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Vietnamese herbal opioid addiction treatment medication
Heantos-4
Mika Turkia
M.Sc, mika.turkia@alumni.helsinki.fi, February 21, 2021
Abstract
Heantos-4 is a non-toxic, non-addictive herbal detoxification medicine for opioid addiction. It was initially
invented in Vietnam in the 1980s and tested and developed further there in the early 1990s. Since 1995
it has been studied in international co-operation, standardized first into earlier versions and finally to
the current version Heantos-4.
The various versions have been utilized at Vietnamese inpatient rehabilitation clinics since 1991. Dur-
ing detoxification it has a predominantly sedative effect. It likely acts as a dopaminergic stabilizer,
counteracting both hyperdopaminergic and hypodopaminergic states.
Up to 2008, an estimated 9000 patients had been treated. An uncontrolled phase III clinical trial
carried out in Vietnam in 2008 indicated an approximately 90% success rate during an initial seven-day
inpatient detoxification treatment. This formally unpublished trial is briefly reviewed in this article. In
2012, Heantos-4 was licensed for over-the-counter outpatient use in Vietnam.
The Heantos-4 formulation consists of extracts of twelve plants commonly used in Traditional Chinese
Medicine (TCM). In addition, animal-based gelatin is utilized as a binding agent. The product has been
said to conform to Good Manufacturing Practices (GMP) standards. The patent of the product belongs
to the national Institute of Chemistry of the Vietnam Academy of Science and Technology (VAST).
An initial hindrance to clinical trials and international adoption was a lack of necessary polypharmacoki-
netic methods for determining the constituent molecules and the active agents of the complex mixture. In
2020 a key active agent l-tetrahydropalmatine (l-THP) was identified. Due to synergistic effects between
components Heantos-4 likely provides better tolerability and a greater therapeutic efficacy in comparison
to l-THP alone.
The article also briefly describes the approximately 40-year history of the development of Heantos, partly
based on unpublished internal documents of the United Nations Development Programme (UNDP).
In the 2000s, a severe opioid epidemic emerged in the United States. More than ever an effective method
for resolving opioid addiction is needed. As of yet only uncontrolled clinical trials of Heantos have been
carried out. There is thus an urgent need for randomized controlled clinical trials.
Keywords: substance abuse, opioid addiction, opioids, opiates, heroin, buprenorphine,
l-tetrahydropalmatine, herbal medicine
ORCID iD: 0000-0002-8575-9838
Introduction and background
The following section presents background information on the development of Heantos. The details are
largely based on an unpublished internal document “United Nations Development Programme: Inter-
national Development of the Anti-Drug Medication HEA(N)TOS. Project background and preliminary
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results of safety and efficacy tests conducted in Vietnam. March 1999”, later referred in the text as (inter-
nal report: UNDP, 1999). The report comprises a collection of various documents: project background,
a description of development of Heantos since 1995, documents from the Hanoi Institute of Chemistry,
agreements between the United Nations Development Programme (UNDP), the United Nations Office
for Project Services (UNOPS) and the Vietnamese government, a statement from Dr. Donald Jasinski
of the Johns Hopkins School of Medicine, descriptions of patient cases, a report of an initial pharmaco-
logical standardization process, results of initial safety and toxicity tests, a report of an initial trial of
110 patients as well as project budgeting information.
One of the documents, “Brief of new and important information on Heantos medicine (VIE/96/003)
project” by the Institute of Chemistry of the Vietnam Academy of Science and Technology (VAST), is
later referred to as (internal report: VAST Institute of Chemistry, 1998). A letter from the Institute
of Orthopaedics Science and Rehabilitation for Wounded Veterans and Invalids which had performed
the initial uncontrolled 110-patient clinical trial will be referred to as (internal report: Institute of
Orthopaedics Science, 1996).
Colonial health policies and their reversal in Vietnam
Vietnam’s history includes the French colonial era (1858–1945). It was followed by the warring era
(1945–76) which included the Vietnam War (1954–75). After the 1976 reunification of North and South
Vietnam, Vietnam became a socialist republic (1976–1991) and subsequently a “socialist-oriented market
economy”.
The opium problem in Vietnam was initiated by British opium flooding from China to Burma (Myanmar)
and to North Vietnam along with migratory Chinese [1]. Opium was swiftly outlawed but after the onset
of colonial rule the French established an opium franchise to finance its expenses which led to opium use
spreading to lowland provinces. By the early 1940s it was estimated that 2% of the population and 20%
of the elite were addicts.
A central feature of French colonial era health policy was marginalization of traditional medicine in
relation to modern biomedicine: a “general, though not overall, rejection of [traditional medicine’s]
public health value” [2]. A situation was created in which a large part of the population lacked access to
the preferred form of healthcare. This marginalization led to decreased economic opportunities and social
capital for practitioners of traditional medicine. There were, in turn, less practitioners and apprentices,
resulting in a decline in the professional skill level of new generations of practitioners.
In 1954, following the end of the colonial rule, strict drug policies were introduced which resulted in a
drop in opium consumption [1]. Yet efforts to eradicate localized opium production in North Vietnam
remained unsuccessful until the 1990s.
A reversal of colonial era policies regarding traditional medicine was declared in president Ho Chi Minh’s
1955 speech which endorsed China’s chairman Mao’s policy of integrating traditional medicine and
biomedicine [2]. The approach of including traditional practitioners in the official healthcare system and
then devising quality control as well as continuous education systems for them aimed at efficient utiliza-
tion of existing human and pharmacological resources. The objective was to enable local and individual
self-sufficiency in healthcare instead of building dependencies on expensive synthetic pharmaceuticals,
out-of-reach treatment facilities and the few biomedicine experts available.
In 1965, the health minister clarified that the prejudice of practitioners of biomedicine against ethnophar-
macology “derives from an erroneous conception of science and a profound ignorance of results obtained
by traditional medicine” [2]. He added that due to the extreme variety of compounds available in medici-
nal plants, random experimentation with them is infeasible and knowledge must be derived from existing
practices. He also noted that unless collected and preserved, the knowledge would disappear in one
generation.
A massive project of collecting, organizing, selecting, analyzing and regulating herbal medicines and
treatment practices was initiated in 1957 [2]. In the following decades a Vietnamese ethnopharmacology
industry was established. The industry adopted relatively strict organizational and regulatory practices
similar to those applied in biomedicine.
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Early development of Heantos
The development of Heantos was initiated in the 1980s by a traditional Vietnamese herbalist Tran Khuong
Dan. Dan’s father and brother were traditional herbalists who were both addicted to opium. His brother
eventually died as a result of the addiction, leaving Dan wondering why his brother had been unable to
heal himself [3]. Dan initiated a search for traditional cures traveling to rural areas and interviewing
opium producers who were known to have developed their own methods for dealing with withdrawal
following the harvest season. He persuaded the opium producers to reveal their secret recipes, in the
end collecting 115 different formulas for managing withdrawal symptoms during periods of no harvest.
However, he was disappointed to find that most formulas contained small amounts of opium while others
were not sufficiently effective [2].
As Dan had been taught principles of traditional medicine by his father, he formulated a theory of the
mechanism of addiction and proceeded to search for herbal components to match the requirements of his
theory [2]. In the tradition of self-experimentation, he deliberately made himself addicted to opium and
tested various mixtures until he found one that successfully assisted in recovery [3,4,5]. After that he
addicted himself to heroin and successfully retested his cure. This self-funded process was said to have
taken 10 years and cost 100,000 US dollars [6].
In September 1990, Dan presented local health authorities his water extract syrup of thirteen components
[2]. A few months later the information had reached the prime minister and the Ministry of Health
granted a license to proceed with trials. Initially named TKD, the name of the product was changed to
Heantos, meaning “the heat of the sun” [7].
According to a report from a Vietnamese rehabilitation institute for war veterans, the institute’s attempts
to detoxify seriously injured and severely opioid-addicted war veterans of the US–Vietnam war of 1955-
1975 had so far been unsuccessful, and as a result the veterans had been eligible to sustaining doses
of morphine at no cost (internal report: Institute of Orthopaedics Science, 1996). Between 1991 and
1995, 110 addicts were enrolled in an initial trial with the original liquid-form Heantos. They had been
addicted for 5-20 years and were primarily using the free morphine but some were supplementing it with
other opiates. 70% were paralyzed and in wheelchairs.
The one-week inpatient treatment consisted of a 72-hour detoxification period followed by three to four
days to “restore the health condition of the detoxed addict” [2]. This initial trial resulted in 109 successful
cases and one unsuccessful case (internal report: Institute of Orthopaedics Science, 1996). After one
year 30% of the patients had needed a second treatment period; later, 5% had needed a third treatment
period. The wording of the report appears to suggest a 100% followup, likely because these veterans
were permanently hospitalized at the institute. Thus, according to the report, during the approximately
five year period the success rate had been 99.1%. A later report stated that until the end of 1998 none
of patients had relapsed (internal report: VAST Institute of Chemistry, 1998).
Between 1991-1995 about 4000 patients were treated in a number of treatment centers, proving successful
“in practically all cases” but “documentation did not comply with internationally recognized standards”
[2]. Due to a lack of resources, thorough follow-ups could not be organized. Heantos was not licensed for
outpatient use and could thus not be self-administered for relapse prevention. The overall relapse rate
was estimated to be about 20% [7]. The full cost of treatment was estimated to range from 70 to 300
US dollars per patient [7].
In 1995, Tran Khuong Dan begun cooperating with the Institute of Chemistry under the auspices of
the Vietnam Academy of Science and Technology (VAST) [2,8]. On December 22, 1995, the National
Centre for Natural Sciences and Technology of Hanoi requested assistance in the further development of
Heantos from the United Nations Development Program (UNDP) (internal report: UNDP, 1999). The
results of the initial 110-patient trial drew the interest of UNDP. The United Nations Office for Project
Services (UNOPS) was chosen to act as an executing agency for the project (internal report: UNDP,
1999).
The Johns Hopkins School of Medicine Chemical Dependence Unit engaged in discussions with Viet-
namese scientists, subsequently confirming that Heantos contained no addictive substances (despite an
earlier conjecture by UN International Drug Control Programme and other Western parties) [2]. These
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developments resulted in an initiation of concerted research efforts aimed at international adoption of
Heantos.
Initially, opiate addictions had mainly been a problem in rural highlands among ethnic minorities with
a tradition of opium poppy cultivation [1,9]. In other areas the issue had been confined to the socially
marginalized and unemployed, including the injured war veterans. By 1997, however, it had begun
spreading to cities. An investigation into reasons behind a sudden increase in traffic accidents found out
that more than half of the taxi drivers in one company used heroin. Primary school children and 15-25
year olds in well-off districts and even nine-year olds were found smoking heroin. 22 people, including
several from the police and the Interior Ministry, were sentenced for trafficking over 800 kg of heroin
between 1992 and 1995. The average official incomes of the sentenced were 100 US dollars a month while
the street price of heroin was around 50,000 US dollars a kilogram.
In 1997, one American multi-drug addict with a history of five-year daily intravenous heroin use was
successfully treated in Vietnam (internal report: UNDP, 1999). The patient mostly slept and denied
experiencing any withdrawal symptoms. In a one-month surveillance the patient was taking Heantos-3,
his physical health had improved and drug screens were negative.
In 1997 and 1998 six more patients from the United States, Europe and Africa were treated in Vietnam
(internal report: VAST Institute of Chemistry, 1998). After 3-12 months there had been no relapses.
In addition, 30 patients in China were treated with 14 patients not relapsing after 7 months (internal
report: VAST Institute of Chemistry, 1998). Six had relapsed after 4 months; for the rest there were
apparently no data.
Between 1995 and 1997 the original liquid form had been developed into capsules of three types: Heantos-
1 for “disinfection and withdrawal of cravings”, Heantos-2 for adjustment of sleep during the first 5 days of
treatment, and Heantos-3 for prevention of relapse, to be taken for 1-6 months after the initial treatment
period (internal report: VAST Institute of Chemistry, 1998). The length of the detoxification period
(the first phase of the one-week treatment period) had been shortened from 72 hours to 36 hours.
Animal testing was performed to determine toxicity. High doses (half of LD50) were initially observed
to cause convulsions but the issue was resolved by adjusting component ratios (internal report: VAST
Institute of Chemistry, 1998). According to a 1998 report by the Vietnamese Institute of Drug Quality
Control, Heantos versions 1-3 did not contain insecticides, addictive substances or toxic alkaloids (internal
report: UNDP, 1999). On mice, all versions of Heantos had a sedative effect. With Heantos 1, the lowest
lethal dose was 10 g/kg. With Heantos-2, the lowest lethal dose was 740 mg/kg and LD50 2650 mg/kg.
With Heantos-3, the lowest lethal dose was 5 g/kg. A one-month long controlled test on rabbits revealed
no differences between groups in any of the common serological parameters tested.
A trial with 200 patients was carried out to determine a standard dose to avoid the convulsion side-
effect (internal report: VAST Institute of Chemistry, 1998). Dosing for Heantos-1 for the whole 36-hour
detoxification period was 25 x 500 mg, dosing of Heantos-2 for the five-day post-detoxification period
was 5 x 250 mg, and dosing of Heantos-3 for the 3-month period after treatment was 100 x 250 mg. The
method was deemed “very effective and completely safe”.
A report by UNOPS stated that “these results and hundreds of clinical reports in Vietnam, indicating
the short-term effectiveness, are only considered so far as anecdotal evidence in the Western world, and
therefore, cannot substitute the scientific scrutiny, which is rigorously imposed by Western regulatory
systems to verify claims for new medications” (internal report: UNDP, 1999). The rationale for initiating
international scientific co-operation was to fulfill the regulatory requirements of the United States Food
and Drug Administration agency (FDA). A 1997 letter from Dr. Jasinski states that Vietnamese results
cannot be dismissed because the methods did not meet American standards, and that an international
research project was in the public interest (internal report: UNDP, 1999). Dr. Jasinski also stated that
the aim of the project was to test the efficacy of Heantos not only for opiate addiction but also for cocaine
addiction.
As Heantos is a herbal product with no toxic or intoxicating properties, fulfilling regulatory requirements
for new medicines would have been technically unnecessary, as the product could simply have been
introduced as an over-the-counter herbal product. Regardless, at the beginning of 1997 the UNOPS
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coordinator estimated the process to take 3-4 years, i.e. to conclude around 2000. The aim was to
establish a foundation for later research of similar herbal products in Western societies.
In 1998, a clinic associated with Tran Khuong Dan was accused of covering up the death of at least one
patient in his care [10]. UNDP and UN International Drug Control Programme (UNDCP) were said
to be in conflict, with UNDCP saying they “are hearing” that there “might have been as many as six
deaths”. In addition, UNDCP suspected that Heantos contain kratom (Mitragyna speciosa): “if that
is the case, then this isn’t a cure, it’s a substitute and it would be no better than the methadone we
give people now”. UNDCP also required proof that the treated addicts “are still off the drugs”. A later
2005 article mentioned a statement by Wahlberg that “rumors circulated that some patients had died
following adverse reactions but subsequent safety evaluations by the Vietnamese authorities have given
Heantos a clean bill of health” [4].
By 1998, three competing herbal opiate detoxification products with different constituents, Vinantidic-
TKC, HuFuSa and Cedemex, had been invented [11,12]. Despite co-operation between UNDP and the
government of Vietnam, by 1999 Heantos had still not been licensed for outpatient use (internal report:
VAST Institute of Chemistry, 1998). HuFuSa, produced by a pharmaceutical factory under the Ministry
of Defense was the only product licensed for sale as an over-the-counter medication and had effectively
a monopoly on the outpatient detoxification product market. The inventor of Cedemex accused officials
of discrimination to protect the monopoly of HuFuSa [11].
In early 1999 a Finnish medical doctor imported a small amount of HuFuSa to Finland and distributed
it to a seven buprenorphine addicts for six-day unsupervised outpatient detoxifications to be performed
at home [13]. The product was in capsule form. Patient experience was positive: HuFuSa was observed
to inhibit most of the physical cravings. Physically the patients described the effect as “the body being
heated up from the inside”. Side-effects included sleepiness, dry mouth, feeling hot, and disturbances
of near vision. According to retrospective self-reports, four of the seven patients initially reduced their
buprenorphine doses (6 mg on average) to zero, one patient from 6 mg to 0.2 mg, and one from 2.5 mg
to 1 mg. One patient failed due to misunderstanding the length of the detoxification period to be six
months instead of six days. The physician was, however, soon forced to stop treating opiate addicts and
the experiments and follow-up were halted. In the end, assumedly 2-3 patients withdrew permanently
from buprenorphine. All in all the results were considered good. With regard to later developments
concerning HuFusa, in 2002 the inventor of HuFuSa was accused of bypassing regulatory requirements,
failing to properly disclose the ingredients of the product, forging documents, and multiplying the price
of the product 27-fold in order to acquire personal financial gain [14]. Currently HuFuSa is no longer
used in Vietnam.
In 1999, five clinicians from the United States, Denmark, Sweden and Norway visited a Heantos clinic
in Hanoi for 10 days, observing a detoxification process of 9 Vietnamese and 5 international patients.
The group concluded that Heantos appeared superior to Western standard methods and it seemed to
suppress all withdrawal symptoms with few complaints from patients [2].
According to a testimonial of one European multi-drug addict with a history of drug use of approximately
15 years, Heantos treatment “took away all the physical pain from the first day. It also got me rid of all
the mental desire. I no longer want to take drugs. I did not do anything special for this to happen. [. . . ]
I do understand that after reading my words you must be thinking that I am still on drugs or completely
off my trolley” [15].
Years 2000–2020
The UN International Drug Control Programme persisted with a skeptical attitude expressed in their
2001 statement that “there is insufficient information available [.. . and that] there does not appear to be
any evidence that Heantos is more effective than any other products available for a similar ‘treatment’ ”
[2].
In February 2002 a patent 2569 on Heantos was granted to the VAST Institute of Chemistry [16]. Despite
that, a 2006 report by a group of international experts on herbal medicine in the treatment of substance
abuse mentions that following the initial phase, the government of Vietnam “appears to have lost interest”
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in Heantos [12]. The report also notes that the Vietnamese expert present at the meeting did not provide
further information.
On project organization, the report describes that “From the late 1990s, toxicity studies and clinical
trials have been agreed and started in the United States (Johns Hopkins University, National Institute
on Drug Abuse), in Germany (since 2001 in Essen) and Denmark and funded from various bilateral
and multilateral sources (e.g. UNDP and UNOPS, UNESCO; while WHO and the UN drug control
bodies did not join)” [12]. Studies were said to be ongoing in Germany and Denmark “as late as 2002”.
Concerning effects, the report mentions that Heantos-1 was “said to have a deliberately negative side
effect: should a patient slip back into drug use, he will suffer painful, convulsive fits”.
The report also states that “given that Heantos is such a complex mixture, satisfying the demands
of regulatory authorities has been a persistent problem, even a 2004 European Union (EU) directive,
designed to lower the hurdles for certain herbal remedies, doesn’t provide much assistance. Non-disclosure
of the constituents of the composition will remain an obstacle for the evaluation of the safety, efficacy
and usefulness of any composite herbal medicine” [12].
An important phytochemical study of Heantos by the Leibniz Institute of Plant Biochemistry in Germany
confirmed the initial Vietnamese results of non-toxicity, and identified 194 constituents from 12 plants
but could not determine which of these were the active ones or what the exact mechanism of action was
[17]. A report related to the study lists seven German and one Vietnamese external collaborators in
the project [7]. Apparently, a standardization protocol had been established, allowing a phase II clinical
study to be performed in 2003-2005 at the University of Essen, Germany [8]. The study was said to have
been “the first one applied to such a complex traditional Asian medicine” [7]. The VAST Institute of
Chemistry noted that the aim of the research was never isolation and synthesis of a single active agent
but, rather, optimization of efficacy and standardization of the product [2]. The result of this work was
the Heantos-4 capsule which combined the previous three separate capsules into one.
Up to 2005 funding was said to have primarily originated from UNDP and the Norwegian government,
with additional support from UNESCO [4]. Randomized controlled patient trials were initially going to
be carried out by Johns Hopkins School of Medicine but it failed to secure funding. In 2001 the regional
government of Nord-Rhein Westfalen agreed to fund a trial in Germany [2,4]. In 2005 a randomized
controlled trial with 60 patients was being planned in Essen, Germany [4]. The trial was, though,
apparently never carried out.
In 2006, Wahlberg stated that “since [the involvement of Johns Hopkins researchers in early 1995], the
ongoing quest to validate the efficacy of Heantos in the treatment of addiction has pretty much read like
concerted efforts to gradually notch up ‘levels of evidence’ as endorsed by the WHO, albeit not without
numerous complications and contestations” [2].
In keeping with the strategy of slowly accumulating further clinical data, by 2008, an estimated 9000
patients had been treated with Heantos in Vietnam [17]. Phase I, II and III clinical studies were carried
out in Vietnam and successfully finalized in 2011 [8,18]. The Vietnamese Drug Administration licensed
production and clinical use of Heantos-4 in 2012. It was said to be effective and cheap with no observed
side effects and also deemed suitable for outpatient use. Subsequently, it was adopted by most of the
Vietnamese addiction treatment centers. A follow-up study in one treatment center indicated a 5–10%
relapse rate three months after treatment [8]. A description of an uncontrolled phase III clinical study
on the manufacturer’s website indicates an approximately 90% success rate [18]. Up to the end of 2020,
clinical trials had still not been carried out outside Vietnam.
According to the manufacturer’s instructions the detoxification period was to be initiated at least 24
hours from the last use of drugs but not before the onset of withdrawal symptoms [19]. On the first
day, depending on body weight and severity of addiction, the dosage of Heantos-4 was 5-6 capsules (500
mg each) twice with 6-7 hours in between the doses. On the second and third days the dosage was 5-6
capsules after meals, four times a day. On days four to seven, the dosage was 5-6 capsules once in the
evening before sleep. If needed, the treatment could be prolonged for up to 10 days.
Due to lack of suitable analytic methods, polypharmacokinetics, i.e. determination of pharmacokinetics of
multicomponent herbal medicines such as Heantos, had been considered “beyond the scope of traditional
research” [20]. It is unclear why UNDP and the universities were determined to pursue this route
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regardless: due to ignorance of the lack of necessary analytical methods, unfounded optimism (assuming
the methods could be invented on the fly) or something else. A method based on metabolomics coupled
with multivariate statistical tools focusing on the comprehensive analysis of small molecules in biofluids
was proposed in 2013 [20].
A strong sedative effect had been observed with high doses. A 2016 study examined effects on burst-firing
of thalamic neurons due to the involvement of thalamus in non-REM sleep and control of arousal [21].
Heantos-4 was observed to inhibit some and potentiate some other types of neuronal calcium currents and
to exacerbate absence seizure activity in a strain of mice highly susceptible to such seizures. Accordingly,
caution may be warranted with seizure-prone individuals. It is unclear whether this feature is related to
the previously mentioned “deliberately negative side effect” of “painful, convulsive fits”.
The first preclinical study on the mechanism of action of Heantos-4 was undertaken at the University
of British Columbia (UBC), Vancouver, Canada, under the guidance of Anthony Phillips and Michael
Krausz [8]. Further studies are still ongoing [21,22,23]. In 2016, the first preclinical assessment of the
effects of Heantos-4 on opiate withdrawal and the rewarding properties of morphine was published [23].
The study suggested Heantos-4 acts as a dopaminergic stabilizer, counteracting both hyperdopaminergic
and hypodopaminergic states. No intrinsic reinforcing properties were observed which indicated low
potential addictive liability. The study also listed 12 constituent herbs and one binding agent of Heantos-
4 as well as the main phytochemical compounds isolated from it. Tetrahydroprotoberberines l-THP and
l-SPD were said to be of principal interest, given the evidence already linking them to models of addiction
[24].
In the 2010s there were attempts for international distribution of Heantos-4 as a dietary supplement but
these seem to have stalled due to either inadequate supply of the product from Vietnam or difficulties
in acquiring international import certificates [25]. A further attempt to distribute an alternative herbal
opiate detoxification product in the United States was blocked by the FDA due to unsubstantiated
advertising [26].
In 2020, almost three decades since the initial official Vietnamese results regarding the 110 war veterans
treated with liquid-form Heantos, an article about neural bases for attenuation of morphine withdrawal
by Heantos-4 capsules was published [22]. A persistent dysfunction of the mesolimbic dopamine system,
with the nucleus accumbens being a key but not the only affected region, had already been recognized as a
key pathological feature of chronic exposure to opioids. Due to this acquired dysfunction, discontinuation
of opioids results in a hypodopaminergic state.
Out of the 194 identified compounds in Heantos-4 the rat model study identified l-tetrahydropalmatine
(l-THP) as a key active ingredient of Heantos-4, with a central dopaminergic mechanism of action [22].
Heantos-4 and its constituent l-THP alone were observed to possess comparable potency in reversing
the hypodopaminergic state in the nucleus accumbens and observed somatic features of withdrawal after
their onset. A single treatment was notably effective and the effect was nearly immediate, observable
in a few minutes after administration. The precise quantity of l-THP for inducing side-effects remains
undetermined but the dosing used in the study was well-tolerated.
The authors noted that the use of combined botanical extracts may account for the clinical success of
Heantos-4 [22]. The component interactions may cause synergistic effects that further attenuate the
withdrawal symptoms. Dias et al. note that “the literature on herbal medicines contains many examples
of beneficial synergistic effects of the combination of different herbs when compared to an individual
active ingredient” [23].
L-tetrahydropalmatine has also been explored as a treatment option for cocaine-use disorders [22]. Anec-
dotal data indicates that Heantos has been used for detoxification from crack cocaine in Brazil [27].
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Composition of Heantos-4 and summary of the clinical trial
This section begins with a brief description of the plants included in Heantos-4 and reviews the existing
uncontrolled phase III trial.
Some properties of the constituent components of Heantos-4
A list of twelve plant-based constituent components and one binding agent has been provided in Dias et
al [23]. The list includes extracts of seven types of roots, a tuber, a rhizome, a branch, a fruit, and a seed.
An analysis on Heantos-4 product has been carried out in Vietnam, the results of which were published
in 2013 in four separate articles in the Vietnam Journal of Chemistry, volume 51. These analyses indicate
which compounds from the constituent plant materials have been extracted into the final product but
the articles were not available online. The following summaries briefly describe key properties of the
individual plant components.
1. Crude polysaccharides of Codonopsis javanica (Radix Campanumoeae ) displayed nerve growth
factor-like neurotrophic activity, have a protective effect on cerebral ischemia-reperfusion injury,
facilitate improvement of learning and memory function in mice, and may be a new type of im-
munomodulator [28].
2. Ophiopogon joponicus root (Radix Ophiopogonis japonici) has traditionally been used in Vietnam
for antitussive, expectorant and tonic purposes [29].
3. Astragalus membranaceus root (Radix Astragali membranacei) compounds have anti-oxidant, anti-
aging, cardioprotective, immune-enhancing, memory and learning enhancing, and hematopoietic
effects [30]. They can protect the mitochondria by scavenging reactive oxygen species, inhibiting
mitochondrial permeability transition, and increasing antioxidant enzyme activity to improve aging
in mice.
4. Licorice root (Radix Glycyrrhizae) contains glycyrrhizin which exhibited in vitro antiviral effi-
cacy against hepatitis A virus, human immunodeficiency virus type 1 and various other viruses,
reduced hepatocellular damage in chronic hepatitis B and C, reduced risk of hepatocellular carci-
noma in hepatitis C virus-induced cirrhosis [31]. Licorice root has also exhibited neuroprotective,
anti-cholinergic, anti-inflammatory, adaptogenic (anti-stress), estrogenic, pulmonoprotective, an-
tithrombotic, antiangiogenic, anti-tyrosinase, wound-healing, antitussive, renoprotective, antiosteo-
porotic, radioprotective, cytoprotective, choleretic, anticolvulsant, vasorelaxant and antiparasitic
activities.
5. Angelica sinensis root (Radix Angelicae sinensis) compounds have antioxidative, anti-inflammatory,
anti-aging, hematopoietic and neuroprotective effects [30,32]. In combination with Astragalus
membranaceus it has traditionally been used to treat diabetes mellitus and this combination has
been observed to ameliorate vascular endothelial cell dysfunction induced by excessive oxidative
stress [33].
6. Rehmannia glutinosa root (Radix Rehmanniae glutinosae) contains catalpol which has been ob-
served to elevate serotonin and brain-derived neurotrophic factor, protecting against depression and
neurodegeneration [34]. It has also demonstrated an increased mitochondrial biogenesis and acti-
vation of PI3K/Akt pathway for insulin sensitizing effect. In addition, catalpol exerted analgesic,
sedative, hepatoprotective, purgative, anti-inflammatory, antimicrobial, antitumor, and antiapop-
tosis actions.
7. Polygala tenuifolia root (Radix Polygalae) has been used for improving cognitive function and for
treatment of insomnia, forgetfulness, depression, cough and palpitation [35]. Its extracts possess
neuroprotective, cognitive-enhancing, antidepressant, hypnotic-sedative, anti-inflammatory, antivi-
ral, antitumor, antioxidant, antiaging, and antiarrhythmic effects.
8. Tuber of Stephania glabra (Tuber Stephaniae glabrae) has traditionally been used for treatment
of asthma, tuberculosis, dysentery, hyperglycemia, cancer, fever, intestinal complaints, sleep dis-
turbances and inflammation [36]. Its components have been shown to possess anti-anxiety, neu-
roprotective, anti-hypertensive, muscle-relaxant, antimicrobial, antihelminthic, anti-diabetic, anti-
allergic, anti-inflammatory and antitumor effects. It is a source of tetrahydropalmatine. It is
endangered in many areas; bioreactor cultivation techniques have been experimented with.
8
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9. Ginger rhizome (Rhizoma Zingiberis) exerts in vitro anti-inflammatory, anti-oxidative, antimicro-
bial and antiviral effects; in vivo, it exerted antipyretic, analgesic, antimicrobial and androgenic
effects [37]. Some ginger constituent chemicals were more potent than aspirin in a cyclooxygenase-
1 (COX-1) inhibitor assay and also potent inhibitors of cyclooxygenase-2 (COX-2). Ginger has
traditionally been used as a broad-spectrum antiemetic but definitive studies are lacking.
10. Cinnamon branch (Ramulus Cinnamomi) compounds exert anti-inflammatory, analgesic and neu-
roprotective effects, among others [38].
11. Chinese date fruit (Fructus Ziziphi jujubae) exerts hepatoprotective, antioxidant and anti-
inflammatory effects [39]. It is traditionally used prophylactically for liver diseases and for man-
agement of hepatitis. A clinical trial about alleviation of idiopathic chronic constipation indicated
some effect.
12. Seeds of a Ziziphus mauritiana tree (Semen Ziziphi mauritianae) contain cyclopeptide alkaloids in-
cluding sanjoinines [40]. Sanjoinines exert sedative activity, and Ziziphus species have traditionally
been used as a treatment for insomnia [41].
Donkey-hide gelatin (Colla Corii asini), gelatin obtained from the skin of the donkey (Equus asinus),
is utilized as a binding agent [23]. It exerts anti-anemia, anti-inflammatory, anti-tumor, anti-fatigue,
bone-repair and positive immunomodulatory activity in vivo [42]. Currently, its production appears
unsustainable [43].
In summary, in addition to the previously mentioned dopaminergic mechanism of action, Heantos-4 likely
exerts sedative, neuroprotective, anti-inflammatory and analgesic effects that are relevant for opiate
detoxification.
The Heantos-4 clinical trial of 2008-2009
An uncontrolled multi-center phase III clinical trial (n=255) with Heantos-4 was carried out in Hanoi,
Vietnam between November 2008 and December 2009. The results appear to have been published only
on the manufacturer’s website and not published in a peer-reviewed journal [18].
Patients had to fulfill ICD-10 criteria for opioid use disorder (F11.23). Exclusion criteria included lack
of withdrawal symptoms on admission, acute or chronic brain, liver, kidney or heart dysfunctions (e.g.
epilepsy), severe mental illness (e.g. schizophrenia), and human immunodeficiency virus infection.
The mean age was 33 years with 2.4% of patients being female. The level of education was relatively
low with 65.4% being unemployed. 4.3% had been addicted for less than a year, 42.7% for 1-5 years,
34.9% for 6-10 years, and 18.0% for more than 10 years. 92.5% used only heroin, 7.8% used heroin and
other opiates or opioids, and one person used heroin and metamphetamine. 31.7% smoked heroin, 49.4%
injected it, with the rest both smoking and injecting.
4.3% used drugs once a day, 25.1% twice a day, 43.5% three times a day, 18.8% four times a day, and 8.2%
at least five times a day. 0.8% were estimated to have a mild addiction, 25.1% a moderate addiction, and
74.1% a severe addiction. 14.1% had not attempted withdrawal before. 14.5% had attempted withdrawal
once, 22.4% twice, 12.2% three times, and 36.9% at least four times; it was not stated which methods had
been used in these attempts. In summary, the demographics indicated a representative patient sample.
Successful treatment was defined as following through the full treatment regime, a remission of withdrawal
symptoms, and a negative opioid screen result at the end of the period. Unsuccessful treatment was
defined as any of the following: the patient not following through the whole treatment regime, a need to
administer medicines other than Heantos-4, a non-remission of withdrawal symptoms, or a positive opioid
screen result at the end of the period. In addition, treatment results were divided into four categories
according to the time to remission (2-3 days, 4-5 days, 6-7 days, > 7 days), reduction in withdrawal
symptoms, and opioid screen test result.
The treatment period was seven days. Withdrawal symptoms were assessed with both self-reporting and
observation five times during the period, scoring each symptom on a three-grade scale. Adverse effects
were graded on a four-grade scale. The treatment regime applied doses of 3.5 g (seven Heantos-4 capsules)
except for three patients who received 3 g doses. On the first day, the first dose was administered at
least 24 hours after the last use of drugs but not until appearance of withdrawal symptoms, and a second
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dose after 6-8 hours later (however, approximately a quarter of patients received only one dose on the
first day). On the second and third days one dose was administered after a meal in the morning and in
the evening. From the fourth to the seventh day one dose was administered in the evening before sleep.
Urine test opioid screens were administered four times, electrocardiogram test twice, and psychological
assessment twice during the period. Standard serological and urine tests were performed twice, before
and after the treatment period.
Of the 255 patients, 230 were classified as successful (90.2%) and 25 unsuccessful (9.8%), respectively.
19 of the 25 underwent full treatment; also they were considered “a moderate success” due to leaving
the hospital with a negative opioid screen and a remission of withdrawal symptoms. Six of the 25 (2.4%
of patients, 24% of unsuccessful) discontinued the treatment period early, two of which (0.8%) were
opioid screen positive when leaving the treatment early due to family emergencies (one death and one
hospitalization of a family member). The rest (n=253) were opioid screen negative. One patient left on
day four for a wedding and another on day five for a job interview. An additional two patients left on
day five, believing they had already succeeded.
The successful and unsuccessful cases differed with respect to the severity of addiction, with only the
severely addicted classified as unsuccessful (25/164, 15.2% probability). The successful cases experienced
only mild withdrawal symptoms whereas the unsuccessful cases experienced moderate symptoms. The
successful cases also required a shorter time to remission of withdrawal symptoms.
In an earlier phase II study, treatment results were assessed as very good in 22.6%, good in 67.7%, fair
in 9.7% and poor in 0% of cases. In this phase III study, the results were assessed as very good in 31.7%,
good in 57.8%, fair in 10.4%, and poor in 0% of cases, respectively.
There appears to have been two overlapping criteria for defining success. On the four-grade scale, no
patients obtained a “poor” result. In addition, all 251 patients who underwent the full treatment period
were opioid screen negative and in remission of withdrawal symptoms. It appears that 25 cases were
classified unsuccessful solely due to administration of diazepam on the second and third days due to
severity of withdrawal symptoms. However, it was concluded that the use of diazepam had enabled
retention in the treatment for 19 patients in the “unsuccessful” group, and the combination of Heantos-
4 and diazepam was said to be “a remarkable success”. The dosing was said to be significantly lower
than standard dosing used in an official national detoxification regime (dosing information was given as
number of pills instead of milligrams).
Interpreted in less strict ways, the trial results could thus be stated as 99.2% success (remission of
withdrawal symptoms and opiate screen negative, n=253), or 97.6% success (remission of withdrawal
symptoms, opiate screen negative, and no interruption of the planned treatment regime, n=249).
The Beck depression inventory (BDI) and Zung Self-Rating Anxiety Scale (SAS) were used to assess
psychological status before and after treatment. Changes in BDI scores before and after treatment were
statistically significant: the percentage of patients with no depression changed from 3.5% to 27.0%, mild
depression from 22.6% to 42.6%, moderate depression from 47.8% to 21.7%, and severe depression from
26.1% to 8.7%. Similarly, changes in SAS scores were statistically significant: the percentage of patients
with no anxiety changed from 23.5% to 67.8%.
No adverse effects or fatalities were observed during the trial. On average patients gained some weight.
There were no notable changes in somatic markers. There was no mention of a follow-up after leaving
the hospital.
Discussion
Comparing the reported success rates of the initial 110-patient and the later 255-patient uncontrolled
trials to typical results of opioid detoxification treatments, it may seem feasible to assume the results
too good to be true. There may also be non-replicable cultural factors contributing to a high success
rate. Regardless, the results could also be seen as an indication of a possible huge opportunity for
improvement. Also the anecdotal Finnish experience with a similar product, HuFuSa, indicated a high
success rate (57%) during initial detoxification self-administered unsupervised at home, a rate much
10
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better than what had been achieved with any other methods in that patient group. A method for relapse
prevention was not available at the time; Heantos-4 is designed to also provide that.
The process of standardization and licensing lasted approximately 15 years in Vietnam, and licensing and
adoption is still uninitiated in other countries. During this time, opioid abuse has famously exploded in
the United States [44]. Assuming that the efficacy of Heantos would be even a fraction of what has been
indicated we may ask: has it been a rational decision to distrust the initial Vietnamese research results
and delay the adoption of Heantos for more than two decades? Are Western societies really able to
afford inefficiencies of this magnitude? Why couldn’t standardization proceed in parallel with emergency
authorized clinical use, as it did in Vietnam?
The case of Heantos could be seen an example of the adverse effects of overregulation. Good intentions
may have led to the opposite result: an effective, affordable and safe treatment may have been ignored
because an incompatible regulatory system was forced onto it. The feasibility of regulatory requirements
to ensure pharmacologically safe treatments could have been compared with the realities of addicts’ lives
in deciding which is the more relevant threat: not knowing the mechanism of action of a substance with
which thousands of patients had already been successfully treated, or the continuing abuse of contami-
nated, completely unregulated substances. Another consideration is whether, given such a situation, the
risk of affordable experimental treatment possibly being ineffective is at all relevant, or whether almost
anything would be worth a try. Also the well-known societal repercussions including crime as well as
judiciary and health care costs should be taken into consideration.
It remains unclear as to whether it would still be best to simply introduce Heantos-4 worldwide as a
dietary supplement. This would ensure just-in-time availability during the often very short time windows
when an addict is both in a hopeful enough mood to initiate a detoxification process as well as free from
external demands to continue drug abuse (e.g. drug debts requiring one to keep selling opioids and
remain in the subculture).
However, production may either already have lagged behind demand or there have been organizational
issues with respect to obtaining international import certificates. Ensuring production and distribution
thus remains an unresolved issue. Assumedly, with effort, most of the herbs can be sustainably cultivated
for the purpose. Alternatively, developing similar products may also be an option.
Conclusions
Currently, finding effective means for solving the opioid epidemic seems more important than ever.
Based on available knowledge, Heantos-4 appears a feasible option for detoxification. It seems highly
recommendable to prioritize international clinical trials for it.
A preliminary comparison of l-THP alone versus Heantos suggested that l-THP alone was associated
with more adverse effects than Heantos. Multicomponent herbals are occasionally known to possess
better tolerability and therapeutic efficacy than isolated agents.
As l-tetrahydropalmatine has also been explored as a treatment option for cocaine-use disorders, in ad-
dition to the planned opioid trials, trials could also be initiated on Heantos-4 treatment of addiction
to stimulants such as cocaine (as intended already in 1997), crack cocaine, amphetamine and metham-
phetamine.
Acknowledgments: the author wishes to thank professor Anthony G. Phillips and professor Tran Van
Sung for comments, professor Ayo Wahlberg for support in the early phases of this research, and Simon
Barber for a grammar check.
Funding: None.
Conflict of Interest: None.
Ethical Approval: Not applicable.
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