TIPS 1328 No.

of Pages 11

Opinion

Tightrope or Slackline? The

Neuroscience of Psychoactive
Substances
Philippe Coulon1,* and Ali Gorji2,3,*
Novel psychoactive substances ood worldwide markets faster than they can
be banned. Legislators struggle to nd a balance between free availability,
prescription systems, and criminalisation, while physicians try to balance risks
and benets of drug treatment and identify drug abuse a tightrope walk.
Classication of psychoactive substances is central to these decision-making
processes but existing classications rely on unrelated, inconsistent, and shifting guidelines that categorise drugs by chemical structure, toxicity, or addictive
potency. We propose that a new categorisation of drugs based on neurobiological mechanisms of action may help to simplify the regulation of drug use,
delivers a neurobiological context, and streamlines classication and future
regulatory directions. We provide guidelines to distinguish between drug abuse
and treatment and to navigate the controversies over legalising or banning
drugs. Finally, we comment on the role neuroscientic research can play in
the future to solve imminent problems in this highly important eld.
Psychoactive Substances
The treatment of psychological and neurological disorders with psychoactive substances has a
long history and can be traced back to ancient and medieval times [16]. The betel nut (Areca
catechu), for example, has been in use as a psychostimulant for over 10 000 years (for a review
see [7]). Compared with this long history, the effect of its primary active ingredient (arecoline, a
partial agonist of muscarinic acetylcholine receptors) in improving learning in patients suffering
from Alzheimer's disease [8] is quite recent. Uses of psychoactive plants for their psychoactive
effects or therapeutic properties have typically been regulated by cultural means instead of by
law, for several centuries [9]. Most psychoactive substances have clinical uses in anaesthesia,
analgesia, promoting sleep or wakefulness, or treating psychological or neurological disorders,
but are used without medical indication for recreational purposes or in self-treatment to change
the state of consciousness, mood, or thinking processes. They are commonly divided by their
properties into psychostimulants (uppers, such as cocaine, amphetamines, and caffeine),
sedatives/hypnotics/narcotics (downers, such as opioids, ketamine, and benzodiazepines),
and hallucinogens (all arounders, such as LSD, mescaline, and bufotenin) [10].
In the past few decades, an international agreement emerged to conne psychoactive substances exclusively to therapeutic or scientic uses. However, the range of psychoactive
compounds derived from plants or chemically synthesised is vast and ever increasing, complicating their regulation. The World Health Organization (WHO) issued a technical report [11] on
the implementation of the 1971 Convention on Psychotropic Substances [12] outlining the
substances that should be banned due to their health or social impact. Similarly, in the UK the
Misuse of Drugs Act 1971 was the tool to identify drugs that should be banned [13]: all

Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy

Trends
Novel psychoactive substances ood
worldwide markets faster than legislators can react. Existing drug classications rely on unrelated, inconsistent,
and shifting guidelines that classify
drugs by chemical structure, harmfulness, or their addictive potency.
Physicians balance risks and benets
of drug treatments and identify drug
abuse of an increasing number of substances. Simultaneously, legislators
struggle to nd a balance between free
availability, prescription systems, and
criminalisation.
A new categorisation of psychoactive
substances seems necessary. We suggest a simplied system based exclusively on neurobiological mechanisms of
action. This may aid the regulation of
drug use, delivers a neurobiological context for addictive potency and long-term
health effects, and streamlines classication and future regulatory directions.

1
Center for Integrative Brain Research,
Seattle Children's Research Institute,
Seattle, WA, USA
2
Epilepsy Research Center,
Neurosurgery Department, Neurology
Department, Westflische WilhelmsUniversitt, Mnster, Germany
3
Shefa Neuroscience Research
Center, Tehran, Iran

*Correspondence:
philippe.coulon@seattlechildrens.org,
coulon@uni-muenster.de (P. Coulon),
gorjial@uni-muenster.de (A. Gorji).

http://dx.doi.org/10.1016/j.tips.2016.04.004
2016 Elsevier Ltd. All rights reserved.

TIPS 1328 No. of Pages 11

substances may be banned which are being or appear to them [the Advisory Council] likely to be
misused and of which the misuse is having or appears to them capable of having harmful effects
sufcient to constitute a social problem. The 1971 Act dened three classes of drugs, A through
C, in descending order of their potential for causing harm: class A includes heroin, cocaine
(including crack), methadone, ecstasy, LSD, and magic mushrooms; class B includes amphetamines, barbiturates, codeine, cannabis, cathinones (including mephedrone), and synthetic
cannabinoids; and class C includes benzodiazepines, ketamine, anabolic steroids, and
N-benzylpiperazine (BZP). Today, this listing and grouping raises some questions. While
cannabis has been legalised in large parts of the world and its potential as a clinical drug
has been revised over the past three decades [14], it is still listed in the same class as
amphetamines and mephedrone and in a higher class than ketamine. Heroin, cocaine, and
methadone are listed in class A despite their highly varying degree of addictiveness and despite
methadone's successful use in the treatment of heroin addiction. While the original idea that the
class determines the penalty for offences is straightforward, the denition of classes lists
individual substances instead of underlying mechanisms and is thus not directly applicable
to drugs that have been newly designed. The annual reports of the International Narcotics
Control Board [15] and the World Drug Reports issued by the United Nations Ofce on Drugs
and Crime [16,17] indicate an alarming and unmanageable number of designer drugs known
as legal highs ooding especially the European markets. In 2012 the European Monitoring
Centre for Drugs and Drug Addiction detected 73 new substances on sale on European
markets, compared with 49 in 2011 [18]. In 2014 this number exceeded 100 new substances
for the rst time [19]. By December 2014, a total of 541 new psychoactive substances were
included in the UN World Drug Report [20]. Production and misuse of novel psychoactive
substances, dened as substances not (yet) under international control, is on the rise worldwide,
while the gures for traditional drugs, such as heroin and cocaine stagnate [17]. Obviously,
novel psychoactive substances emerge faster than they can be banned by legislation, and laws
enabling precautionary actions are considered. The New Zealand government, for instance,
recently enacted legislation that requires evidence of low risk before new psychoactive drugs
can be legally sold [21], a long-overdue reverse-onus clause. In this light, the Misuse of Drugs Act
1971 seems outdated, insufcient, and misguiding. An alternative system should address and
unify the following concepts: (i) categorise the drug's neurobiological mechanism; and (ii) rate its
potential for health and social damage. We therefore suggest that categorising known and future
drugs of abuse should be based on the neurobiological mechanisms that are the cause of their
negative impacts on health and society. We give an outline of the relevant topics of current
research in neuropsychopharmacology, including drug renement potential, and discuss the
importance of future research for legal approaches to controlling psychoactive substances.

Categorisation of Psychoactive Substances Based on Neurobiological

Mechanisms
How should psychoactive substances be categorised, especially concerning their potential to
harm human health? The WHO plays the role of a scientic arbiter on scientic and medical
aspects in the classication of controlled substances under the international drug control
treaties [22] but their Expert Committee addresses wider responsibilities in a broader public
health approach. To cover the whole range of psychoactive substances and to consider a
fundamentally new approach to drug classications, these committees will require additional
resources and expertise from research. Research in the past three to four decades has
advanced to such an extent that a fundamentally new approach to drug classication is required.
We suggest that a simplied drug classication may be helpful. This may be achieved by dividing
the basic mechanisms of action into just two hazard groups.
Group I includes substances that are highly addictive, strongly hallucinogenic, and/or cause
delusional states of mind (non compos mentis) in combination with a high potential for long-term

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TIPS 1328 No. of Pages 11

changes in chemical synaptic transmission. High addictiveness is ultimately expressed in

substance seeking [7] and is a result of a drug's pharmacodynamics, pharmacokinetics,
and metabolic compatibility. Research on the neurobiology of addiction has shown that
substance seeking of most drugs of abuse is caused by activation of the mesolimbic dopaminergic system, the orbitofrontal cortex, and the extended amygdala [2328]. In addition, some
highly addictive substances, such as cocaine and heroin, modify the activity of the endogenous
opioid system and produce adaptive alterations that play crucial roles in their harmful effects [29].
The transition to addiction and chronic drug seeking involves neuroplasticity in all of the above
structures, most likely begins with a cascade of neuroadaptations, and nally causes alterations
of intracellular messenger pathways, transcription factors, and immediate early gene expression
in reward circuits [30]. If a drug mimics a neurotransmitter in a reward system but has a higher
afnity than the physiological transmitter, it becomes potentially detrimental to the physiological
function of these neuronal networks, as is the case for heroin (opioid receptors), barbiturates
(GABAA receptors), and some hallucinogens (LSD, bufotenin, 5-HT receptors). Receptor afnity
was proposed as a tool for the classication of psychoactive drugs over 30 years ago [31] and
such afnity proles were found to permit a clinically meaningful classication of psychoactive
drugs and to be useful in the assessment of newly synthesised compounds at an early stage of
drug development. Taken together, these factors determine our group I: neuroplasticity of
reward circuitry (dopaminergic system) to cause substance seeking, high receptor afnity
causing detrimental adaptations in physiological signalling and function, and delusional cognitive
states (serotonergic signalling, GABAergic signalling).
Group II includes drugs that may also have a potential for long-term changes in chemical
synaptic transmission but which lack immediately hazardous effects. Changes in neuroplasticity
are mostly in serotonergic and/or noradrenergic pathways and the drugs cause little or no
substance seeking, have only modulatory effects on physiological signalling, do not cause
reduced consciousness (in regular doses required to cause the desired effect), and have no
acutely toxic effects.
We categorise each mechanism of action of psychoactive substances (Figure 1) as group I or
group II (Table 1). Psychoactive substances have diverse mechanisms and, in a simplied view,
all mechanisms eventually impact chemical synaptic transmission, although extrasynaptic ion
channels seem to play a much larger role than previously assumed (see next section). Examples
of the most common mechanisms of action on the subcellular, cellular, and neuronal network
levels can be found in Table 1 and their mechanisms are illustrated in Figure 1.
In previous suggestions, a medical purpose for a psychoactive drug has been proposed as a
basis for drug classications: Substances with no accepted medical use were considered the
most dangerous. However, heroin, for instance, was clinically used as an analgesic, cough
suppressant, and antidiarrhoeal and would not have been a class I controlled drug according to
classication systems relying on accepted medical use [12,13,32]. Opiates in general have a
high therapeutic potential and their clinical use has greatly reduced suffering. Vice versa,
cannabis is still a class I drug according to this schedule, although today its medical use as
an analgesic for chronic pain is widely accepted. Thus, accepted medical use does not seem a
viable criterion, since it requires knowledge of a medical indication and comparison with
alternatives (which may or may not exist) and may change drastically with new research.
Moreover, it has been suggested that, when utilised and administered by competent medical
personnel, psychoactive agents offer relief for psychopathological suffering [33], which is
certainly a viable medical use. Genetic, biological, social, and cultural factors inuence the
effects of a substance on a person and the outcome of substance use [22] and no classication
system can take all of these factors into account. Later suggestions of classication systems
included approaches to rationally assess the harm of substances in physical, dependence, and

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Docking 3e
Priming

Incoming acon potenal

3d
3a

Fusion
Clearing
Acve zone

1
2
Receptors

Enzymac
Hydrolysis

50
mV

Reuptake

5 ms

3b

3c
Mitochondrion
Endosome

MAO

Na+ Channel

Budding

Axon terminal

Loading
Readily
Releasable
Pool
Release

Glial cell

Recycling
Endocytosis

Ca2+ Channel
Synapc
cle

Postsynapc density

Dendric
spine

Postsynapc
potenal
20
mV
5 ms

Dendrite
3f

Figure 1. Effects of Psychoactive Substances on Synaptic Transmission. An incoming action potential triggers the
fusion of neurotransmitter-lled vesicles via voltage-dependent ion channels (Na+ and Ca2+ channels) and subsequent
increases of the intracellular Ca2+ concentration. The neurotransmitter is released into the synaptic cleft, where it activates
postsynaptic receptors (see top-left inset). Activation of these receptors causes ion uxes that give rise to an excitatory or
inhibitory postsynaptic potential (EPSP, IPSP). Some psychoactive substances are similar to the neurotransmitter and have
the same or a stronger effect (1). Other psychoactive substances modulate the receptor (2), modulate neurotransmitter
release (3a), inhibit neurotransmitter reuptake (3b), prevent neurotransmitter decomposition by blocking enzymatic
hydrolysis (3c), alter vesicle loading with neurotransmitters (3d), or prevent the docking, priming, and fusion processes
(3e). Finally, by acting on extrasynaptic ion channels (3f), psychoactive substances may alter the generation of action
potentials of the pre- and/or postsynaptic neuron. Examples are given in Table 1. MAO, monoamine oxidase.

social aspects [34]. While providing a comprehensive set of risk parameters and a rational and
reproducible classication system, the authors acknowledge that distinct categorisation is
necessary for political, social, and judicial reasons. It was found that indeed, the correlation
between classication by the Misuse of Drugs Act and harm rating was not signicant, which
raised questions about the validity of the Misuse of Drugs Act classication. Moreover, it has
been suggested that abused substances can be rank ordered on the basis of their potential
acute lethality [35]. However, toxicity does not reect nonlethal effects such as dangerous
performance decrements that cause a burden to the user and society [35]. We therefore suggest
that, while important and useful for assessing a substance's potential threat to public health,
acute toxicity should not play a role in drug classication but should, rather, be dealt with
separately. Future research must further determine whether our suggestion is an improvement.
As a basis for discussion, the neurobiology of drugs and the severity of their impact on
neurophysiological signalling seems viable.

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Table 1. Mechanisms of Action of Psychoactive Drugs

Psychoactive Substance
or Class of Substance

Action on

Mechanism of Action on
Chemical Synaptic
Transmission

Mechanism
Number in
Figure 1

Group
(Reason)

5-MeO-dimethyltryptamine
(DMT)

5-HT1A, 5-HT1B,
5-HT2A, 5-HT2C,
5-HT6

Activation, reuptake
inhibitor [50]

1, 3b

I (d)

II

Alcohol (ethanol)

NMDAR, GluR

Inhibition [51,52]

GABAA

Amplication [51]

Various others:
nAChR,
endogenous
opioids, 5-HT3R,
GlyR, L-type Ca2+
channel, GIRKs

nAChR: activation [53],

endogenous opioids:
activation [54], GlyR:
activation [55,56], L-type
Ca2+ channel: inhibition
[57], GIRKs: activation [58]

3f

Amphetamines [e.g.,
amphetamines (speed),
cathinone (Catha edulis),
methamphetamines
(crystal), MDMA (ecstasy)]

Dopamine,
noradrenalin,
serotonin, VMAT

Increased neurotransmitter
release, dopamine
releaser [59,60]

3a, 3d

I (n, d)

Anaesthetics, gaseous:
nitrous oxide, xenon

nAChR, NMDAR

Inhibition [61]

II

Anaesthetics, volatile: [e.g.,

urane (desurane,
sevourane, isourane),
halothane, chloroform]

GABAA, GlyR

Activation [61]

II

nAChR, NMDAR/
AMPAR

Inhibition [61]

Various ion
channels

Activation or shift in voltage

dependence of[1_TD$IF] activation,
thereby inhibition of
synaptic transmission [62]

3f

Barbiturates (e.g.,
barbituric acid, allobarbital,
amobarbital, barbital,
cyclobarbital,
heptabarbital,
pentobarbital,
phenobarbital,
secobarbital)

Directly: GABAA

Activation of receptor or
increase of GABA action
[63]

I (n?, h, d)

Benzodiazepines [e.g.,
alprazolam (Xanax[7_TD$IF]),
diazepam (Valium),
unitrazepam (Rohypnol),
midazolam (Dormicum)]

Modulatory:
GABAA

Increase of GABA action

[63]

II

Bufotenin

5-HT2A, 5-HT2C

Activation [64]

I (d)

Caffeine

Adenosine
receptor (A1R and
A2AR), indirectly:
dopaminergic
system

Inhibition [60,65]

II

Cannabinoids (e.g.,
tetrahydrocannabinol,
anandamide, synthetic
cannabinoids such as CP47, 497, and JWH-018)

Directly:
cannabinoid CB1
receptor
(presynaptic);
indirectly:
GABAergic and
glutamatergic
synapses

Inhibition [44]

3e

II

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Table 1. (continued)
Psychoactive Substance
or Class of Substance

Action on

Mechanism of Action on
Chemical Synaptic
Transmission

Mechanism
Number in
Figure 1

Group
(Reason)

Cocaine
Crack

Dopamine,
noradrenalin,
serotonin
transporter

Reuptake inhibitor,
dopamine uptake blocker,
but effect as enhanced
neurotransmitter release
[60,66]

3a, 3b

I (n, d)

DMT

5-HT2A, 5-HT2C,
s1-receptor

Activation [67,68]

I (d)

Ibogaine (Tabernanthe
iboga)

Simultaneous
alteration of
various
neurotransmitter
systems [32]

NMDAR: activation [69],

serotonin, dopamine
transporter: inhibition [70],
VMAT: inhibition [70], kreceptor: activation, 5HT2A: activation [71,72],
weak 5-HT3 ligand, s2receptor: activation [73],
afnity for nAChR,
moderately binds to
subtype /4b2 and more
strongly /3b4 (to the latter
as a noncompetitive
antagonist) [74,75], mreceptor: possibly
antagonism [76]

Sev.

II

Ibotenic acid, muscimol

(Amanita muscaria)

GABAA

Activation [63]

II

Ketamine

NMDAR, opioid
receptors (m, d, k,
s) GABAA, mACh
antagonist

NMDAR: inhibition
(noncompetitive
antagonist) [77]; opioid
receptors: complex action,
both agonist and
antagonist, mAChR:
unknown mechanism,
possibly antagonism
[78,79]

Sev.

I (h, d)

LSD

5-HT2A

Activation [80]

I (h, d)

Monoamine oxidase (MAO)

inhibitors (e.g., iproniazid,
phenelzine, isocarboxazid,
tranylcypromine,
moclobemide)

Directly:
monoamine
oxidase,
indirectly:
dopamine,
noradrenalin,
serotonin

Increase of transmitter
system by inhibition of
transmitter decomposition
[81]

3a, 3c

II

Mescaline

5-HT2A

Activation [82]

I (h, d)

Methylphenidate (Ritalin)

Dopamine
transporter,
NMDAR via s1receptor

Dopamine and
noradrenalin reuptake
inhibitor [83]; NMDAR:
activation/enhancement
[84]

1, 3b

II

Nicotine

Directly: nAChR,
indirectly:
adrenalin,
dopamine,
serotonin, GABA,
glutamate
(NMDAR)

Inhibition of acetylcholine
system, inhibition of
GABAergic systems, gain
of function of dopaminergic
system [85]

Sev.

II

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Table 1. (continued)
Psychoactive Substance
or Class of Substance

Action on

Mechanism of Action on
Chemical Synaptic
Transmission

Mechanism
Number in
Figure 1

Group
(Reason)

Opioids (e.g., morphine,

opium, heroin, endorphins,
dynorphin, encephalin)

Opioid receptors
(m, d, k), possibly
also GABAergic
system

Activation [86] (GABA:

inhibition [87])

I (n, h, d)

Phencyclidine (PCP, angel

dust)

NMDAR, nAChR,
s-receptor,
dopamine and
noradrenalin
transporter

NMDAR: inhibition, binds to

open channels only, use
dependent; nAChR [88]

I (n, d)

Salvinorin A (diviner's sage,

Salvia divinorum)

k receptor

Activation [89,90]

II

The table provides an overview of psychoactive substances, their presumed mechanisms of action, and their proposed
category.
5-HTx, 5-hydroxytryptamine (serotonin) receptor subtype x; AMPAR, AMPA receptor; GIRK, G protein-coupled inward
rectifying K+ channel; GluR, glutamate receptor; GlyR, glycine receptor[3_TD$IF]; mAChR, muscarinic acetylcholine receptor; nAChR,
nicotinic acetylcholine receptor; NMDAR, NMDA receptor;[4_TD$IF] VMAT, vesicular monoamine transporter.
?, mechanism of action as yet unknown or controversial; Sev., several mechanisms.
Reasons for group I: n, neuroplasticity of reward circuitry; h, high receptor afnity causing detrimental adaptations in
physiological signalling and function; d, delusional cognitive states. See section on categorisation of psychoactive
substances based on neurobiological mechanisms for details. For further information on the listed substances, the reader
is referred to the literature cited in the table.

The Role of Neuroscience and Neuropsychopharmacology in the Evaluation

of Psychoactive Substances
Evidently, psychoactive substances have benecial and adverse effects and it depends on the
individual whether the adverse effects may be tolerated. An individual's state can be subdivided
into pathophysiological (i.e., healthy or diseased) and psychological (i.e., healthy or in a state of
depression or addiction). Ideally, the benecial effects can be separated from the adverse effects
by rational drug design. If the two effects are based on different mechanisms, isolating the
mechanism causing the benecial effect may help to minimise or abolish adverse side effects. An
improved understanding of the neurobiological mechanisms underlying drug effects (Table 1
and Figure 1) can lead to better strategies in the prevention of substance abuse and in the
prevention or treatment of psychiatric disorders, substance dependence, and addiction and to
improved pharmacological treatment using psychoactive substances.
Elucidating the full potential of a substance requires continuing research, toxicology, and clinical
trials. Opium and cannabis have greatly contributed to our understanding of the process of pain
transmission by characterising the receptor types and endogenous ligands involved in nociception. Today, activation of the CB1 receptor is considered to be a means to alleviate headache
in patients suffering migraine with aura [36]. Continuing research may clarify the exact mechanisms by which this effect is achieved and enable the identication or design of a drug with a
more specic analgesic action and fewer neuropsychopharmacological side effects.
It seems that extrasynaptic receptors and ion channels have been underestimated as targets of
psychoactive substances. These receptors and ion channels may have completely different
signalling cascades than synaptic receptors and may thus open a new eld of research. By
acting on ion channels, psychoactive substances may change the intrinsic properties of a
specic neuronal ensemble with a dened function. Studies investigating the effect of morphine
on nociceptive processing in the medial and lateral pain pathways in awake rats have recently
been performed [37,38] and concluded that morphine exerts its analgesic effects through
reducing neuronal activity in both cortical and thalamic neurons. Revealing the effects of

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morphine on individual neurons and their intrinsic properties, identifying the neuronal populations
that respond to opioid treatment, and ultimately understanding the role of the neuronal networks
these neurons form in the CNS could open new pathways for pain treatment via supraspinal
mechanisms of analgesia and could possibly aid in understanding and treating substance
dependence. For example, the K+-conducting ion channels known [9_TD$IF]as [10_TD$IF]M-channels [1_TD$IF](KV [5_TD$IF]7.2
[12_TD$IF]and [13_TD$IF]7.3), are known to stabilise[14_TD$IF] the membrane potential, thereby controlling neuronal excitability
[3941], and have recently been shown to produce effective analgesia [41]. Currents through
GABAA receptors may also occur at extrasynaptic sites. In contrast to phasic inhibition by
synaptic release, this so-called tonic inhibition is produced by the activation of high-afnity
receptors by ambient GABA at extrasynaptic sites [42,43]. Baclofen's clinical action, in particular
in the treatment of alcohol dependence and withdrawal, may be due to GABAB-mediated
enhancement of tonic GABAA currents throughout the brain [42], an action it shares with ethanol
but without the latter's addictive potency. These examples demonstrate that research in these
elds can yield tremendous advances for therapies and treatments. Moreover, knowledge of all
of the mechanisms of action of a psychoactive substance can be crucial for their classication.
For example, D-9-tetrahydrocannabinol (THC), the active compound in cannabis, mimics a
neurotransmitter, and in this is similar to opiates. However, opiate signalling causes downstream
modications of the dopaminergic reward circuitry. Cannabis, by contrast, mimics anandamide,
which activates the CB-1 receptor, inhibits calcium channels in the presynaptic membrane, and
ultimately leads to a reduced neurotransmitter release [44].

Concluding Remarks
Alcohol, hypnotics, sedatives, opioids, cannabis, cocaine, amphetamines, and hallucinogens
are among the most frequently used and abused psychoactive substances. Antidepressants
and neurocognitive enhancers should perhaps also be counted in this group. Research has
contributed considerably to explaining the mechanisms of action of these substances by
elucidating the physiological or pathophysiological basis of the respective mental states, by
investigating the effects of these substances on neurons or neuronal networks, and by investigating adverse effects, substance tolerance, and addiction as well as the health and social
impact. In summary, research in neuropsychopharmacology can provide tremendous advances
in treatment strategies and in our general understanding of brain function.
Unfortunately, funding largely concentrates on potential new drugs. Once a drug is available and
sold, interest in public or commercial funding for research on alternative uses or improvements
seems to diminish. Providing sufcient funds for basic, non-commercial research in neuropsychopharmacology is thus of primary interest (see Outstanding Questions). Since any
research on these substances requires their availability, a solid framework must be in place
to establish free access to substances for basic neuroscientic research. This may leave public
banning of hazardous substances unaffected, but which substances or mechanisms of action
are to be banned, and which substances may be freely available, cannot be decided without the
background knowledge provided by neuroscientic research. The existing framework provided
by, for example, the Misuse of Drugs Act seems outdated and in need of an update. We
therefore propose that a characterisation of psychoactive substances based on neurobiological
mechanisms should be taken into consideration. This may simplify the regulation of drug use,
delivers a neurobiological context for addictive potency and long-term health effects, and thus
provides a means of staying ahead of drug design by streamlining regulatory directions.
Alongside judicial intricacies and social controversies, it has become increasingly difcult for
physicians to calculate the risks and to balance the possible positive and negative outcomes of
drug treatment. It increasingly resembles a tightrope or slackline walk: jurisdiction must nd a
balance between banning, the prescription systems, and free availability; physicians have to
distinguish between drug treatment and drug abuse. On the one hand, it is often argued that

Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy

Outstanding Questions
Which substances or mechanisms of
action are to be banned and which substances should be freely available? The
new categorisation we suggest here can
be a rst step only and is intended as a
basis for future discussions. A complete
and comprehensive retooling requires a
broad consensus among the scientic
community across elds.
What is the optimal balance between
treatment with potential drugs of abuse
(to reduce suffering) and drug addiction
(increased suffering)? Does a prescription system provide adequate control?
What is the origin of addiction? What is
the genetic basis of drug addiction?
Answering these questions can complete the transition from a social problem to a medical problem and from
disdain to sympathy.
Can new and improved treatment
strategies be developed for psychological and physiological disorders based
on the neurobiological mechanisms of
action of novel psychoactive substances? How can research in drug renement and alternative uses of existing
substances be improved and better
funded?

TIPS 1328 No. of Pages 11

omission to ban or to legalise a substance may suggest that it is harmless. On the other hand,
judicial bans are already in place for numerous substances but seem to be ineffective in
preventing abuse. Legislation has the duty to protect from harm, and this involves protection
of an individual from hazardous substances. Moreover, addiction and its associated criminal
activity have always posed threats to individuals and to society. Nevertheless, criminalisation of
self-harm is neither a morally acceptable nor an effective measure for controlling psychoactive
substances.
What differentiates the legally available drugs from illicit drugs? It is argued that alcohol is
inherently no less dangerous than illicit drugs, and dependence on nicotine in tobacco causes
more deaths and health problems than dependence on any other psychoactive substance [22].
Tobacco ranks ninth in mortality and morbidity in countries with high mortality and third in
countries with low mortality [45]. In 2002, 5500 billion cigarettes were manufactured and
consumed by 1.2 billion smokers in the world [46]. The annual per capita consumption of
alcohol is well above 10 l of pure ethanol in Western and Central Europe and just under 10 l in
North America and Australia [47]. Tobacco smoking and drinking alcohol cause the majority of
drug-related medical problems. It seems hypocrisy to issue a general ban on drugs and exclude
the ones that are most widely used and cause by far the most medical and, in the case of alcohol,
social problems. The absolute numbers of both deaths and life-years lost are far larger for legal
substances [16,48] than for the illicit opiates, cocaine, and amphetamines combined. However,
there are far fewer illegal drug users than there are users of alcohol and tobacco. Thus, when
taking into account the total number of users, the amount and severity of abuse-related
problems are comparably low for these drugs. While, on average, 1819 life-years were lost
for users of opiates, cocaine, and amphetamines, it was 5 years for users of tobacco and 2 years
for alcohol [16,48,49]. It seems that life-years lost may serve as a viable criterion for categorising
substances. These numbers, however, take decades to determine [49].
Recent events and developments have shown that it is essential to continue research to improve
the therapeutic risk balance and to identify possible drug effects, even years after licensing or
thousands of years after the rst reports of recreational use or abuse. Continuing efforts to nd
novel mechanisms of psychoactive substances and to investigate already-licensed drugs not
only allows the expansion of therapeutic strategies but also helps to reduce risks and potentially
saves lives. Improving our knowledge regarding the basic mechanisms of action of psychoactive
substances may also allow reduction of the abuse potential by drug renement and improve our
fundamental research strategies.
Acknowledgments
The authors thank Erwin-Josef Speckmann, Peter Mullen, Thomas Budde, Carole E. Landisman, and Anna Ventura for
helpful comments and discussion.

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