatisation and marginalisation.  

Finally the Committee notes that it is important to continue to collect and disseminate accurate 
information on tetrahydrofuranylfentanyl to users, practitioners, policy makers, decision makers and 
those who may be at risk of accidental exposure. An additional challenge in respect to reducing risk in 
users and potential users is the balance between providing information to prevent harm and the 
unintended consequences of communicating the risks of opioids. There is evidence that using terms 
to describe them as 'potent', 'strong', 'deadly', and 'toxic' can lead some individuals to specifically seek 
out these substances. Such unintended promotion of the substances may also extend to former users 
and other groups. 

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RISK ASSESSMENT I THF-F 

ANNEX 1 

Technical report on N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]oxolane-2-carboxamide 
(tetrahydrofuranylfentanyl; THF-F) 

Introduction 

In accordance with Article 5 of the Council Decision 2005/387/JHA on the information exchange, risk-
assessment and control of new psychoactive substances (1) on 25 April 2017, the EMCDDA and 
Europol launched the Joint Report procedure for N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-
2-carboxamide (tetrahydrofuranylfentanyl) on the basis of data reported by the Member States to the 
European Union Early Warning System in accordance with Article 4 of the Council Decision. The 
information collection process for the Joint Report was completed in June 2017. The report was 
submitted to the EU Institutions in July 2017 (EMCDDA, 2017a). In accordance with Article 6 of the 
Council Decision, on 14 September 2017, the Council of the European Union requested that a risk 
assessment on tetrahydrofuranylfentanyl should be carried out by the extended Scientific Committee 
of the EMCDDA. 

In order to prepare for the risk assessment, and, to facilitate the risk assessment process, the 
EMCDDA is responsible for the collection and analysis of data on the substance to be assessed as 
well as drafting a technical report. This technical report has been prepared for the risk assessment of 
tetrahydrofuranylfentanyl that will be held at the EMCDDA premises in Lisbon on Wednesday 8 
November 2017. 

Some of the sections in this report were prepared under EMCDDA contracts (ref. CT.17.SAT.0084.1.0 
and CT.17.SAT.0110.1.0). 

Data sources 

The information in this technical report is derived from: 

  data reported by the Member States, Turkey, and Norway to the EMCDDA and Europol in 

accordance with Council Decision 2005/387/JHA (EMCDDA, 2017a); and,  

  data collected through systematic searches of open source information, including the 
scientific and medical literature, patents, official reports, grey literature, online drug 
discussion forums and related websites, and online vendors selling 
tetrahydrofuranylfentanyl. 

Search strategy  

Literature searches used both chemical structure and text queries in online databases; searches were 
conducted in August 2017. The retrieved publications were then scanned for additional relevant 
references (snowballing technique). 

(1) OJ L 127, 20.5.2005, p. 32.  

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RISK ASSESSMENT I THF-F 

Chemical structure-based searches were done in SciFinder® (American Chemical Society, Chemical 
Abstract Service) and Reaxys® (Elsevier) databases using both the exact structure and substructure 
of tetrahydrofuranylfentanyl as well as a similarity search. Structural and text-based searches in 
SureChEMBL patent database retrieved no hits. 

Textual searches were conducted online in PubMed (National Center for Biotechnology Information), 
Web of Science™ (Thomson Reuters), and in popular English-language online drug forums. The 
search terms used were: ‘tetrahydrofuranylfentanyl’, ‘tetrahydrofuranyl-fentanyl’, ‘tetrahydrofuranyl 
fentanyl’, ‘THF-F’, ‘fentanyl tetrahydrofuranyl analog’.  

The REACH registered substances database hosted by the European Chemicals Agency (ECHA) 
was searched using the CAS registry numbers listed above. The searches returned no hits. 

Cursory, though repeated, inspections of English-language Internet forums covered Bluelight, Drugs-
forum, ecstasydata.org, Erowid, Eve&Rave, Reddit and The Vespiary. 

Additionally, the scientific networks of the authors were contacted to obtain information. 

Note 

It is important to note that when interpreting the information on self-reported user experiences in this 
report, it is not possible to confirm the specific substance(s) that have been claimed to be used; 
similarly it is also not possible to confirm the strength, purity, dose/amount, etc., used. Moreover, the 
actual composition of the substance/product may differ over time and different geographical areas. In 
addition, the information provided on user websites may not necessarily be representative of other 
users of tetrahydrofuranylfentanyl and should be regarded as illustrative only. In general, given the 
difficulties of collecting accurate self-reported data, it should be interpreted with caution. 

Report prepared by 

Simon Brandt (2), Simon Elliott ( 3), Michael Evans-Brown ( 4), Helgi Valur Danielsson (4), Anabela 
Almeida (4), Rita Jorge (4), Rachel Christie (4), Sofía Sola (4), Ana Gallegos (4), and Roumen Sedefov 
(4). 

Acknowledgements 

The EMCDDA would like to extend their sincere thanks and appreciation to: the Early Warning 
System (EWS) correspondents of the Reitox national focal points and experts from their national early 
warning system networks; the Europol national units and Europol Project Synergy; and, Dr István 
Ujváry, iKem BT, Budapest, Hungary for reviewing some of the sections of this report. 

(2) School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, United Kingdom. 
(3) Alere Forensics, Malvern, Worcestershire, United Kingdom. 
(4) European Monitoring Centre for Drugs and Drug Addiction. 

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Section A. Physical, chemical, pharmaceutical and pharmacological 
information 

A1. Physical, chemical, and pharmaceutical information 

A1.1. Physical and chemical description 

Chemical description and names 

N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide (tetrahydrofuranylfentanyl) is a 
tetrahydrofuran-2-carboxamide derivative of N-phenyl-1-(2-phenylethyl)piperidin-4-amine (4-ANPP) 
and structurally related to fentanyl, which is a propionamide (Table 1). Tetrahydrofuranylfentanyl 
contains one basic nitrogen atom in the piperidine ring and readily forms salts with organic or 
inorganic acids. 

Tetrahydrofuranylfentanyl has one positional isomer, which is 3-tetrahydrofuranylfentanyl. In 3-
tetrahydrofuranylfentanyl, the carboxamide is attached to the 3-position of the tetrahydrofuran ring 
( 5).Tetrahydrofuranylfentanyl contains a stereogenic centre thus allowing for the existence of a pair of 
enantiomers, (S)-tetrahydrofuranylfentanyl and (R)-tetrahydrofuranylfentanyl. There is no information 
on the actual enantiomer found on the European drug market or whether it is the racemic mixture. 

Until recently (Helander et al., 2017), information about tetrahydrofuranylfentanyl could not be 
identified in the scientific literature, which suggests that this compound appears to have no published 
history. 

Tetrahydrofuranylfentanyl is a close structural relative of fentanyl ( 6,7), which is a fast and short-acting 
synthetic opioid that has been widely used in clinical practice as an adjunct to general anaesthesia 
during surgery and for pain management.  

Tetrahydrofuranylfentanyl is the saturated derivative of furanylfentanyl ( 8) which was the subject of an 
EMCDDA–Europol Joint Report in January 2017 and risk-assessed under the auspices of the 
Scientific Committee of the EMCDDA in May 2017 (EMCDDA, 2017b). Tetrahydrofuranylfentanyl is 
also structurally related to acetylfentanyl and acryloylfentanyl, both of which were the subject of 
EMCDDA–Europol Joint Reports in December 2015 and November 2016, following reports of deaths 
in Europe. In February 2017, the risk assessment meeting on acryloylfentanyl (EMCDDA, 2017c) was 
convened. On 25 September 2017, the Council of the European Union decided that acryloylfentanyl 
should be subjected to control measures across the European Union (Council of the European Union, 
2017). 

(5) Throughout this report, ‘tetrahydrofuranylfentanyl’ refers to 2-tetrahydrofuranylfentanyl. 
(6) http://www.emcdda.europe.eu/publications/drug-profiles/fentanyl  
(7) Fentanyl is included in Schedule I of the United Nations Single Convention on Narcotic Drugs, 1961, as amended by the 
1972 Protocol. 
(8) Tetrahydrofuranylfentanyl contains a tetrahydrofuran (aliphatic ring), whereas furanylfentanyl contains a furan (aromatic 
derivative of tetrahydrofuran). Furanylfentanyl might be used as a precursor for the synthesis of tetrahydrofuranylfentanyl; 
however, this has not been documented.  

24 

 
 
 
 
 
                                                           
RISK ASSESSMENT I THF-F 

FIGURE 1 
The molecular structure, molecular formula and molecular mass of tetrahydrofuranylfentanyl 
(left), furanylfentanyl (middle) and fentanyl (right). The asterisk denotes a chiral carbon. 

Tetrahydrofuranylfentanyl 

Furanylfentanyl 

Fentanyl 

O
*

O

N

O

O

N

N

N

O

N

N

C24H30N2O2 

C24H26N2O2 

C22H28N2O 

378.52 g/mol 

374.48 g/mol 

336.48 g/mol 

Fifteen fentanils are controlled under the United Nations Single Convention on Narcotic Drugs, 1961, 
as amended by the 1972 Protocol: 3-methylfentanyl, 3-methylthiofentanyl, acetyl-alpha-
methylfentanyl, acetylfentanyl, alpha-methylfentanyl, alpha-methylthiofentanyl, beta-hydroxy-3-
methylfentanyl, beta-hydroxyfentanyl, para-fluorofentanyl and thiofentanyl, are controlled under 
Schedule I and IV; alfentanil, butyrfentanyl, fentanyl, remifentanil and sufentanil are controlled under 
Schedule I. The controls on acetylfentanyl and butyrfentanyl entered into force in 2016 and 2017, 
respectively. 

Names and other identifiers 

Systematic International Union of Pure and Applied Chemistry (IUPAC) name: 

N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide 

Chemical Abstract name:  

2-Furancarboxamide, tetrahydro-N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]- 

Other names:  

N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]tetrahydrofuran-2-carboxamide 

N-(1-Phenethylpiperidin-4-yl)-N-phenyltetrahydrofuran-2-carboxamide 

25 

 
 
 
  
 
 
RISK ASSESSMENT I THF-F 

Chemical Abstract Service Registry Numbers (CAS RNs) (9):  

Not registered  

PubChem SID ( 10):  

Not registered  

IUPAC International Chemical Identifier Key (InCHI Key) (11):  

OHJNHKUFSKAANI-UHFFFAOYSA-N 

SMILES ( 12):  

O=C(C1=CC=CO1)N(C2=CC=CC=C2)C3CCN(CCC4=CC=CC=C4)CC3 

Common names:  

Tetrahydrofuranylfentanyl; tetrahydrofuranfentanyl; tetrahydrofuran fentanyl; tetrahydrofuranyl 
fentanyl; tetrahydrofuran-fentanyl; THF-F 

Street names:  

THF-fentanyl; tetrahydrofuran-F; Tetra. 

Identification and analytical profile 

Physical description  

Tetrahydrofuranylfentanyl hydrochloride has been described as a crystalline solid (Cayman Chemical 
Company, 2017) and the free base as a white powder (SWGDRUG, 2017). Tetrahydrofuranylfentanyl 
hydrochloride has been reported to be soluble in dichloromethane, methanol and water (Slovenian 
National Forensic Laboratory, 2017). Due to its similarity to fentanyl, the free base could be expected 
to be sparingly soluble in water; the hydrochloride and citrate salt could be expected to have greater 
aqueous solubility. Tetrahydrofuranylfentanyl, similar to fentanyl, is expected to be lipophilic ( 13). 
Tetrahydrofuranylfentanyl has been seized as a liquid and in powder form. A more detailed 
description of seizures and collected samples can be found in Section C. 

Chemical stability and typical reactions 

Specific information about tetrahydrofuranylfentanyl could not be identified. For long-term storage it is 
recommended that tetrahydrofuranylfentanyl, supplied as a solid, is stored at -20 °C (Cayman 
Chemical Company, 2017).  

(9) The Chemical Abstract Service Registry Number (CAS RN) is a unique numeric identifier assigned by the Chemical Abstract 
Service Division of the American Chemical Society to a specific, single chemical substance. Search conducted on 23 October 
2017. 
(10) Search conducted on 23 October 2017 at https://pubchem.ncbi.nlm.nih.gov. 
(11) InChI Key is a unique, non-proprietary structural identifier of chemical substances useful in electronic sources. 
(12) The simplified molecular-input line-entry system (SMILES) is a unique, non-proprietary structural identifier of chemical 
substances useful in electronic sources. 
(13) The respective calculated LogP values for tetrahydrofuranylfentanyl and fentanyl are 3.04 and 3.89 (ACD/ChemSketch 
2015 release version, Advanced Chemistry Development Inc., Toronto, Canada). The respective LogP values calculated by 
StarDrop version 6.3.1 software (Optibrium Ltd, Cambridge, UK) for acryloylfentanyl and fentanyl are 4.18 and 3.89. The 
measured LogP value for fentanyl is 4.05 (Hansch et al., 1995). 

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RISK ASSESSMENT I THF-F 

Analytical profile 

Analytical data for tetrahydrofuranylfentanyl include: gas chromatography mass spectrometry (GC-
MS), high performance liquid chromatography (high resolution) (tandem) mass spectrometry (LC-
HRMS), Fourier transform infrared spectroscopy attenuated total reflectance (FTIR-ATR), proton 
nuclear magnetic resonance (1H NMR) spectroscopy and gas chromatography condensed phase 
infrared spectroscopy and ion chromatography (GC- (MS)-IR) (Helander et al., 2017; Slovenian 
National Forensic Laboratory, 2017; SWGDRUG, 2017). Studies on the ability to differentiate between 
the 2- and 3-tetrahydrofuranylfentanyl isomers or enantiomers could not be identified ( 14). 

It is possible that immunoassays for fentanyl may not detect or distinguish between 
tetrahydrofuranylfentanyl and fentanyl due to the structural similarity between the two substances (US 
DEA, 2016a). Identification of tetrahydrofuranylfentanyl therefore would require further confirmatory 
analysis using more suitable detection techniques, such as (tandem) mass spectrometry (Helander et 
al., 2017). Similarly, tetrahydrofuranylfentanyl is not expected to give a positive response to tests 
developed for morphine-type opioids. 

Recently, a new bioassay-based method which relies on the activation of the μ-opioid receptor 
signalling pathway for the detection of synthetic opioids, including tetrahydrofuranylfentanyl, has been 
reported (Cannaert et al., 2017). 

Methods and chemical precursors used for the manufacture  

No information was reported to the EMCDDA about the chemical precursors or manufacturing 
methods used to make the tetrahydrofuranylfentanyl that has been detected on the drug market in 
Europe. However, analysis of a collected sample of tetrahydrofuranylfentanyl that was test purchased 
from an online vendor apparently based in China also identified ‘4-aminophenyl-1-
phenethylpiperidine’, i.e. N-phenyl-1-(2-phenylethyl)piperidin-4-amine (4-ANPP) (Slovenian National 
Forensic Laboratory, 2017), which is a commonly used precursor for synthesising many fentanyl 
analogues.  

Detailed or quantitative information available with regards to route-specific by-products produced 
during the synthesis of tetrahydrofuranylfentanyl is not available. 

Synthesis 

A synthesis procedure for tetrahydrofuranylfentanyl could not be identified in the literature. It is likely 
that its synthesis relies on precursors and synthetic methods similar to those used for the 
manufacture of pharmaceutical fentanyl and other fentanyl analogues. Accordingly, methods 
developed for the multistep synthesis of fentanyl are applicable to tetrahydrofuranylfentanyl but use a 
different acylating agent in the acylation of the appropriate 4-phenylaminopiperidine precursor. For 
example, the synthesis method of tetrahydrofuranylfentanyl could use the acylation of the N-phenyl-1-
(2-phenylethyl)piperidin-4-amine (4-ANPP) intermediate, a precursor common to fentanyl and other 
fentanyl analogues, with tetrahydrofuran-2-carbonyl chloride (Figure 2). As mentioned above, the 
detection of the 4-ANPP precursor was reported as part of the analysis of a test purchase product. 
The preparation of the 3-tetrahydrofuranylfentanyl isomer would be expected to involve the use of 
tetrahydrofuran-3-carbonyl chloride as the acylating agent. It has been demonstrated that N-(2-
furoyl)piperazine could be directly reduced to N-(tetrahydro-2-furoyl)piperazine (Gluchowski et al., 
2000) but whether this is applicable to the reduction of furanylfentanyl to tetrahydrofuranylfentanyl 

(14) 3-Tetrahydrofuranylfentanyl is also commercially available as a reference standard: 
https://www.caymanchem.com/product/22664  

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RISK ASSESSMENT I THF-F 

remains to be studied. If this were feasible then it would suggest that furanylfentanyl might serve as a 
precursor to tetrahydrofuranylfentanyl.  

FIGURE 2 
A possible step of the synthesis of tetrahydrofuranylfentanyl. 

Most of these synthetic procedures are relatively straightforward. Due to the typical high potency of 
fentanils there is a risk of severe poisoning following accidental exposure during their manufacture. 
Extreme care must be taken when carrying out the final synthetic step as well as when purifying and 
handling the substances. Likewise, accidental exposure to the fentanils could pose a risk of poisoning 
to the public, law enforcement, emergency personnel, as well as medical and forensic laboratory 
personnel. In addition to exercising extreme caution when handling materials suspected to contain 
fentanils, personnel should be equipped with appropriate protective equipment. The antidote naloxone 
should be readily available to personnel in sufficient quantities; training in resuscitation, including the 
administration of naloxone, should also be available (IAB, 2017; US CDC, 2013; US CDC, 2016; US 
DEA, 2017b).  

The 4-ANPP precursor, as well as N-phenethyl-4-piperidone (NPP, a pre-precursor), were scheduled 
in 2017 and are listed in Table I of the United Nations Convention against Traffic in Narcotic Drugs 
and Psychotropic Substances, 1988 (CND, 2017). The scheduling came into force on 18 October 
2017 (INCB, 2017). In 2010, the U.S. Drug Enforcement Administration placed 4-ANPP (named 
ANPP in the regulation) into Schedule II of the Controlled Substances Act in 2010 following its use as 
a precursor to make fentanyl in illicit laboratories (US DEA, 2010). Other routes developed for the 
production of fentanyl may also be used for the manufacture of tetrahydrofuranylfentanyl. These 
methods have been reviewed (Soine, 1986; Carroll and Brine, 1989; Hsu and Banks, 1992; Fritschi 
and Klein, 1995; Yadav et al., 2010; Vardanyan and Hruby, 2014). To date, there is no information on 
the actual method(s) used for the production of tetrahydrofuranylfentanyl that has been detected on 
the European drug market. 

Typical impurities encountered in seized and collected samples 

There are no quantitative data available on the impurities detected in seized and collected samples 
reported to the EMCDDA. A collected sample of tetrahydrofuranylfentanyl was reported to contain 4-
ANPP (Slovenian National Forensic Laboratory, 2017), which, as mentioned above, is a commonly 
used precursor for synthesising many fentanils.  

A1.2. Physical/pharmaceutical form  

Data from seizures and collected samples reported to the EMCDDA have noted that 
tetrahydrofuranylfentanyl has typically been detected in powders and liquids. 

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RISK ASSESSMENT I THF-F 

A1.3. Route of administration and dosage  

As with other fentanils, tetrahydrofuranylfentanyl can be administered orally as a powder (including in 
capsules), as tablets, or as a solution (using nasal sprays) or by insufflation of a powder; it can also 
be administered intranasally or sublingually via a spray; inhaled by smoking or vaporizing; and, 
administered by injection (intravenous and intramuscular). Of note is that ready-to-use nasal sprays 
purportedly containing solutions of tetrahydrofuranylfentanyl have been offered by online vendors in 
Sweden. However, it is worth noting that some of these products are not always labelled and/or they 
may be sold as another substance. This finding extends to the use of other fentanils that have 
appeared in Europe in the past few years, including acryloylfentanyl (EMCDDA, 2017c; Ujváry et al., 
2017) and furanylfentanyl (EMCDDA, 2017b). 

Data reported to the EMCDDA regarding an acute intoxication with confirmed exposure to 
tetrahydrofuranylfentanyl noted that the substance was administered intra-nasally by nasal spray 
(Section D1.2). 

Dosage 

Limited information is available regarding the dose and the dose regimens of 
tetrahydrofuranylfentanyl. It is not possible to currently discern the ‘typical’ dosages administered by 
users. Doses appear to differ depending on factors such as the route of administration, the tolerance 
of the users, the use of other drugs, and the desired effects. Given the difficulties of collecting such 
data, it should be used with caution. Furthermore, the purity, amount and/or composition of the 
substance ingested are not typically known by the user. Moreover, the actual composition of the 
substance may differ over time and different geographical areas.  

One comment made on a user forum suggested that, upon insufflation, tetrahydrofuranylfentanyl was 
‘active at 2 mg’ and that ‘up to over 10 mg seems comfortable’ in a user who also used kratom (15) 
‘several times a week’ (16). 

A2. Pharmacology, including pharmacodynamics and pharmacokinetics  

Pharmacologically, tetrahydrofuranylfentanyl is an opioid receptor agonist. 

Pharmacodynamics 

In vitro studies 

The currently available data suggests that tetrahydrofuranylfentanyl ( 17) binds to the μ-opioid receptor 
(MOR) with high selectivity (Ki = 0.95 nM) over the κ- and δ-opioid receptors (KOR and DOR) with Ki 
values of 741 nM and 1,730 nM, respectively (Table 1) (18) (US DEA, 2017a).  

Table 1 provides a summary of additional binding and functional activity data that illustrate that 
tetrahydrofuranylfentanyl (EC50 = 89 nM, [35S]GTPγS binding assay, Emax = 73.8%) functioned as a 
MOR agonist (19). In comparison, morphine (EC50 = 22.2 nM, [35S]GTPγS binding assay, Emax = 
81.0%) and fentanyl (EC50 = 15.2 nM, Emax = 90.4%) were approximately 4- and 6-times more potent 

(15) Kratom refers to the M. speciosa plant known to contain constituents (e.g. mitragynine) with opioid-like activity (Raffa, 
2015).  
(16) https://drugs-forum.com/threads/tetrahydrofuranylfentanyl-info.295272/ (last accessed 07 September 2017). 
(17) Isomeric composition not specified. 
(18) Ki represents the equilibrium inhibition constant for the test drug displacing the radioligand. 
(19) EC50 represents the concentration that causes a half-maximal response of the agonist.  

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RISK ASSESSMENT I THF-F 

than tetrahydrofuranylfentanyl and all three test drugs exhibited comparable efficacy under these in 
vitro conditions. 

TABLE 1 
Opioid receptor binding and functional activity data of tetrahydrofuranylfentanyl (THF-F)* 
(adapted and modified from US DEA, 2017a). 

MOR 

THF-F  

DAMGO 

Morphine 

Fentanyl 

Naltrexone 

[3H]DAMGO binding Ki (nM) 

0.95 ± 0.32 

0.252 ± 
0.052 

0.223 ± 
0.051 

0.056 ± 
0.010 

0.092 ± 0.017 

IC50 (nM) 

4.4 ± 1.5 

– 

– 

– 

[35S]GTPγS binding 

THF-F  

DAMGO 

Morphine 

Fentanyl 

Stimulation EC50 (nM) 

89 ± 16 

15.2 ± 3.3 

22.2 ± 2.8 

15.2 ± 2.1 

Maximal stimulation (%)* 

73.8 ± 5.0 

98.0 ± 4.1 

81.0 ± 1.8 

90.4 ± 2.2 

– 

– 

– 

DOR 

THF-F  

DPDPE-OH  Morphine 

Fentanyl 

Naltrexone 

[3H]DPDPE binding Ki (nM) 

1,730 ± 260 

2.77 ± 0.50 

186 ± 13 

249 ± 57 

17.4 ± 4.8 

IC50 (nM) 

2,200 ± 300 

– 

– 

– 

[35S]GTPγS binding 

THF-F  

DPDPE-OH  Morphine 

Fentanyl 

Stimulation EC50 (nM) 

1,440 ± 550 

8.8 ± 2.1 

566 ± 56 

850 ± 140 

Maximal stimulation (%)** 

16.2 ± 3.7 

99.53 ± 0.34 

79.6 ± 5.5 

62.1 ± 30 

– 

– 

– 

KOR 

THF-F  

U-50,488H 

Morphine 

Fentanyl 

Nor-BNI 

[3H]U-69,593 binding Ki (nM)  741 ± 44 

0.274 ± 
0.063 

30.2 ± 1.4 

121 ± 11 

0.38 ± 0.10 

IC50 (nM) 

1,720 ± 270 

– 

– 

– 

[35S]GTPγS binding 

THF-F  

U-50,488H 

Morphine 

Fentanyl 

Stimulation EC50 (nM) 

5,790 ± 430 

1.62 ± 0.32 

65 ± 19 

700 ± 110 

Maximal stimulation (%)** 

62.1 ± 5.3 

96.5 ± 7.7 

73.2 ± 5.9 

60.8 ± 8.5 

– 

– 

– 

* In receptor binding experiments, transfected Chinese hamster ovary (CHO) cells expressing human δ- and κ-
opioid receptors and rat μ-opioid receptors were used. Experimental details for functional activity studies are 
not reported. DOR: delta opioid receptor; KOR: kappa opioid receptor; MOR: mu opioid receptor; DAMGO: Tyr-
Ala-Gly-N-Me-Phe-Gly-ol, DPDPE: Tyr-Pen-Gly-Phe-Pen [disulfide bridge: 2-5]; U-69,593: (+)-(5α,7α,8β)-N-
methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide; U-50,488H: trans-(±)-3,4-dichloro-N-
methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate salt; Nor-BNI: norbinaltorphimine; 
U-69,593: (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide. SEM: 
standard error of the mean.  

Numbers represent the means ± SEM from at least three independent experiments, each conducted with 

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RISK ASSESSMENT I THF-F 

duplicate determinations. Standard compounds are the agonists DPDPE (delta), U50,488H (kappa) and 
DAMGO (mu) and the antagonists naltrexone (delta and mu) and nor-BNI (kappa). 

** Maximal stimulation by test compound is normalized to the maximal stimulation by DPDPE (delta), U50,488H 
(kappa) or DAMGO (mu) above basal. Negative values indicate inhibition of basal [35S]GTPγS binding. 

Tetrahydrofuranylfentanyl showed moderate affinity toward KOR (Ki = 741 nM) with low potency and 
moderate relative efficacy (EC50 = 5,790 nM, [35S]GTPγS binding assay, Emax = 62.1%). As far as 
DOR was concerned, binding affinity, potency and efficacy were relatively low (Ki = 1,730 nM, EC50 = 
1,440 nM, [35S]GTPγS binding assay, Emax = 16.2%), which suggested a MOR selective profile, at 
least under these in vitro conditions. All test drugs used as positive control (Table 1) were shown to 
be efficacious agonists.  

These in vitro studies have established tetrahydrofuranylfentanyl to be a MOR agonist. It is not 
known, however, to what extent this MOR agonist effect, which is responsible for causing respiratory 
depression (among other effects), would translate to high toxicity in vivo. 

These data also indicated that saturation of the furanyl ring (also found in furanylfentanyl, subject of a 
recent risk assessment in May 2017 (EMCDDA, 2017b) led to a significant drop in potency, when 
investigated under identical in vitro conditions. For example, tetrahydrofuranylfentanyl displayed a 34-
fold reduction in affinity (furanylfentanyl Ki = 0.0249 nM) and 35-fold drop in potency at MOR 
(furanylfentanyl EC50 = 2.52 nM, [35S]GTPγS binding) although furanylfentanyl was found to be 
somewhat more efficacious relative to the MOR agonist DAMGO (20) (furanylfentanyl Emax = 55.5% vs. 
Emax = 73.8%, Table 1, see above) (EMCDDA, 2017b; US DEA, 2016b). 

Animal studies 

Results from animal studies could not be identified. 

Pharmacokinetics 

Apart from a recent conference abstract briefly discussing in vitro experiments with a series of 
fentanyl analogues, no in vitro or in vivo studies could be identified in the literature. According to this 
report (Wilde et al., 2017), in a human liver microsomal preparation the predominant metabolic step 
for tetrahydrofuranylfentanyl appears to be N-desalkylation, as in the case of fentanyl. Hydroxylation 
of the piperidine ring and the phenylethyl side chain, N-oxidation and amide hydrolysis to 4-ANPP 
were also observed. 

The extent to which the biotransformation products are comparable to furanylfentanyl or other closely 
related analogues remains to be investigated. It seems likely that some overlap might exist, including 
the amide hydrolysis product 4-ANPP (Watanabe et al., 2017).  

There is some information on the biological activity of 4-ANPP using intact guinea pig ileum 
preparations. Compared to fentanyl (IC50 = 4 nM), 4-ANPP was significantly less potent in inhibiting 
contractions of ileum segments induced by coaxial electrical stimulation (IC50 = 12,000 nM). The IC50 
value determined for morphine was 50 nM (Schneider and Brune, 1986). Two metabolites showed 
activity in this study: the phenolic derivative hydroxylated at the 4-position of the phenylethyl moiety of 
fentanyl ( 21), the activity (IC50 = 240 nM) of which was found to lie between morphine and pethidine 

(20) DAMGO: Tyr-Ala-Gly-N-Me-Phe-Gly-ol.  
(21) Systematic name: N-{1-[2-(4-hydroxyphenyl)ethyl]piperidin-4-yl}-N-phenylpropionamide. 

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RISK ASSESSMENT I THF-F 

(IC50 = 1,300 nM), and the benzylic alcohol type derivative hydroxylated at the alpha-position, i.e. 
benzylic methylene, of the phenylethyl moiety of fentanyl which had an IC50 value of 50 nM.  

One user described the ‘high’ obtained from insufflating an estimated (‘eyeballed’) of 20 mg of 
tetrahydrofuranylfentanyl to last for about 2 hours (route of administration (‘insufflation’) (22).  

Inter-individual genetic variability in metabolising enzymes 

Specific information about tetrahydrofuranylfentanyl could not be identified. For fentanyl, oxidative 
dealkylation by hepatic CYP3A4 and by CYP3A5 isoenzymes to norfentanyl has been demonstrated 
(Guitton et al., 1997, Jin et al., 2005, Labroo et al., 1997) The variation of the expression of the genes 
coding for these CYP3A isoenzymes among populations might be of clinical significance (Meyer and 
Maurer, 2011) but further studies are needed to examine the toxicological significance, if any, of such 
polymorphisms.  

Interactions with other substances and other interactions  

Specific information about tetrahydrofuranylfentanyl could not be identified, although it seems 
conceivable that interactions observed with fentanyl might equally apply (Preston, 2016). For 
example, should tetrahydrofuranylfentanyl undergo oxidative dealkylation by hepatic CYP3A4 and by 
CYP3A5 isoenzymes then the use of this substance with inhibitors of these isoenzymes, such as 
clarithromycin, erythromycin, fluconazole, grapefruit juice, indinavir, itraconazole, ketoconazole, 
nefazodone, ritonavir, saquinavir, suboxone, verapamil (23) may result in increased plasma 
concentration of tetrahydrofuranylfentanyl. This could increase the risk of poisoning, including 
potentially fatal respiratory depression.  

The concomitant use of other central nervous system (CNS) depressants with 
tetrahydrofuranylfentanyl, such as other opioids, sedatives/hypnotics (such as the benzodiazepines 
and the z-drugs), ethanol, pregabalin, gabapentin, tranquillisers, and sedating anti-histamines, may 
produce additive depressant effects.  

The use of fentanyl with serotoninergic agents, such as selective serotonin re-uptake Inhibitors 
(SSRIs) (the most commonly prescribed antidepressants) or serotonin norepinephrine re-uptake 
inhibitors (SNRIs) or monoamine oxidase inhibitors (MAOIs) has been associated with a serotonin 
syndrome, a potentially life-threatening condition. This association is likely to extend to illicit drugs, 
which act on the serotonergic system. It is not known if this association is also seen with 
tetrahydrofuranylfentanyl.  

Effects on ability to drive and operate machines 

No studies of the effects of tetrahydrofuranylfentanyl on the ability to drive and operate machines 
have been performed. However, it is well established that opioid analgesics, such as fentanyl, impair 
the mental and physical ability required to drive and operate machines. This effect is likely to extend 
to tetrahydrofuranylfentanyl. 

(22) https://drugs-forum.com/threads/tetrahydrofuranylfentanyl-info.295272/ (last accessed 07 September 2017).   
(23) For a more comprehensive list of drug interactions with fentanyl, see, for example, 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124&source
=homeMedSearch&keyword=fentanyl&category=human&isNewQuery=true 

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A3. Psychological and behavioural effects 

Information on the psychological and behavioural effects of tetrahydrofuranylfentanyl is limited. From 
the data available, it appears that the psychoactive profile of tetrahydrofuranylfentanyl might share at 
least some similarities with other opioid analgesics such as fentanyl and heroin ( 24).These would 
include relaxation and euphoria; at higher doses, sedation and profound intoxication may occur. 

A4. Legitimate uses of the product  

Tetrahydrofuranylfentanyl is used as an analytical reference material in clinical and forensic case 
work/investigations as well as scientific research. There is currently no information that suggests 
tetrahydrofuranylfentanyl is used for other legitimate purposes. 

There are no reported uses of tetrahydrofuranylfentanyl as a component in industrial, cosmetic or 
agricultural products. In addition, a search of the Registration, Evaluation, Authorisation and 
Restriction of Chemicals (REACH) registered substances database hosted by the European 
Chemicals Agency (ECHA) using the CAS Registry Number for tetrahydrofuranylfentanyl returned no 
results. 

There is no marketing authorisation (existing, on-going or suspended) for tetrahydrofuranylfentanyl 
neither in the European Union nor in the Member States that responded to the request for information 
from the European Medicines Agency, which was undertaken as part of the Joint Report process 
(EMCDDA, 2017a). 

There is no information to suggest that tetrahydrofuranylfentanyl is currently used in the manufacture 
of a medicinal product in the European Union. However, in the absence of a database on the 
synthetic routes of all medicinal products it is not possible to confirm whether or not 
tetrahydrofuranylfentanyl is currently used in the manufacture of a medicinal product.  

Section B. Dependence and abuse potential 

B1. Animal data  

No studies were identified that have investigated the dependence and/or abuse potential of 
tetrahydrofuranylfentanyl in animal models.  

B2. Human data  

No studies were identified that have investigated the dependence and/or abuse potential of 
tetrahydrofuranylfentanyl in humans.  

While no specific data exist for tetrahydrofuranylfentanyl, it is well established that opioid analgesics 
such as fentanyl have an abuse liability and can induce tolerance and dependence. Research is 
required in order to examine these effects with tetrahydrofuranylfentanyl. 

(24) One user described a ‘Nice rush, high lasts about 2 hours, very clean and warm. Taking maybe (eyeballed) 20 mg within 2 
hours caused intense nausea’ https://drugs-forum.com/threads/tetrahydrofuranylfentanyl-info.295272/ (last accessed 07 
September 2017).   

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Section C. Prevalence of use 

Information from seizures, collected and biological samples 

Tetrahydrofuranylfentanyl was formally notified on 23 December 2016 by the EMCDDA on behalf of 
Sweden, in accordance with Article 4 of the Council Decision. The Reporting Form details a seizure of 
22 millilitres of pale yellow liquid that was seized on 29 September 2016 by Swedish Police in 
Karlstad. The substance was analytically confirmed by GC-MS, liquid chromatography–high resolution 
mass spectrometry (LC–HRMS) and NMR by the Swedish National Forensic Centre.  

Two Member States (Slovenia and Sweden) have reported detections of tetrahydrofuranylfentanyl ( 25) 
(EMCDDA, 2017a).  

It is important to note that detections of tetrahydrofuranylfentanyl may be under-reported since the 
substance is not routinely screened for in Europe. Three Member States (Austria, Slovenia and 
Sweden) reported that tetrahydrofuranylfentanyl is part of routine screening in some, but not all, 
laboratories. 

Information from seizures 

In total, 53 seizures of tetrahydrofuranylfentanyl were reported to the EMCDDA and Europol. All of 
these were reported by Sweden. Of these, 26 seizures occurred in 2016, and the other 27 in the first 
6 months of 2017.  

A majority of the seizures were made by police at street-level (50 cases), with the remaining three 
seizures made by customs. 

Physical forms seized included:  

 

liquids (48 seizures; amounting to a total volume of 950 millilitres of substance)  

  powders (5 seizures; 99.4 grams) 

No quantitative information on purity was reported. In all the cases, tetrahydrofuranylfentanyl was the 
only substance reported as detected.  

Information from collected samples 

Slovenia reported a sample of a brown powder which was purchased from an Internet vendor. The 
sample was apparently shipped from China and was received in August 2016. The precursor 4-ANPP 
was also detected in the sample. 

Information from biological samples 

Serious adverse events (deaths and acute intoxications) with confirmed exposure to 
tetrahydrofuranylfentanyl from biological samples are discussed in Section D. 

(25) ‘Detections’ is an all-encompassing term and may include seizures and/or collected and/or biological samples that are 
analytically confirmed. Seizure means a substance available (seized) through law enforcement activities (police, customs, 
border guards, etc.). Collected samples are those that are actively collected by drug monitoring systems (such as test 
purchases) for monitoring and research purposes. Biological samples are those from human body fluids (urine, blood, etc.) 
and/or specimens (tissues, hair, etc.).  

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Availability, supply, price 

The available data suggests that tetrahydrofuranylfentanyl is sold online as a powder and as ready-to-
use nasal sprays. 

Information on production 

No information was reported in relation to the production of tetrahydrofuranylfentanyl. 

Information on trafficking 

No information was reported to the EMCDDA in relation to the trafficking of tetrahydrofuranylfentanyl. 
Information on the source of tetrahydrofuranylfentanyl is limited to one report regarding a test 
purchase of the substance. Here, the substance was ordered from an online vendor apparently based 
in China (see above). 

Availability from Internet vendors 

Tetrahydrofuranylfentanyl is sold on the surface web. Its availability on the darknet is not currently 
known. As mentioned above, a collected sample of the substance was ordered from an online vendor 
apparently based in China which supplied 5 grams. 

In addition, two sites apparently based in Sweden offered tetrahydrofuranylfentanyl in liquid form as 
nasal sprays at claimed concentrations of 10 mg/ml and 13 mg/ml. The price of a 10 ml nasal spray 
(both concentrations) was EUR 51. The price for 25 ml was EUR 118 (for the 13 mg/ml solution). 

Prevalence of use  

No studies were identified that have investigated the prevalence of use of tetrahydrofuranylfentanyl in 
the general population. Given its pharmacology and that it is sold openly as a ‘legal’ replacement to 
illicit opioids, it would be expected that users looking for substitutes for opioids, which would include 
individuals who use illicit opioids, such as heroin and/or prescription opioids, may seek out 
tetrahydrofuranylfentanyl and other fentanils. It also appears that there is interest in this substance by 
some psychonauts. Overall, the available information does not suggest widespread use of the 
substance. 

Of additional note is that, in the past few years, fentanils have been sold in Europe as ready-to-use 
nasal sprays. In some cases they have also been sold as e-liquids for vaping. In general, these novel 
products could make it easier to use such substances (with similar effects to injecting) and make them 
more socially acceptable, potentially expanding their use in new user groups. These are new 
developments that will require careful monitoring. Nasal sprays claiming to contain 
tetrahydrofuranylfentanyl have been offered by online vendors within the European Union. 

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Section D. Health risks 

D1. Acute health effects 

D1.1. Animal data 

Data on the acute toxicity, abuse liability, and dependence producing potential of 
tetrahydrofuranylfentanyl could not be identified.  

D1.2. Human data 

No clinical studies were identified that have examined the acute health effects of 
tetrahydrofuranylfentanyl and/or its metabolites in humans. Although the pharmacology and toxicology 
of tetrahydrofuranylfentanyl remains largely unstudied, the available data suggests that the nature of 
its effects share some similarities with opioid analgesics such as morphine and fentanyl. The acute 
effects of these types of opioids include: euphoria, relaxation, analgesia, sedation, bradycardia, 
hypothermia, miosis, and respiratory depression or arrest. They also have an abuse liability and 
dependence potential (Cox, 2011; Dahan et al., 2001; Pattinson, 2008; Romberg et al., 2003). 

Similar to other opioid analgesics, the most serious acute health risk associated with 
tetrahydrofuranylfentanyl use is probably respiratory depression, which can lead to apnoea, 
respiratory arrest and death (Cox, 2011; Dahan et al., 2001; Pattinson, 2008; White & Irvine, 1999). 
This risk may be greater due to: the difficulty in diluting the substance; a lack of experience with its 
effects and dosing; the use of other central nervous system depressants at the same time (such as 
other opioids, benzodiazepines, gabapentanoids, and alcohol); a lack of tolerance to opioids; and, 
using the substance alone (such as at home) which would make it more difficult for users to call for 
help in the case of poisoning. 

The antidote naloxone should reverse acute poisoning caused by tetrahydrofuranylfentanyl (Kim and 
Nelson, 2015). 

Recent clinical and community experience in treating poisonings caused by fentanils suggests that 
larger than normal doses and repeated doses of naloxone may be required to manage the poisoning 
in some cases; longer periods of observation may also be required (Klar et al., 2016; Moss et al., 
2017; Somerville et al., 2017; Sutter et al., 2017). 

Data from serious adverse events associated with tetrahydrofuranylfentanyl are discussed below. 
Information from a single case of acute intoxication with confirmed exposure to 
tetrahydrofuranylfentanyl, suggests that the clinical features of poisoning may be similar to those 
found with fentanyl and other opioid analgesics. These include reduced level of consciousness or 
unconsciousness, respiratory depression and arrest, and miosis. 

Acute intoxications reported by the Member States 

A single case of acute intoxication with confirmed exposure to tetrahydrofuranylfentanyl was reported 
to the EMCDDA ( 26). The case occurred in Sweden in October 2016, and involved a 26 year old male 
who had administered 8 actuations of a 'fentanyl' nasal spray. The poisoning was classed as severe. 
The clinical features were consistent with the use of an opioid analgesic, and included reduced 

(26) In addition, Sweden also reported 2 acute intoxications with suspected exposure to tetrahydrofuranylfentanyl. These cases 
are not discussed further in this report. 

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consciousness, respiratory depression and miosis. The patient was treated with 0.2 mg of naloxone 
(route of administration and response was not reported). The only other substance detected was 
flunitrazolam. The patient survived. This case has also been published in the literature (Helander et 
al., 2017). 

Acute intoxications identified from other sources 

Acute intoxications identified from other sources are limited to the case presented above (Helander et 
al., 2017). 

Deaths reported by the Member States 

A total of 14 deaths were reported by 1 Member State: Sweden. In all cases, exposure to 
tetrahydrofuranylfentanyl was analytically confirmed from post-mortem samples (femoral blood or 
muscle).  

The deaths occurred between September 2016 and March 2017 with 8 occurring in 2016 and 6 in 
2017. 

Of these deaths, 8 were male (57%) and 6 were female (43%). The mean age of the males was 31 
years (median 29) and ranged from 25 to 41 years; the mean age of the females was 32 years 
(median 30) and ranged from 29 to 38 years. 

Circumstances and cause of death 

In all but one case, the individuals were found dead (predominantly in a home environment). In all 
cases there was a lack of information regarding symptoms experienced by the deceased prior to 
death. Consequently, it was not possible to identify or evaluate ante-mortem symptoms (especially in 
relation to acute intoxication). 

The cause of death was reported in 13 out of 14 cases. In at least 12 deaths, intoxication with 
tetrahydrofuranylfentanyl was reported either as the primary cause of death or as likely to have 
contributed to death (even in presence of other substances); other substances were detected in all 14 
cases. 

Tetrahydrofuranylfentanyl was quantified in 5 cases. Post-mortem femoral blood concentrations 
ranged from 2 to 54 ng/g blood (median 18 ng/g blood). Due to the toxicity of opioids and variability in 
user tolerance, determination of a ‘fatal’ concentration based on a post-mortem blood concentration 
may not be reliable. In the majority of circumstances involving fentanils, the mere presence of the 
drug is of significance whether concentration has been determined or not, especially in situations of 
poly-drug use. 

A range of other substances were detected in the reported deaths, including: benzodiazepines, 
zopiclone, pregabalin, antidepressants, antipsychotics, antihistamines, synthetic cathinones, 
anticonvulsants and ethanol. Other opioids were detected in 3 of the deaths; tramadol, 
benzodioxolfentanyl and acryloylfentanyl. 

Overall, whilst other substances may have contributed some toxicity, a synergistic effect with 
tetrahydrofuranylfentanyl would have been likely with other central nervous system depressants such 
as ethanol, benzodiazepines, opioids, etc. Nevertheless, the apparent fentanyl-like nature of 
tetrahydrofuranylfentanyl means that the primary toxic contribution could be attributed to the 

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tetrahydrofuranylfentanyl and death may not have occurred if tetrahydrofuranylfentanyl had not been 
used. An assessment of the Toxicological Significance Score (TSS) (Elliott, Sedefov, & Evans-Brown, 
2017) incorporating the above considerations showed that tetrahydrofuranylfentanyl had a TSS value 
of 3 (high) in 13 out of 14 of the deaths (where it was cited as the cause of death or is likely to have 
contributed to death). In the remaining death, an alternative pathological cause of death was cited 
(TSS value of 1, low). 

Deaths identified from other sources 

Since December 2016, at least 2 deaths associated with tetrahydrofuranylfentanyl have been 
reported in the United States. No further details are available on these cases (US DEA, 2017a). 

D2. Chronic health effects 

D2.1. Animal data 

No studies were identified that have investigated the chronic health effects of 
tetrahydrofuranylfentanyl in animals. 

D2.2. Human data 

No studies were identified that have investigated the chronic health effects of 
tetrahydrofuranylfentanyl in humans. 

D3. Factors affecting public health risks 

D3.1. Availability and quality of the new psychoactive substance on the market  

Tetrahydrofuranylfentanyl is being sold on the surface web as a drug in its own right. It has been sold 
as a ‘research chemical’ in several physical forms, such as powders and ready-to-use nasal sprays. 

D3.2. Availability of the information, degree of knowledge and perceptions amongst users 
concerning the psychoactive substance and its effects 

Due to its relatively recent availability on the drug market, the availability of information, degree of 
knowledge and perceptions amongst users concerning tetrahydrofuranylfentanyl and its effects are 
limited. 

D3.3. Characteristics and behaviour of users  

No studies were identified that have examined the characteristics and behaviours of users of 
tetrahydrofuranylfentanyl. Section C (above) and Section E6 (below) provides additional information 
on the likely user groups of tetrahydrofuranylfentanyl. 

D3.4. Nature and extent of health consequences 

Acute health risks 

Although the pharmacology and toxicology of tetrahydrofuranylfentanyl remains largely unstudied, the 
available data suggests that the nature of its effects share some similarities with opioid analgesics 
such as morphine and fentanyl.  

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The acute effects of these types of opioids include: euphoria, relaxation, analgesia, sedation, 
bradycardia, hypothermia, and respiratory depression. They also have an abuse liability and 
dependence potential (Cox, 2011; Dahan et al., 2001; Pattinson, 2008). 

Similar to other opioid analgesics, the most serious acute risk arising from the use of 
tetrahydrofuranylfentanyl is probably from respiratory depression, which can lead to apnoea, 
respiratory arrest, and death (Cox, 2011; Dahan et al., 2001; Pattinson, 2008; White & Irvine, 1999).  

In general, this risk may be exacerbated by:  

 

 

the difficulty in diluting/using fentanils (as they are typically highly potent), which can lead to a 
toxic dose being accidentally used (de Boer et al., 2003; Sutter et al., 2017); 

the apparent rapid onset of severe poisoning following use (Somerville et al., 2017); 

  using routes of administration that allow large amounts of the substance to rapidly reach the 

central nervous system (such as injecting, insufflation, and inhalation) (Macleod et al., 2012);  

  availability of easy to use dosage forms (such as nasal sprays and e-liquids); 

 

lack of awareness and experience of users with these new substances (effects and dosage); 

  use of other central nervous system depressants (such as other opioids, benzodiazepines, 

and alcohol) (e.g. van der Schrier et al., 2017) ;  

 

lack of tolerance to opioids in opioid-naïve persons (such as new or former users); 

  use in environments where it may be difficult to summon help in the event of poisoning (e.g. 

alone in a home environment) (Somerville et al., 2017); 

 

limited availability of the antidote naloxone in community settings (EMCDDA, 2015; EMCDDA, 
2016; Somerville et al., 2017). 

In addition, and, often unknown to users, the fentanils are sold as heroin or mixed with heroin. They 
are also used to make counterfeits of highly sought-after analgesics and benzodiazepines. They have 
also been sold in or as drugs such as cocaine (Klar et al., 2016; SFDPH, 2015; Sutter et al., 2017; 
Tomassoni et al., 2017). Due to this, users may not be aware that they are using a fentanil; in some 
cases these individuals will have no tolerance to opioids nor access to community naloxone 
programmes. Overall, these factors may increase the risk of life-threatening poisoning. 

Given the above risks, poisonings by fentanils may manifest as outbreaks which have the potential to 
overwhelm emergency responders and other local healthcare systems (Klar et al., 2016; SFDPH, 
2015; Sutter et al., 2017; Tomassoni et al., 2017). 

Accidental exposure to the fentanils may also pose a risk to non-users, including family and friends, 
law enforcement and emergency responders. Such risks may need to be assessed so that, where 
required, appropriate procedures, training and environmental and personal protective measures can 
be provided for handling materials suspected to contain these substances (IAB, 2017; US CDC, 2016; 
Moss et al., 2017; US DEA, 2017a). Any required responses should continue to ensure the delivery of 

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prompt and appropriate care to patients with suspected overdose (Cole & Nelson, 2017; Lynch, 
Suyama, & Guyette, 2017). 

Managing poisoning 

The antidote naloxone should reverse acute poisoning caused by tetrahydrofuranylfentanyl (Kim and 
Nelson, 2015; Ujváry et al., 2017). Recent clinical and community experience in treating poisonings 
caused by fentanils suggests that larger than normal doses and repeated doses of naloxone may be 
required to manage the poisoning in some cases, longer periods of observation may also be required 
(Klar et al., 2016; Moss et al., 2017; Somerville et al., 2017; Sutter et al., 2017). This may reflect, 
among other factors, the high potency of the fentanils, their half-lives, the dose an individual is 
exposed to, and, the relatively short half-life of naloxone. 

Chronic health risks 

While there is limited data, the chronic health risks of tetrahydrofuranylfentanyl might share some 
similarities to opioids such as heroin and other fentanils. This may include dependence. 

D3.5. Long-term consequences of use 

While there is limited data, the chronic health risks of tetrahydrofuranylfentanyl might share some 
similarities to opioids such as heroin and other fentanils. This may include dependence. 

D3.6. Conditions under which the new psychoactive substance is obtained and used, including 
context-related effects and risks 

There is limited data on the conditions which tetrahydrofuranylfentanyl is obtained and used. 
Tetrahydrofuranylfentanyl is offered for sale on the surface web, typically as powders and ready-to-
use nasal sprays.  

Section E. Social risks 

While there have been no studies on the social risks of tetrahydrofuranylfentanyl, it is likely that some 
of the risks are similar to those associated with illicit opioids, including fentanyl and heroin. 

E1. Individual social risks 

There is no information on the individual social risks that may be associated with the use of 
tetrahydrofuranylfentanyl. Given that tetrahydrofuranylfentanyl appears to act as an opioid analgesic, 
any such risks may have some similarities with those associated with illicit opioids. These may 
negatively impact on education or career, family or other personal and social relationships and may 
result in marginalisation. 

E2. Possible effects on direct social environment 

There is no information on the possible effects of tetrahydrofuranylfentanyl on the direct social 
environment. Given that tetrahydrofuranylfentanyl appears to act as an opioid analgesic, any such 
effects may have some similarities with those associated with the use of illicit opioids. 

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E3. Possible effects on society as a whole 

There is no specific information on the possible effects of tetrahydrofuranylfentanyl on society as a 
whole.  

As discussed above, accidental exposure to the fentanils may pose a risk of poisoning to those who 
may come into contact with the substances. This includes the family and friends of users, law 
enforcement, emergency personnel, medical and forensic laboratory personnel as well as custodial 
settings and postal services. Where required, these risks should be assessed and appropriate 
procedures, training, and protective measures should be implemented. This may include training in 
managing poisoning, including in resuscitation and adequate provision of naloxone to reverse 
poisoning. Any required responses should continue to ensure the delivery of prompt and appropriate 
care to patients with suspected overdose (Cole & Nelson, 2017; Lynch, Suyama, & Guyette, 2017). 

E4. Economic costs 

There are no data on the health and social costs related to tetrahydrofuranylfentanyl. 

E5. Possible effects related to the cultural context, for example marginalisation 

There are no data on the possible effects of tetrahydrofuranylfentanyl related to the cultural context. 

E6. Possible appeal of the new psychoactive substance to specific population groups 
within the general population 

While no specific examples are available on the possible appeal of tetrahydrofuranylfentanyl to 
specific user groups (aside from psychonauts), it is reasonable to assume tetrahydrofuranylfentanyl 
may be sought by those looking for ‘legal’ substitutes for illicit opioids, such as heroin and/or 
prescription opioids.  

As discussed above, the open sale of solutions of fentanils in novel dosage forms—such as ready-to-
use nasal sprays and e-liquids for vaping—poses additional concerns. These novel forms have the 
potential to make the use of fentanils easier (with similar effects to injecting) and more socially 
acceptable.  

Section F. Involvement of organised crime 

F1. Evidence that criminal groups are systematically involved in production, trafficking 
and distribution for financial gain 

There is no specific information to suggest the involvement of organised crime or established criminal 
groups in the manufacture, distribution and supply of tetrahydrofuranylfentanyl. 

Slovenia reported a collected sample of tetrahydrofuranylfentanyl to Europol and the EMCDDA where 
the country of origin was reported as China ( 27). 

(27) The sample also contained 4-aminophenyl-1-phenethylpiperidine (4-ANPP), a precursor that can be used for the synthesis 
of fentanyl and many fentanil analogues. 

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The seizure of an illicit laboratory producing fentanils in Europe in 2013 (EMCDDA, 2017b) suggests 
that the capability to manufacture fentanils may exist within the European Union. 

F2. Impact on the production, trafficking and distribution of other substances, including 
existing psychoactive substances as well as new psychoactive substances 

No information was reported nor identified concerning the impact of tetrahydrofuranylfentanyl on the 
production, trafficking and distribution of other substances, including existing psychoactive 
substances as well as new psychoactive substances. 

F3. Evidence of the same groups of people being involved in different types of crime 

No information was reported nor identified concerning evidence of the same groups of people being 
involved in different types of crime related to the availability of tetrahydrofuranylfentanyl. 

F4. Impact of violence from criminal groups on society as a whole or on social groups or 
local communities (public order and safety) 

No information was reported nor identified concerning incidents of violence related to the availability 
of tetrahydrofuranylfentanyl. 

F5. Evidence of money laundering practices, or impact of organised crime on other 
socioeconomic factors in society 

No information was reported nor identified concerning evidence of money laundering practices, or 
impact of organised crime on other socioeconomic factors in society related to the availability of 
tetrahydrofuranylfentanyl. 

F6. Economic costs and consequences (evasion of taxes or duties, costs to the judicial 
system)  

No information was reported nor identified concerning the economic costs and consequences related 
to the availability of tetrahydrofuranylfentanyl. 

F7. Use of violence between or within criminal groups 

No information was reported nor identified concerning the use of violence between or within criminal 
groups related to the availability of tetrahydrofuranylfentanyl. 

F8. Evidence of strategies to prevent prosecution, for example through corruption or 
intimidation 

No information was reported nor identified concerning evidence of strategies to prevent prosecution 
related to the availability of tetrahydrofuranylfentanyl. 

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Participants of the risk assessment meeting,  
7-8 November 2017  

Extended Scientific Committee  

Dr Anne Line BRETTEVILLE-JENSEN 
Norwegian Institute for Alcohol and Drug Research, Oslo 
Chair of the Scientific Committee 

Professor Dr Gerhard BUEHRINGER 
Addiction Research Unit, Department of Clinical Psychology and Psychotherapy, Technische 
Universität Dresden, Institut für Therapieforschung (IFT), Munich 

Professor Dr Paul DARGAN 
Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London 

Dr Marina DAVOLI 
Department of Epidemiology, Lazio Regional Health Service, Rome 

Professor Dr Gabriele FISCHER 
Medical University Vienna, Center of Public Health, Vienna 

Professor Dr Henk GARRETSEN 
Faculty of Social and Behavioural Sciences, Tilburg University, Tilburg 

Professor Dr Krzysztof KRAJEWSKI 
Department of Criminology, Jagiellonian University, Krakow 

Dr Fernando RODRÍGUEZ de FONSECA 
Fundación IMABIS, Hospital Universitario Carlos Haya de Málaga, Málaga 

Professor Dr Rainer SPANAGEL 
Institute of Psychopharmacology, Central Institute of Mental Health, Mannheim 

Dr Wim BEST 
Utrecht University, Faculty of Science, Freudenthal Institute, Utrecht 

Dr Simon BRANDT 
School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool 

Professor Dr Gaetano Di CHIARA 
Biomedical Sciences Department, University of Cagliari, Cagliari 

Professor Dr Éva KELLER 
Semmelweis University, Department of Forensic and Insurance Medicine, Budapest 

Dr Claude GUILLOU 
Directorate F – Health, Consumers and Reference Materials, DG Joint Research Centre, European 
Commission 

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RISK ASSESSMENT I THF-F 

Edith HOFER 
Organised Crime and Drugs Policy Unit, DG HOME, European Commission 

Dr Leon Van Aerts 
Section Pharmacology, Toxicology and Biotechnology, College ter Beoordeling van Geneesmiddelen, 
Medicines Evaluation Board, Utrecht, on behalf of European Medicines Agency 

Werner VERBRUGGEN 
Europol’s Drug Unit, Europol 

Paul GRIFFITHS 
Scientific Director, EMCDDA 

Dr Roumen SEDEFOV 
Head of Unit, Supply reduction and new drugs unit, EMCDDA 

Invited external experts 

Professor Dr Volker AUWÄRTER 
Freiburg University, Institute of Forensic Medicine, Freiburg 

Dr Robert KRONSTRAND 
Dep. Forensic Genetics and Toxicology, Swedish National Board of Forensic Medicine, Linköping 

Professor Dr Bela SZABO 
Institute of Experimental and Clinical Pharmacology and Toxicology, Freiburg 

Dr István UJVÁRY 
Budapest University of Technology and Economics, Budapest 

EMCDDA staff present 

Anabela ALMEIDA 
Action on new drugs sector, Supply reduction and new drugs unit 

Rachel CHRISTIE 
Action on new drugs sector, Supply reduction and new drugs unit 

Michael EVANS-BROWN 
Action on new drugs sector, Supply reduction and new drugs unit 

Ana GALLEGOS 
Action on new drugs sector, Supply reduction and new drugs unit 

Rita JORGE 
Action on new drugs sector, Supply reduction and new drugs unit 

Joanna DE MORAIS 
Action on new drugs sector, Supply reduction and new drugs unit 

Sofía SOLA 
Action on new drugs sector, Supply reduction and new drugs unit 

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RISK ASSESSMENT I THF-F 

Recommended citation: 

TD-AK-18-007-EN-N 

European Monitoring Centre for Drugs and Drug Addiction (2018), Report on the risk assessment of N-phenyl-N-
[1-(2-phenylethyl)piperidin-4-yl]oxolane-2-carboxamide (tetrahydrofuranylfentanyl; THF-F) in the framework of the 
Council Decision on new psychoactive substances, Risk Assessments, Publications Office of the European 
Union, Luxembourg. 

The risk assessment report and technical annex of the publication are published in the original version that has 
not been edited. 

About the EMCDDA 

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the central source and confirmed 
authority on drug-related issues in Europe. For over 20 years, it has been collecting, analysing and disseminating 
scientifically sound information on drugs and drug addiction and their consequences, providing its audiences with 
an evidence-based picture of the drug phenomenon at European level.  

The EMCDDA’s publications are a prime source of information for a wide range of audiences including: 
policymakers and their advisors; professionals and researchers working in the drugs field; and, more broadly, the 
media and general public. Based in Lisbon, the EMCDDA is one of the decentralised agencies of the European 
Union. 

Related publications and websites 

EMCDDA 

I Risk assessment of new psychoactive substances — operating guidelines, 2010 
www.emcdda.europa.eu/html.cfm/index100978EN.html 

EMCDDA and Europol 

I EMCDDA-Europol Joint Report on a new psychoactive substance N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]tetrahydrofuran-2-carboxamide (tetrahydrofuranylfentanyl), 2017  
www.emcdda.europa.eu/publications/joint-reports/thf-f  

I EMCDDA–Europol 2016 Annual Report on the implementation of Council Decision 2005/387/JHA, 
Implementation reports, 2017 www.emcdda.europa.eu/publications/implementation-reports/2016 

I EMCDDA–Europol Early-warning system on new psychoactive substances — operating guidelines, 2007 
www.emcdda.europa.eu/html.cfm/index52448EN.html 

These and all other EMCDDA publications are available from emcdda.europa.eu/publications 

I EMCDDA Action on new drugs website: www.emcdda.europa.eu/drug-situation/new-drugs 

Legal notice: Neither the EMCDDA nor any person acting on behalf of the EMCDDA is responsible for the use that might be made of 
the following information. 

Luxembourg: Publications Office of the European Union 
doi:10.2810/097948 I ISBN 978-92-9497-320-7 

© European Monitoring Centre for Drugs and Drug Addiction, 2018 
Reproduction is authorised provided the source is acknowledged. 
This publication is only available in electronic format. 

EMCDDA, Praça Europa 1, Cais do Sodré, 1249-289 Lisbon, Portugal 
Tel. (351) 211 21 02 00 I info@emcdda.europa.eu  
emcdda.europa.eu I twitter.com/emcdda I facebook.com/emcdda 

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