doi:10.1093/brain/awl092 Brain (2006), 129, 1081–1083

SC IENTIF IC COMMENTARY

Challenges of marijuana research

The use of any drug ideally represents a decision based on

objective, scientifically based cost–benefit analyses that factor

in both the short and long-term effects of that exposure.

Pharmacological, toxicological, pharmacokinetic and phar-

macodynamic investigations that are deemed to be essential

for the rational use of any therapeutic agent are therefore part

of the usual drug approval process. With regard to marijuana,

sociopolitical factors have intervened in this scientific pro-

cess. Three major lay perspectives appear to dominate the

societal view of marijuana—the ‘reefer madness’ camp hold-

ing the view that there are no redeeming attributes to the ‘evil

weed’, the ‘innocuous’ camp who consider it to be a harmless

recreational substance and the ‘medical marijuana’ camp that

believes marijuana to be a panacea for a multitude of aches,

pains and chronic diseases with, of course, every shade of

opinion in-between. On the scientific front, three trends

preface nearly every recent journal article concerning

marijuana—the significant prevalence of marijuana use, the

changes in age of first use (Kohn et al., 2005; Monshouwer

et al., 2005) and the increasing strength of the drug, leading to

higher acute and chronic exposures (National Institute

on Drug Abuse, 2005; Pijlman et al., 2005). For example,

in 2004�96.8 (40.2%), 25.5 (10.6%) and 14.6 (6.1%) million

Americans aged 12 and older were considered to have

used marijuana within their lifetime, the last year, and

the last month, respectively (Office of National Drug

Control Policy, 2006). However, in the 3 of the 11 states

in which medical use of marijuana is legal, and for which

statistics are available, 0.05% of the population are registered,

i.e. legal, users (General Accounting Office, 2002). Even

though marijuana is available from pharmacies in the

Netherlands, 80% of users secure their drug via illicit

channels (Erkens et al., 2005). Therefore, large numbers

of people—adults, pregnant women, adolescents and

children—acutely and/or chronically inhale/ingest imprecise

dosages of marijuana of unknown purity via pharmaceuti-

cally inelegant dosage forms without the complement of

knowledge concerning the pharmacological actions, the

toxicological risks and the pharmaceutical quality of the pro-

duct that would be required for the approval and use of any

other drug.

Cogent, scientifically based research into marijuana is

essential but is also very difficult for a number of important

reasons. Firstly, there are logistical issues inherent in studying

any substance that is illegal in most countries. Specifically,

there are numerous hurdles that must be surmounted to

secure a Schedule I substance approval for acute studies;

there are problems with subject memory and honesty in

determining recent and chronic exposures; and there is a

heightened need for confidentiality and non-disclosure agree-

ments in order to legally protect study participants. Second,

marijuana is a natural product, inherently variable in its

strength and composition, even when acquired through

legitimate channels (Pearson, 2004). Investigations of the

acute response require a standardized drug product and

administration utilizing standardized methods. In spite of

these methodological controls, consistent D9-tetrahydrocan-

nabinol (THC) plasma levels between or within subjects may

not be achieved (Ponto et al., 2004), making determination of

the dose–response relationship from a single smoked dose

potentially problematic. The variability in potency (due to

time and non-existent product quality assurance) coupled

with the unpredictable route of administration (i.e. smoking)

will potentially result in unreliable assessments of immediate

and lifetime exposures. Therefore, estimates of the lifetime

number of ‘joints’ or cumulative THC exposure are critical

pieces of information but represent only crude approxima-

tions of actual exposures. Third, the pharmacokinetics and

pharmacodynamics of marijuana do not lend themselves to

easy examination. Pharmacokinetically, marijuana has a long

half-life due to accumulation in body fat and extensive

enterohepatic recirculation, and it exhibits user-dependent

bioavailability. Pharmacodynamically, tolerance is known

to develop to various pharmacological effects (e.g. cardiovas-

cular effects: Grotenhermen, 2003; Gonzalez et al., 2005) and

the relationship between THC plasma concentrations and

psychotropic effects are generally described by a hysteresis

over time (Grotenhermen, 2003). Furthermore, ascertaining

the time frame of acute, chronic and withdrawal effects, and

the onset of a true abstinent state, requires a kinetic/dynamic

sophistication beyond a positive or negative urine test. For

example, urine tests generally are positive for 3–5 days after a

single exposure but THC may remain detectable for up to

12 days. More troubling, urine levels of metabolites may

fluctuate between positive and negative results for days,

the duration of which is dependent on the previous magni-

tude and frequency of use (Ellis et al., 1985; Grotenhermen,

2003). Fourth, studying a potential drug of abuse entails

various ethical dilemmas. Ideally, the comparison group

should be completely drug naive. For acute response studies,

it is considered to be unethical to introduce a potential drug

of abuse to a naive subject or to reintroduce the agent to an

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abstinent user. As a result, comparative groups are generally

‘occasional’ users. Hence, the nature of the comparison group

is highly dependent on definition of the user group. Addi-

tionally, for studies of chronic users, the investigator is placed

in the position of potentially ‘encouraging’ the on-going use

of an illicit substance. Finally, in examining the effects of an

exogenous agent that has endogenous counterparts, there will

always be questions regarding any alterations in brain struc-

ture and function of the ‘chicken or egg’ type, i.e. did the

altered functioning create the need for enhanced cannabinoid

stimulation or did the enhanced cannabinoid stimulation

create the altered functioning? Baseline data (i.e. before

marijuana use), especially brain structure/function informa-

tion, are essentially non-existent and impossible to obtain

ethically in any prospective manner. Limited amounts of

pre-exposure neuropsychological testing data (e.g. standar-

dized school-based tests: Block and Ghoneim, 1993) when

available may prove to be a valuable resource (Fried et al.,

2005) in characterizing pre-exposure states. Furthermore,

specific effects may not be tied to the dichotomous

user/non-user state or to the continuum of dosage but may

be related to the specific timing of exposures (e.g. neuro-

developmental effects: Viveros et al., 2005). Therefore, infor-

mation on all aspects of marijuana use—howmuch, how long

and when—must be secured from the subject, making the

quality of the data highly dependent on reliability of memory

and honesty of the research subjects.

In this issue, Chang and colleagues (page 1906) report on

what appears to be a neuroadaptive state in chronic

marijuana users. These investigators utilized BOLD fMRI

to examine the brain activation patterns in chronic marijuana

users (N = 24) and matched control subjects (N = 19) during

a set of visual attention tasks with graded levels of difficulty.

In addition, neuropsychological testing was performed. The

chronic marijuana users were divided into two groups, active

users (N = 12) and abstinent users (N = 12), based on results

of urine testing. Three hypotheses were investigated. Firstly,

that marijuana users would show an altered attention net-

work when compared with the control group; this altered

network would entail decreased activation in the normal

attention network and enhanced activation in compensatory

brain regions. Second, active users when compared with

abstinent users would show greater use of these compensatory

regions with increasing attentional load. Third, both user

groups would exhibit normal cognitive function, providing

evidence for neuroadaptation to the chronic marijuana sta-

tus. Three additional pieces of information were determined

for each user subject, specifically the age of first use, the

cumulative THC exposure and the duration of abstinence.

As expected, all three groups had similar neurocognitive

function and task performance, but altered patterns of

brain activation. Marijuana users exhibited less activation

in significant portions of the normal attention network

and greater activation in several smaller, assumed to be com-

pensatory, regions. There was an inverse correlation between

BOLD signal changes and estimated lifetime THC exposure

in the cerebellum, potentially indicative of a down-regulation

of CB1 receptors. On the other hand, there was a positive cor-

relation between the duration of abstinence and the BOLD

signal in parts of the normal attentional network. ‘Age of first

use’ was related to the activation patterns observed, with sub-

jects initiating use earlier in adolescence exhibiting greater

activation in compensatory regions and those initiating use

later in adolescence showing greater activation in the normal

attention network. Cumulative THC exposure and ‘age of

first use’ interacted significantly whereas ‘abstinence status’

did not.

There are a number of inevitable limitations associated

with this study arising from the difficulties outlined above.

First and foremost is the reliance on urine-testing results

to classify marijuana-user subjects into the ‘active’ and

‘abstinent’ groups. Active users were asked to abstain from

marijuana use for at least 4 h but without monitored absti-

nence or [THC], so the actual pharmacological influences

(i.e. acute or chronic effects) cannot be ascertained. Abstinent

users had negative urine tests with the range of ‘abstinence’

from 0.5 to 156 months but with the majority of subjects only

assessed within the first 2 months. Rather than a group of

truly drug-free subjects, this group may reflect a mixture of

subjects with low and residual [THC], those undergoing

withdrawal and individuals truly free of THC-mediated

effects.

From these results, the brain, in response to chronic

marijuana exposure, appears to undergo neuroadaptation

by accessing compensatory processes in order to maintain

normal cognitive performance. Important questions remain

concerning the ability of these processes to accommodate

tasks of greater cognitive demand or the impact of tapping

into reserves prior to the advent of aging processes that

depend on such reserves to maintain cognition. The average

age in this study was �30 years, not that of the ‘baby-

boomers’ now confronting age-associated cognitive declines.

The degree of the compensation necessary appears to be

related to the age of initial use and the cumulative exposure.

The demographic trends in use and the enhanced potency of

marijuana highlight the importance of verifying these rela-

tionships. Abstinence appears potentially to ‘normalize’ brain

activation patterns; however, only serial imaging during

monitored abstinence will reliably determine the role of

reversible and non-reversible changes.

The work of Chang et al. (2006) sheds light on a potential

mechanistic explanation (i.e. neuroadaptation) of the incon-

gruity (i.e. how can the brain be altered without an apparent

change in cognition?) that fuels the attitudinal schism of

society on using marijuana. Replication of these results

with careful subject classification, exposure and abstinence

documentation, a variety of tasks and a broader age range

should further enhance our understanding of the risks and

benefits. Marijuana, with its therapeutic potentials and public

health consequences, warrants scientific scrutiny and the

acquisition of objective information regarding all aspects

of the substance itself and the cannabinoid system more

1082 Brain (2006), 129, 1081–1083 Scientific Commentary

generally—difficult as that may be, unencumbered by the

burdens of sociopolitical pressures and biases.

Laura L. Boles Ponto

PET Imaging Center

University of Iowa Hospitals and Clinics

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