Health Risks of Marijuana Use

by James Geiwitz, Ph.D.

September 19, 2001

Contents

1.0: INTRODUCTION

The purpose of this report is to examine the research evidence for
and against the hypothesis that marijuana use involves risk to the
user’s health. It is prepared for Robert Moore Stewart (Attorney) in
two Constitutional Question Notices (Court File Numbers 112460 and
112476, Victoria Registry) on behalf of Leon Edward Smith (Defendant).

My credentials for writing this report are as follow: I have a Ph.D.
in experimental design and analysis from the University of Michigan.
I have written 10 textbooks, all of which have had sections on
marijuana use and abuse in North America; therefore, I have followed
the research on marijuana for over 25 years. On January 15, 2001,
the Committee on Hemp Risks prepared a report for Health Canada on
the health risks of THC (the psychoactive ingredient in marijuana) in
industrial hemp foods and cosmetics. I was the chair of that
committee and chief author of the report. Also on the committee were
the top marijuana researchers in the world, including Franjo
Grotenhermen, M.D., of the nova Institute in Germany; John P. Morgan,
M.D., Professor of Pharmacology, CUNY Medical School; Paul Consroe,
Ph.D., Professor of Pharmacology and Toxicology, University of
Arizona; and David Pate, Ph.D., Senior Technical Officer, HortaPharm
BV, Amsterdam. Dr. Grotenhermen is chair of the International
Association for Cannabis as Medicine. Dr. Morgan has prepared the
recreational drug section of the Merck Manual for many editions.
Dr. Consroe is a founding member of the International Cannabinoid
Research Society. Drs. Morgan, Consroe, and Pate presented their
research to the US Institute of Medicine’s task force on medical
marijuana and is included in their report, Marijuana and Medicine:
Assessing the Science Base (National Academy Press, 1999). The
Institute of Medicine prepared this report for the White House Office
of National Drug Control Policy as the “definitive” review of
research on medical marijuana in the US.

This report will focus on four areas of potential risk, the four
major areas in which toxic effects of THC have been suggested:

  • acute neurological effects
  • brain development
  • reproductive system
  • immune system

In addition, this report will discuss the scientific methods of
cannabis research, in an attempt to resolve conflicting claims about
health risks.

Much of the discussion in this report is based on two major reviews
of the health risks of THC, one by Dr. Grotenhermen et al. (THC
Limits for Food, nova Institute, 1998) and the other by Dr. Morgan et
al. (Marijuana Myths, Marijuana Facts: A Review of the Scientific
Evidence, Lindesmith Center, 1997), as well as the Institute of
Medicine’s report referenced above. (It is worthy of note that the
Grotenhermen and the Morgan reviews agree in every significant
conclusion; the Institute of Medicine report agrees in substance,
although it is more cautious, calling for further research.) For
critical issues, the primary research is cited.

2.0: THE TOXICOLOGY OF THC

The preponderance of evidence clearly indicates that THC is one of
the least toxic chemicals that humans ingest. At doses achieved by
heavy marijuana users, there is no evidence of genetic damage or
effects on fertility, pregnancy, or offspring. Similarly, there is
no evidence of damage to the hormonal or immune systems.

Research that finds damaging effects of THC generally falls into one
of two categories: 1) studies that are not replicated by later
research using more appropriate experimental designs; and 2) studies
that use massive quantities of THC, far beyond the doses employed by
heavy marijuana users.

2.1: Genetic Effects

In doses typical for consumers of marijuana, THC is not genotoxic,
mutagenic, or carcinogenic, and it has no effect on cell metabolism.
THC does not result in chromosomal breaks.

At extremely high doses applied directly to cells, THC reduces the
synthesis of DNA, RNA, and proteins. These effects are nonspecific,
that is, unrelated to the typical receptor activation in the human
body.

In regard to genotoxic effects, marijuana consumption is obviously
safe for consumers.

2.2: Pregnancy and Offspring

Animal studies of the effects of THC on pregnancy are inconsistent,
even with doses of 10-20 mg/kg, a hundred times higher than the
Lowest Observed Effect Level (LOEL) for psychotropic effects. A few
studies purported to show impairment of cerebral development in
children of chronic cannabis consumers, but these studies were never
replicated and are now discredited. The No Observed Effect Level
(NOEL) for pregnancy variables (parturition, duration of pregnancy,
infantile abnormalities, birth weight) is above the range of human
consumption by chronic marijuana consumers.

There is no realistically demonstrated danger to pregnant women or
their offspring from consumption of marijuana.

2.2.1: Pregnancy

Greenland et al., 1982, found more meconium staining and longer
duration of labour in marijuana users, but this study has never been
replicated, even by Greenland’s lab. For centuries, cannabis has
been used for pain relief during birth. The general conclusions
permitted by the research are that no birth complications can be
observed in mothers who ingest marijuana levels of THC over a long
period of time.

Gibson et al., 1983, found more premature births in marijuana users,
but this study has never been replicated. Most studies find no
marijuana-induced change in the duration of gestation.

2.2.2: Birth defects and brain development

Birth defects associated with THC have been found only in animal
studies in which the THC was injected, in very high doses, directly
into the abdomen. In humans, there is no evidence whatsoever for a
link between marijuana use and fetal malformations or Minor Physical
Anomalies (MPAs).

Studies that show a decreased birth weight in rat pups after THC
ingestion have been clearly discredited. The decrease, when it
occurs (at high doses), is due to reduced food and water intake of
exposed dams; there is no difference between these animals and
pair-fed controls.

Evidence is accumulating that the cannabinoid-anandamide receptor
system might play a role in cerebral development in fetuses and
neonates. Daily administration of 5 mg/kg THC to pregnant rats
doubles the activity of the enzyme tyrosine hydroxilase (TH) in
specific brain cells of their fetuses (Hernandez et al., 1997). TH
is believed to be a key factor in the development of neurons. In
contrast, one animal study has established a disturbance of
mesolimbic dopaminergic neurons among perinatally THC-exposed males
which persists in adult animals (Garcia-Gil et al., 1997). However,
the significance of these data for humans smoking marijuana is very
probably nil.

Animal studies have generally found behavioural problems only at high
doses. For example, no behavioural effects in offspring were
observed after dosing the pregnant rats with 50 mg/kg/day. Hutchings
et al., 1987, found nipple attachment problems in rat offspring
exposed to 50 mg/kg/day, but the problems were clearly related to
decreased food and water intake in the dams; the offspring of
pair-fed controls were indistinguishable from the offspring of
experimental animals.

In humans, the offspring of chronic users show no differences from
normal in sleeping, eating, mental tests, and psychomotor tests. One
researcher (Dreher, 1994, 1997) found the offspring of chronic users
to be more lively and less irritable, with fewer tremors; these
babies were more easily quieted, yet more responsive to novel
stimuli. These results have not been replicated, but they show the
extreme inconsistency of marijuana studies. The more common finding
is, simply, no difference.

Studies that have attempted to find brain damage from THC have been
unsuccessful. Marijuana levels of THC do not kill brain cells. In
one study, monkeys were forced to inhale five marijuana cigarettes a
day for a year; there was no evidence of brain damage (Zimmer &
Morgan, 1997). In humans, with brain damage assessed by CAT scans,
no damage was observed in spite of the high dose: nine marijuana
cigarettes a day.

2.3: Hormonal Systems and Reproductive Capabilities

Some high-dosage animal studies suggest that THC may act on the
hypothalamus pituitary-adrenal axis and adversely affect the sex
steroid hormones. However, there is no reliable finding of adverse
effects in animals (male or female) within the range of human
consumption of marijuana. The slight effects that sometimes appear,
disappear with repeated doses (tolerance). In humans, no effects
were discovered regarding the function or concentration of sexual
hormones or other parameters relevant for reproduction such as sperm
quantity and quality.

In one representative study, men were dosed with up to 20 marijuana
cigarettes a day (!) for a month (Hembree et al., 1979). The
researchers found some decrease in sperm concentrations and motility.
The decreased factors were not outside of “normal” range, and by the
end of the month, the sperm factors had returned to normal, despite
continued dosing.

In men, a few studies found effects of chronic marijuana use on
luteinizing hormone (LH), which is related to testosterone
production, although the effect disappears with time, even if THC
doses remain constant. Other studies found no such LH effect. There
is no effect of THC on testosterone, follicle stimulating hormone
(FSH), or prolactin. There are no effects on puberty. A
representative study (Mendelson et al., 1978) found no effect of
marijuana smoking on testosterone level, in spite of the high doses:
120 marijuana cigarettes in 21 days.

In women, the conclusions are the same: There are no reliable
effects of THC on the menstrual cycle, estrogen levels, progesterone,
prolactin, LH, or FSH. The few studies of positive effects involved
high-dosage inhalation, effects that quickly disappeared as tolerance
developed.

In some animal studies, THC reduced the level of adrenocorticotropin
(ACTH), which is secreted by the adenohypophysis and stimulates the
production of glucocorticoids (cortisol) in the suprarenal cortex.
This result could not be replicated in human chronic consumers of
marijuana. THC has no effect in humans on the thyroid hormones or on
glucose metabolism.

2.4: Immune System

“Cell experiments and animal studies demonstrate that THC has
suppressive effects on the humoral and cell-mediated immunity.
However, the majority of those can be attributed to toxic unspecific
effects. Many analysed parameters required extremely high doses to
exhibit any significant effect and the effects were dose-dependent
with the threshold concentration being precisely determinable. When
applying lower doses, one often observed differentially
immunostimulating effects or no effects at all. For many immune
parameters the NOEL is … irrelevant to the human consumption
situation. In studies of man or of cells of marijuana users the
effects observed were often contradictory. If such effects were
found at all, they were weak even in case of heavy cannabis use and
of questionable relevance to health. The World Health Organisation
summarised in its most recent cannabis report: ‘Many of their effects
appear to be relatively small, totally reversible after removal of
the cannabinoids, and produced only at concentrations or doses higher
than those required for psychoactivity (WHO, 1997, p. 27)'”
(Grotenhermen et al, 1998, p. 53).

2.4.1: Suppression versus enhancement

THC and the immune system is the most thoroughly researched topic in
the area of subliminal biological effects. Much of the early
research, which demonstrated immune system suppression, has been
discredited. For example, Nahas et al. (1974) found that THC
decreases the number of T-lymphocytes – which control cell-mediated,
acquired immunity. Later studies found no such decrease. Dax et al.
(1989), for example, found no change in T- or B-lymphocytes (humoural
immunity) or in T-cell subtypes before, during, or subsequent to
administration of THC to chronic users. Wallace et al. (1988)
reported similar findings, with a twist: an increase in helper
T-cells (CD4). These findings should be interpreted as
immunoenhancement, because helper T-cells stimulate the proliferation
and activation of other immune cells.

Nahas et al. (1977) found in vitro suppression of T-cell
proliferation in response to mitogens, which stimulate cell division.
Other researchers criticized Nahas’s method – applying THC in massive
doses to human cells in a petri dish – and called the results
“meaningless.” Better studies failed to replicate Nahas’s work and,
instead, found immune system stimulation at lower doses (Pross et
al., 1993; Luo et al., 1992).

Let us be clear about these findings: What the research shows is
immune system suppression at very high doses, but immune system
stimulation (enhancement) at low doses. These effects have been
demonstrated for both the T- and B-lymphocytes. This means that the
amounts of THC in marijuana probably strengthen the immune system of
humans. High doses have nonspecific toxic effects, likely the cause
of any damage, whereas low doses act through specific receptor-based
effects. It’s a basic principle of pharmacology: low doses may be
curative whereas high doses are poisonous.

One last point: With an oral dose of THC of 0.1-0.2 mg/kg (the
psychotropic threshold), the blood plasma reaches a maximum
concentration of 3-5 ng/ml. In the cell studies, the concentration
is 10 ug/ml, or 10,000 ng/ml – 2000 to 3000 times the dose that
produces the marijuana “high.”

2.4.2: Humans and disease

Marijuana smokers show an enhanced response to antigens (which
trigger antibodies) compared to cigarette smokers and cancer patients
(Hollister, 1992), which supports the conclusion of THC strengthening
the immune system and casts additional doubt on the high dosage cell
studies. On a more general level. absolutely no epidemiological
evidence exists relating marijuana use and infectious diseases (Hall
et al., 1994). In cancer and AIDS patients, THC is used to reduce
pain and depression, stimulate appetite, and prevent nausea and
vomiting. AIDS patients, who suffer from a damaged immune system,
are not harmed by THC (Di Franco et al., 1996).

2.5: THC and Cancer

Immune-system stimulation by THC at low doses should be apparent in
macro-level health benefits. The stunning (but rarely reported)
success of THC treatments of cancer may be representative. One of
the first studies had rats ingest a large dose (50 mg/kg) of THC
daily for two years. At the completion of the experiment, 70 percent
of the dosed animals were still alive, but only 45 percent of the
control (undosed) animals survived. This sizeable difference was due
almost entirely to a reduced incidence of cancer in the animals given
THC (Chan et al., 1996).

A more direct test of THC’s cancer-fighting properties was performed
on rats with brain tumours (Galve-Roperh et al., 2000). The tumours,
called gliomas, are fatal in humans. The researchers infused THC
directly into the rats’ brains. The control rats (no THC) died in
two to three weeks. In a third of the THC-dosed rats, the tumour was
eliminated. Another third lived eight to nine weeks, instead of the
two to three weeks of the control (no THC) rats. A third of the
THC-dosed rats gained no benefit. The researchers claim that the THC
works by stimulating the cancer cells to “commit suicide” in a
natural process called “apoptosis.” Normal cells were unharmed. The
THC in this experiment was very low dosage, and the cancers were at a
late stage, when untreated rats were already starting to die. The
researchers suggest that THC would work even better if given earlier.

2.6: Miscellaneous Issues

2.6.1: Marijuana use in children

It is true that children generally respond more severely to chemical
toxins; alcohol consumption, for example, is riskier for children
than for adults. But in the case of THC, which operates on specific
receptors, children’s use of marijuana is actually safer than
adult’s use because children have fewer receptors. Children with
cancer, for example, tolerate considerably higher doses of THC than
adults, with no symptoms of psychoactivity (Abrahamov et al., 1995;
Fride & Mechoulam, 1996). A similar study of children with cancer
taking nabilone, a THC analog, found that high doses were well
tolerated: “Particularly for some adolescent patients, it can turn a
five day course of chemotherapy from a dreaded ordeal into something
accepted with a shrug of the shoulders” (Dalzell et al., 1986).

2.6.2: Cannabinoids other than THC

Anti-marijuana scientists often make the point that there are 66
cannabinoids in marijuana, that THC is only the best known and most
frequently studied. Therefore, even if THC were found safe, one of
the other 65 might be unsafe. This number is misleading. It
represents the sum total of cannabinoids found in detectable quantity
in at least one cannabis variety in at least one study in the history
of cannabis research. The only cannabinoids proven to be
manufactured by the marijuana plant are THC, CBD, CBC, and
(presumably) their common biogenetic precursor, CBG (Pate, 2000).
CBD predominates, with an accompanying fraction of THC. CBC is found
in significant quantities only in tropical marijuana. CBG is found
only in very small amounts. To this short list can be added minor
quantities of the THC degradation products, CBN and delta-8 THC. The
remaining 60 cannabinoids exist in almost undetectable amounts – in
fact, usually none at all – in any given sample. Anti-marijuana
researchers admit that CBD poses few risks. CBN is considered to be
“as dangerous as THC,” but the research that “proves” this is the
same research that “proves” that THC is risky. We believe this
research to be problematic, if not invalid.

Since heavy, chronic consumption of whole marijuana has been shown to
be safe, it is highly unlikely that any ingredient of marijuana would
be found to pose health risks.

2.6.3: Health risks of smoking marijuana

Like tobacco smoke, marijuana smoke contains a number of irritants
and carcinogens. Early research showing that lung damage by a single
marijuana cigarette was greater than by a single tobacco cigarette
have been superseded by better research concluding the two types of
smoking are equally harmful. A tobacco smoker, however, may consume
40 or more cigarettes a day, whereas marijuana smokers are considered
“heavy users” if they consume 5 joints in 24 hours. There have been
zero cases of lung cancer or emphysema attributable to marijuana
smoking.

Because of prohibition, marijuana growers have developed new
varieties with higher levels of THC. Police reports of 30% abound,
but the highest recorded in the research literature is 14%; the
marijuana of the sixties was about 3%. In any case, high levels of
THC actually make marijuana safer, because less smoke need be
inhaled to achieve the “high.”

AIDS patients who use marijuana face an increased risk of
aspergillosis, a pulmonary disease. Aspergillosis is caused by
fungal spores that sometimes develop in improperly stored marijuana.
Careful screening of marijuana supplies for AIDS patients is a good
idea.

It is clear that most of the health risks of marijuana are due to the
method of ingestion: smoking. Other, safer methods, such as baked
goods, are available and should be used by people with lung disorders.

3.0: THE SCIENCE OF THC RISK ASSESSMENT

There are research reviews that claim no health risks from marijuana
use and there are other reviews that claim just the opposite. The
science of THC is not unlike other areas of science: Science does
not prove anything. It deals in probabilities, and its methods are
designed to estimate the degree of error in an estimate or in a
probabilistic relationship. Most scientists view their procedures as
a search for error, whereas the general public perceives it as a
search for truth. In reality, it is a search for truth by way of
estimating error.

The nature of science is such that one can always argue the opposite
to a suggested proposition, with some evidence in support. Global
warming, for example, is supported by the bulk of the evidence, but
there are enough data leaning toward the opposite conclusion that the
National Post can claim that global warming is a hoax. Similarly,
scientists paid by the tobacco industry can mount a claim, with data
support, that smoking does not cause lung cancer.

When a scientific question has political ramifications (such as
global warming or smoking), the goals of science are often perverted,
as different camps seek to generate evidence for their position. The
US War on Drugs is such a camp. Beginning in the 1960s, the US
government offered scientists millions of dollars to “prove that
marijuana is harmful.” The research cited by opponents of marijuana
decriminalization includes much of this “advocacy science,” which
produced highly misleading conclusions about the effects of THC.

The following section is, in effect, a manual on how to do advocacy science.

3.1: Extreme Dosing

The major deficiency with most reports of harm from THC is the
massive doses required to demonstrate such effects. In one study,
monkeys were given the human equivalent of 15 kg of marijuana in a
single dose. Similarly, the petri-dish studies of the effects of THC
on body cells used concentrations 2000 to 3000 times the threshold
level for psychotropic effects.

In a review of the effects of THC on the human immune system (which
found none), the reviewers note that some animals given large doses
do show effects; doses are forty to one thousand times the
psychoactive doses for humans (Zimmer & Morgan, 1997). Similarly, an
attempt to find brain damage in monkeys failed to do so, in spite of
the dose: five marijuana cigarettes a day for a year.

These are extreme examples, but far from rare. Almost all of the
studies that show damage from THC use high to very high doses, even
compared to marijuana levels. When compared to the low doses from
hemp foods and cosmetics, the high-dose studies are irrelevant.

THC at marijuana levels acts on compound-specific binding sites
(cannabinoid receptors). Only at high concentrations (far beyond
that encountered in marijuana use) do nonspecific, toxic effects
occur. Most if not all chemicals will damage body cells and systems
at high concentrations – for example, numerous deaths have been
recorded in people who for psychiatric reasons drink excessive
amounts of water. And pharmaceuticals that are toxic at high
concentrations are often beneficial at low doses, as seems to be the
case with THC and the immune system.

3.2: Cannabinoid Receptors and Tolerance

The fact that THC at marijuana doses acts not nonspecifically but,
rather, specifically at receptor sites on neurons provides a further
margin of safety for users. For one reason, neurochemical receptors
generally show tolerance – that is, decreasing effect with repeated
or sustained exposure. For most harmful chemicals, the toxicity
increases (and the NOEL decreases) with duration of exposure. But,
with THC, the opposite occurs, because of tolerance. For example,
high doses of THC in female monkeys resulted in hormonal changes and
a disruption of their menstrual cycle. After six months of high
doses, the hormone levels and the menstrual cycles returned to normal
(Smith et al., 1983). Tolerance can be observed in the cases of most
THC effects.

Chronic exposure to THC does not irreversibly alter the cannabinoid
receptors (Westlake et al, 1991).

At marijuana doses, THC’s effects are almost entirely receptor based,
with little or no nonspecific toxicity. This means that even if a
troubling effect of THC were to be established, the risk would be
shortlived.

3.3: Extrapolation from Animal Studies

A major disagreement exists between the camps finding no health risks
of marijuana and those claiming the opposite regarding the value of
animal studies. Many of the risks reported by anti-marijuana
researchers come from studies in which high doses were given to rats
or mice. That’s OK, they say, because of “similarities” between
humans and rodents in the pharmacokinetics and metabolism of THC and
in the brain distribution of cannabinoid receptors.

However, the application of rat data to human risk assessments is an
uncertain and often misleading extrapolation, with numerous pitfalls.
For example, the extrapolation of doses is problematic. Typically, a
dose given to rats is reported in milligrams of THC per kilogram of
body weight. The dose for humans to produce the same effects is then
calculated using the body weight of humans. The average human weighs
about 70 kg. So an effect caused by a 2 mg dose to a rat weighing
0.2 kg translates to a 700 mg dose to humans (about 50 times the dose
for a human “high”).

This kind of extrapolation may be meaningless, because many
biological processes (e.g., metabolic rate) are unrelated to body
weight. For this reason, some researchers use comparisons of body
surface (mg/m2) instead of body weight. It has been found that
body-surface comparisons predict more accurately human tolerance for
anti-cancer drugs from animal data than do body-weight comparisons.
But body surface is also a poor basis for extrapolation for many
drugs. Other bases include pharmacokinetics (absorption, metabolism,
excretion, etc.) and toxicological estimates such as the “lethal
dose” studies.

The lethal-dose studies are a lesson: In rats, the lethal dose is
around 1300 mg/kg. Extrapolated on the basis of body surface, the
lethal dose in dogs should be about
350 mg/kg and in monkeys, about 650 mg/kg. But dogs lived after a
dose of 3000 mg/kg, and monkeys survived 9000 mg/kg. The lethal dose
in these animals could not be established. The primates should have
been 50 percent more sensitive to THC than rats, but were at least
five to ten times less sensitive. The extrapolation from rats to
higher mammals was wildly inaccurate.

There are significant differences between the reproductive and
hormonal systems of rats and mice and those of humans (Mendelson and
Mello, 1984). Mice, for example, are especially disposed to fetal
malformations. In general, data on smaller animals leads to highly
inaccurate estimates of THC toxicity in larger animals.

Reliable data on the toxicity of marijuana in humans must be based on
studies with human subjects.

3.6: The Fallibility and Abuse of Science

Studies of the effects of THC on humans are inconsistent, for a
number of reasons: Many studies use small samples (that is, few
subjects), and small-sample studies are notoriously unreliable (that
is, inconsistent). For scientific purposes, small-sample studies are
practically worthless. A young man who smokes pot fails to go
through puberty; the child of a pot smoker develops cancer: These
are meaningless anecdotes, although such studies are widely touted as
proof of THC’s dangers.

Most of the marijuana studies on humans compare chronic users with
“matched” control subjects. This experimental design produces data
that are often misleading, because the researchers are comparing two
groups that differ in many ways. True matching is impossible, since
one can never know all the factors that influence the life of a test
subject. For example, many chronic marijuana smokers use other drugs
as well, including cigarettes and alcohol. In addition, human
subjects often lie about their drug use, making assignment to groups
difficult. Results from such studies are often unreliable or
difficult to interpret.

As we’ve mentioned, the US War on Drugs has distorted the scientific
infrastructure and produced a plethora of biased findings. A study
that purports to have found deleterious THC effects is quickly
published, whereas a study that finds THC safe is not. In the latter
case, researchers may suppress the data or peer review might
disparage the experiments (Levy and Koren, 1990). Finally, if
well-designed experiments demonstrating the safety of THC are
published, government publications often ignore them, focusing
instead on the studies that support the official view. This
pseudo-science we have termed “advocacy science.”

True science consists of a search for conclusions to explain
previously established facts, theories to explain observed data.
Advocacy science consists of a search for facts to support a
previously established opinion.

4.0: CONCLUSIONS

Reviews that do show health risks of marijuana are typically based on
poorly-designed research, e.g., using massive doses of THC, far more
than even those levels consumed by the heaviest marijuana smokers.
Every study showing health risks has been discredited or refuted;
cannot be replicated; or has been shown to be in error by a majority
of studies on a given topic.

Apart from potential dangers from nonTHC factors in marijuana smoke,
the best research shows clearly that there are no substantiated
health risks associated with marijuana use. Indeed, there may well
be health benefits (in addition to the proven benefits of medical
marijuana), as marijuana levels of THC seem to strengthen the immune
system.

Laws prohibiting marijuana on the basis of health risks cannot be
justified by the research literature.

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